The effects of phototherapy and melanocytes on keratinocytes

PubMed Central

Tang, Luyan; Wu, Wenyu; Fu, Wenwen; Hu, Yao

2018-01-01

Phototherapy is widely used in the treatment of vitiligo. Previous studies have focused on the effects of ultraviolet (UV) radiation on melanocytes; however, the biological effects of phototherapy and melanocytes on keratinocytes remain to be elucidated. To investigate and assess the effects of clinically doses of broad band (BB)-UVA, narrow band (NB)-UVB and melanocytes on human keratinocytes in vitro, clinical doses of BB-UVA or NB-UVB radiation and human melanoma cell A375 co-culture were performed as stress divisors to HaCaT cells. Cell proliferation, expression of protease-activated receptor-2 (PAR-2) and nuclear factor E2-related factor 2 mRNA, lipid peroxidation and intracellular antioxidant level of keratinocytes were analyzed. It was demonstrated that UV radiation inhibited the proliferation of cells apart from following exposure to low dose (1 J/cm2) UVA. Medium dose (5 J/cm2) UVA radiation had no adverse effects on lipid peroxidation and increased antioxidant levels in HaCaT cells. Medium (200 mJ/cm2) and high (400 mJ/cm2) doses of UVB radiation induced cellular damage due to increased lipid peroxidation as indicated by levels of malondialdehyde. Furthermore, A375 co-culture treatment induced a similar effect on the lipid peroxidation of HaCaT as with low dose UVB radiation. Therefore, the results of the present study determined that clinical doses of BB-UVA and NB-UVB radiation had varying effects on proliferation and related protein levels in HaCaT cells. Co-culture with A375 had similar effects as those of low dose UVA and UVB radiation, in which the PAR-2 expression was significantly upregulated. PMID:29545869

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

PubMed

Fakih, Marwan G; Fetterly, Gerald; Egorin, Merrill J; Muindi, Josephia R; Espinoza-Delgado, Igor; Zwiebel, James A; Litwin, Alan; Holleran, Julianne L; Wang, Kangsheng; Diasio, Robert B

2010-07-15

We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2). Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. Copyrighth 2010 AACR.

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Two Schedules of Vorinostat in Combination with 5-Fluorouracil and Leucovorin in Patients with Refractory Solid Tumors

PubMed Central

Fakih, Marwan G.; Fetterly, Gerald; Egorin, Merrill J.; Muindi, Josephia R.; Espinoza-Delgado, Igor; Zwiebel, James A.; Litwin, Alan; Holleran, Julianne L.; Wang, Kangsheng; Diasio, Robert B.

2010-01-01

Purpose We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat × 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks. Experimental Design Vorinostat doses were escalated in a standard 3 × 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m2 i.v. over 2 hours followed by FU 400 mg/m2 i.v. bolus and 2,400 mg/m2 over 46 hours (sLV5FU2). Results Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU. Conclusions The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily × 3 or 600 mg orally twice daily × 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination. PMID:20463088

Prediction of Vancomycin Dose for Recommended Trough Concentrations in Pediatric Patients With Cystic Fibrosis.

PubMed

Amin, Raid W; Guttmann, Rodney P; Harris, Quianna R; Thomas, Janesha W

2018-05-01

Vancomycin is a key antibiotic used in the treatment of multiple conditions including infections associated with cystic fibrosis and methicillin-resistant Staphylococcus aureus. The present study sought to develop a model based on empirical evidence of optimal vancomycin dose as judged by clinical observations that could accelerate the achievement of desired trough level in children with cystic fibrosis. Transformations of dose and trough were used to arrive at regression models with excellent fit for dose based on weight or age for a target trough. Results of this study indicate that the 2 proposed regression models are robust to changes in age or weight, suggesting that the daily dose on a per-kilogram basis is determined primarily by the desired trough level. The results show that to obtain a vancomycin trough level of 20 μg/mL, a dose of 80 mg/kg/day is needed. This analysis should improve the efficiency of vancomycin usage by reducing the number of titration steps, resulting in improved patient outcome and experience. © 2018, The American College of Clinical Pharmacology.

Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients.

PubMed

Kim, In-Wha; Moon, Yoo Jin; Ji, Eunhee; Kim, Kyung Im; Han, Nayoung; Kim, Sung Ju; Shin, Wan Gyoon; Ha, Jongwon; Yoon, Jeong-Hyun; Lee, Hye Suk; Oh, Jung Mi

2012-05-01

The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year after kidney transplantation. One hundred and thirty-two Korean kidney recipients who received tacrolimus were genotyped for ABCB1 (exons 12, 21, and 26) and CYP3A5 (intron 3). Tacrolimus trough levels, dose, or dose-adjusted trough levels and complications were compared among patients during the early stage (3, 7, 14, 30, and 90 days) and up to 1 year according to the genotypes. A donor source-adjusted linear mixed model with multilevel analysis adjusting for age, body weight, hematocrit, and serum creatinine showed that CYP3A5 genotype is associated with dose-adjusted level of tacrolimus (p < 0.001). The influence of ABCB1 polymorphisms on the pharmacokinetics or complications of tacrolimus was less certain in our study. The incidence of acute rejections was significantly higher in recipients of cadaveric donor kidney (p < 0.05). A generalized estimating equation model analysis showed that alopecia and hyperlipidemia were associated with dose-adjusted level of tacrolimus (p < 0.001). Genotype of CYP3A5 variants along with significant clinical covariates may be useful in individualizing tacrolimus therapy in kidney transplantation patients.

Statistical model based iterative reconstruction (MBIR) in clinical CT systems. Part II. Experimental assessment of spatial resolution performance.

PubMed

Li, Ke; Garrett, John; Ge, Yongshuai; Chen, Guang-Hong

2014-07-01

Statistical model based iterative reconstruction (MBIR) methods have been introduced to clinical CT systems and are being used in some clinical diagnostic applications. The purpose of this paper is to experimentally assess the unique spatial resolution characteristics of this nonlinear reconstruction method and identify its potential impact on the detectabilities and the associated radiation dose levels for specific imaging tasks. The thoracic section of a pediatric phantom was repeatedly scanned 50 or 100 times using a 64-slice clinical CT scanner at four different dose levels [CTDIvol =4, 8, 12, 16 (mGy)]. Both filtered backprojection (FBP) and MBIR (Veo(®), GE Healthcare, Waukesha, WI) were used for image reconstruction and results were compared with one another. Eight test objects in the phantom with contrast levels ranging from 13 to 1710 HU were used to assess spatial resolution. The axial spatial resolution was quantified with the point spread function (PSF), while the z resolution was quantified with the slice sensitivity profile. Both were measured locally on the test objects and in the image domain. The dependence of spatial resolution on contrast and dose levels was studied. The study also features a systematic investigation of the potential trade-off between spatial resolution and locally defined noise and their joint impact on the overall image quality, which was quantified by the image domain-based channelized Hotelling observer (CHO) detectability index d'. (1) The axial spatial resolution of MBIR depends on both radiation dose level and image contrast level, whereas it is supposedly independent of these two factors in FBP. The axial spatial resolution of MBIR always improved with an increasing radiation dose level and/or contrast level. (2) The axial spatial resolution of MBIR became equivalent to that of FBP at some transitional contrast level, above which MBIR demonstrated superior spatial resolution than FBP (and vice versa); the value of this transitional contrast highly depended on the dose level. (3) The PSFs of MBIR could be approximated as Gaussian functions with reasonably good accuracy. (4) Thez resolution of MBIR showed similar contrast and dose dependence. (5) Noise standard deviation assessed on the edges of objects demonstrated a trade-off with spatial resolution in MBIR. (5) When both spatial resolution and image noise were considered using the CHO analysis, MBIR led to significant improvement in the overall CT image quality for both high and low contrast detection tasks at both standard and low dose levels. Due to the intrinsic nonlinearity of the MBIR method, many well-known CT spatial resolution and noise properties have been modified. In particular, dose dependence and contrast dependence have been introduced to the spatial resolution of CT images by MBIR. The method has also introduced some novel noise-resolution trade-off not seen in traditional CT images. While the benefits of MBIR regarding the overall image quality, as demonstrated in this work, are significant, the optimal use of this method in clinical practice demands a thorough understanding of its unique physical characteristics.

Comparison of potential risks of lactic acidosis induction by biguanides in rats.

PubMed

Bando, Kiyoko; Ochiai, Shoko; Kunimatsu, Takeshi; Deguchi, Jiro; Kimura, Juki; Funabashi, Hitoshi; Seki, Takaki

2010-10-01

Lactic acidosis has been considered to be a side effect of some biguanides, after phenformin was withdrawn from the market because of its association with lactic acidosis. The potential of lactic acidosis induced by biguanides at human therapeutic exposure levels, however, has not been examined. Then, we compared the risk of lactic acid at doses providing exposure levels comparable to human therapeutic doses. Metformin and phenformin were orally administered to rats for up to 28 days, and plasma drug concentrations and blood lactic acid levels were examined. Metformin did not elevate lactic acid levels at the dose corresponding to higher systemic drug exposure than human therapeutic level, even for repeated doses. In contrast, phenformin elevated lactic acid levels at the dose corresponding to lower exposure than human therapeutic level, and sustained high levels were observed up to 24h post-dose; furthermore, these changes were enhanced by repeated doses. Direct comparison at each rat equivalent dose clearly indicated that lactic acid levels of phenformin were higher than those of metformin. These non-clinical findings suggest that metformin dose not increase lactic acid levels like phenformin does, and therefore may not increase the risk for lactic acidosis at human therapeutic exposure level. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Bayesian Dose-Response Modeling in Sparse Data

NASA Astrophysics Data System (ADS)

Kim, Steven B.

This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a wrong parametric assumption. In this regard, we consider a robust experimental design which does not require any parametric assumption.

Center of cancer systems biology second annual workshop--tumor metronomics: timing and dose level dynamics.

PubMed

Hahnfeldt, Philip; Hlatky, Lynn; Klement, Giannoula Lakka

2013-05-15

Metronomic chemotherapy, the delivery of doses in a low, regular manner so as to avoid toxic side effects, was introduced over 12 years ago in the face of substantial clinical and preclinical evidence supporting its tumor-suppressive capability. It constituted a marked departure from the classic maximum-tolerated dose (MTD) strategy, which, given its goal of rapid eradication, uses dosing sufficiently intense to require rest periods between cycles to limit toxicity. Even so, upfront tumor eradication is frequently not achieved with MTD, whereupon a de facto goal of longer-term tumor control is often pursued. As metronomic dosing has shown tumor control capability, even for cancers that have become resistant to the same drug delivered under MTD, the question arises whether it may be a preferable alternative dosing approach from the outset. To date, however, our knowledge of the coupled dynamics underlying metronomic dosing is neither sufficiently well developed nor widely enough disseminated to establish its actual potential. Meeting organizers thus felt the time was right, armed with new quantitative approaches, to call a workshop on "Tumor Metronomics: Timing and Dose Level Dynamics" to explore prospects for gaining a deeper, systems-level appreciation of the metronomics concept. The workshop proved to be a forum in which experts from the clinical, biologic, mathematical, and computational realms could work together to clarify the principles and underpinnings of metronomics. Among other things, the need for significant shifts in thinking regarding endpoints to be used as clinical standards of therapeutic progress was recognized. ©2013 AACR.

Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

PubMed Central

Larsen, R A; Bauer, M; Weiner, J M; Diamond, D M; Leal, M E; Ding, J C; Rinaldi, M G; Graybill, J R

1996-01-01

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily). PMID:8878602

Reformulation of a clinical-dose system for carbon-ion radiotherapy treatment planning at the National Institute of Radiological Sciences, Japan

NASA Astrophysics Data System (ADS)

Inaniwa, Taku; Kanematsu, Nobuyuki; Matsufuji, Naruhiro; Kanai, Tatsuaki; Shirai, Toshiyuki; Noda, Koji; Tsuji, Hiroshi; Kamada, Tadashi; Tsujii, Hirohiko

2015-04-01

At the National Institute of Radiological Sciences (NIRS), more than 8,000 patients have been treated for various tumors with carbon-ion (C-ion) radiotherapy in the past 20 years based on a radiobiologically defined clinical-dose system. Through clinical experience, including extensive dose escalation studies, optimum dose-fractionation protocols have been established for respective tumors, which may be considered as the standards in C-ion radiotherapy. Although the therapeutic appropriateness of the clinical-dose system has been widely demonstrated by clinical results, the system incorporates several oversimplifications such as dose-independent relative biological effectiveness (RBE), empirical nuclear fragmentation model, and use of dose-averaged linear energy transfer to represent the spectrum of particles. We took the opportunity to update the clinical-dose system at the time we started clinical treatment with pencil beam scanning, a new beam delivery method, in 2011. The requirements for the updated system were to correct the oversimplifications made in the original system, while harmonizing with the original system to maintain the established dose-fractionation protocols. In the updated system, the radiation quality of the therapeutic C-ion beam was derived with Monte Carlo simulations, and its biological effectiveness was predicted with a theoretical model. We selected the most used C-ion beam with αr = 0.764 Gy-1 and β = 0.0615 Gy-2 as reference radiation for RBE. The C-equivalent biological dose distribution is designed to allow the prescribed survival of tumor cells of the human salivary gland (HSG) in entire spread-out Bragg peak (SOBP) region, with consideration to the dose dependence of the RBE. This C-equivalent biological dose distribution is scaled to a clinical dose distribution to harmonize with our clinical experiences with C-ion radiotherapy. Treatment plans were made with the original and the updated clinical-dose systems, and both physical and clinical dose distributions were compared with regard to the prescribed dose level, beam energy, and SOBP width. Both systems provided uniform clinical dose distributions within the targets consistent with the prescriptions. The mean physical doses delivered to targets by the updated system agreed with the doses by the original system within ±1.5% for all tested conditions. The updated system reflects the physical and biological characteristics of the therapeutic C-ion beam more accurately than the original system, while at the same time allowing the continued use of the dose-fractionation protocols established with the original system at NIRS.

Automatic Exposure Control Systems Designed to Maintain Constant Image Noise: Effects on Computed Tomography Dose and Noise Relative to Clinically Accepted Technique Charts

PubMed Central

Favazza, Christopher P.; Yu, Lifeng; Leng, Shuai; Kofler, James M.; McCollough, Cynthia H.

2015-01-01

Objective To compare computed tomography dose and noise arising from use of an automatic exposure control (AEC) system designed to maintain constant image noise as patient size varies with clinically accepted technique charts and AEC systems designed to vary image noise. Materials and Methods A model was developed to describe tube current modulation as a function of patient thickness. Relative dose and noise values were calculated as patient width varied for AEC settings designed to yield constant or variable noise levels and were compared to empirically derived values used by our clinical practice. Phantom experiments were performed in which tube current was measured as a function of thickness using a constant-noise-based AEC system and the results were compared with clinical technique charts. Results For 12-, 20-, 28-, 44-, and 50-cm patient widths, the requirement of constant noise across patient size yielded relative doses of 5%, 14%, 38%, 260%, and 549% and relative noises of 435%, 267%, 163%, 61%, and 42%, respectively, as compared with our clinically used technique chart settings at each respective width. Experimental measurements showed that a constant noise–based AEC system yielded 175% relative noise for a 30-cm phantom and 206% relative dose for a 40-cm phantom compared with our clinical technique chart. Conclusions Automatic exposure control systems that prescribe constant noise as patient size varies can yield excessive noise in small patients and excessive dose in obese patients compared with clinically accepted technique charts. Use of noise-level technique charts and tube current limits can mitigate these effects. PMID:25938214

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

Impact of High-Dose Vitamin D3 Supplementation in Patients with Crohn's Disease in Remission: A Pilot Randomized Double-Blind Controlled Study.

PubMed

Narula, Neeraj; Cooray, Mohan; Anglin, Rebecca; Muqtadir, Zack; Narula, Alisha; Marshall, John K

2017-02-01

To assess the tolerability and efficacy of high-dose vitamin D3 in patients with Crohn's disease (CD). This was a randomized, double-blind placebo-controlled trial of high-dose vitamin D3 at 10,000 IU daily (n = 18) compared to 1000 IU daily (n = 16) for 12 months in patients with CD in remission. The primary outcome was change in serum 25-hydroxy-vitamin D levels. Secondary outcomes included clinical relapse rates and changes in mood scores. High-dose vitamin D3 at 10,000 IU daily significantly improved 25-hydroxy-vitamin D levels from a mean of 73.5 nmol/L [standard deviation (SD) 11.7 nmol/L] to 160.8 nmol/L (SD 43.2 nmol/L) (p = 0.02). On an intention-to-treat basis, the rate of relapse was not significantly different between patients receiving low- and high-dose vitamin D3 (68.8 vs 33.3%, p = 0.0844). In per-protocol analysis, clinical relapse of Crohn's disease was less frequently observed in patients receiving a high dose (0/12 or 0%) compared to those receiving a low dose of 1000 IU daily (3/8 or 37.5%) (p = 0.049). Improvement in anxiety and depression scores and a good safety profile were observed in both groups treated with vitamin D3. Oral supplementation with high-dose vitamin D3 at 10,000 IU daily significantly improved serum 25-hydroxy-vitamin D levels. Rates of clinical relapse were similar between both groups. Larger studies using high-dose vitamin D3 for treatment of inflammatory bowel diseases are warranted. CLINICALTRIALS. NCT02615288.

Successful treatment of solitary toxic thyroid nodules with relatively low-dose iodine-131, with low prevalence of hypothyroidism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ross, D.S.; Ridgway, E.C.; Daniels, G.H.

1984-10-01

Forty-five patients with solitary toxic thyroid adenomas received 131I (mean dose, 10.3 mCi) for treatment of hyperthyroidism and were followed for 4.9 +/- 3.2 years (range, 0.5 to 13.5). Seventy-seven percent were euthyroid by 2 months, 91% by 6 months, and 93% by 1 year. Only 3 patients did not respond to a single dose of 131I, but all responded to multiple doses. Late recurrent hyperthyroidism occurred in 3 patients at 4.5, 6, and 10 years after treatment with a single dose of 131I. No patient developed clinical hypothyroidism, and none had a low serum thyroxine level associated with anmore » elevated serum thyrotrophin level. Three patients developed minimal elevations in serum thyrotrophin levels: 1, 4, and 7.5 years after 131I treatment, their thyrotrophin levels were 8.4, 6.2, and 9.6 microU/mL, respectively. All 3 had normal serum thyroxine levels and were clinically euthyroid. Mean serum thyroxine concentrations of all patients were unchanged between 1 and more than 9 years of follow-up. These data suggest that solitary toxic adenomas may be treated with relatively low doses of 131I (5 to 15 mCi), and that post-treatment hypothyroidism is very unusual.« less

Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies.

PubMed

Bays, Harold E; Ballantyne, Christie M; Doyle, Ralph T; Juliano, Rebecca A; Philip, Sephy

2016-09-01

Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved at a dose of 4g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500mg/dL) hypertriglyceridemia. This post-hoc exploratory analysis examined the relationship of icosapent ethyl dose with EPA concentrations in plasma and red blood cells (RBCs) across 3 clinical studies-a phase 1 pharmacokinetic study in healthy adult volunteers and 2 pivotal phase 3 studies (MARINE and ANCHOR) in adult patients with hypertriglyceridemia-and examined the relationship between EPA levels and TG-lowering effects in MARINE and ANCHOR. In all 3 studies, icosapent ethyl produced dose-dependent increases in the concentrations of EPA in plasma and RBCs. In both MARINE and ANCHOR, these dose-dependent EPA increases correlated with the degree of TG level lowering (all P<0.01). In patients with high TG levels (≥200mg/dL) and treated with icosapent ethyl 4g/day, the end-of-treatment plasma and RBC EPA concentrations were >170μg/mL and>70μg/mL, respectively. These studies support icosapent ethyl as producing predictable dose-dependent pharmacokinetics/pharmacodynamics, with TG level lowering dependent upon icosapent ethyl dose and EPA concentrations in plasma and RBCs. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Statistical model based iterative reconstruction (MBIR) in clinical CT systems: experimental assessment of noise performance.

PubMed

Li, Ke; Tang, Jie; Chen, Guang-Hong

2014-04-01

To reduce radiation dose in CT imaging, the statistical model based iterative reconstruction (MBIR) method has been introduced for clinical use. Based on the principle of MBIR and its nonlinear nature, the noise performance of MBIR is expected to be different from that of the well-understood filtered backprojection (FBP) reconstruction method. The purpose of this work is to experimentally assess the unique noise characteristics of MBIR using a state-of-the-art clinical CT system. Three physical phantoms, including a water cylinder and two pediatric head phantoms, were scanned in axial scanning mode using a 64-slice CT scanner (Discovery CT750 HD, GE Healthcare, Waukesha, WI) at seven different mAs levels (5, 12.5, 25, 50, 100, 200, 300). At each mAs level, each phantom was repeatedly scanned 50 times to generate an image ensemble for noise analysis. Both the FBP method with a standard kernel and the MBIR method (Veo(®), GE Healthcare, Waukesha, WI) were used for CT image reconstruction. Three-dimensional (3D) noise power spectrum (NPS), two-dimensional (2D) NPS, and zero-dimensional NPS (noise variance) were assessed both globally and locally. Noise magnitude, noise spatial correlation, noise spatial uniformity and their dose dependence were examined for the two reconstruction methods. (1) At each dose level and at each frequency, the magnitude of the NPS of MBIR was smaller than that of FBP. (2) While the shape of the NPS of FBP was dose-independent, the shape of the NPS of MBIR was strongly dose-dependent; lower dose lead to a "redder" NPS with a lower mean frequency value. (3) The noise standard deviation (σ) of MBIR and dose were found to be related through a power law of σ ∝ (dose)(-β) with the component β ≈ 0.25, which violated the classical σ ∝ (dose)(-0.5) power law in FBP. (4) With MBIR, noise reduction was most prominent for thin image slices. (5) MBIR lead to better noise spatial uniformity when compared with FBP. (6) A composite image generated from two MBIR images acquired at two different dose levels (D1 and D2) demonstrated lower noise than that of an image acquired at a dose level of D1+D2. The noise characteristics of the MBIR method are significantly different from those of the FBP method. The well known tradeoff relationship between CT image noise and radiation dose has been modified by MBIR to establish a more gradual dependence of noise on dose. Additionally, some other CT noise properties that had been well understood based on the linear system theory have also been altered by MBIR. Clinical CT scan protocols that had been optimized based on the classical CT noise properties need to be carefully re-evaluated for systems equipped with MBIR in order to maximize the method's potential clinical benefits in dose reduction and/or in CT image quality improvement. © 2014 American Association of Physicists in Medicine.

Statistical model based iterative reconstruction (MBIR) in clinical CT systems: Experimental assessment of noise performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ke; Tang, Jie; Chen, Guang-Hong, E-mail: gchen7@wisc.edu

Purpose: To reduce radiation dose in CT imaging, the statistical model based iterative reconstruction (MBIR) method has been introduced for clinical use. Based on the principle of MBIR and its nonlinear nature, the noise performance of MBIR is expected to be different from that of the well-understood filtered backprojection (FBP) reconstruction method. The purpose of this work is to experimentally assess the unique noise characteristics of MBIR using a state-of-the-art clinical CT system. Methods: Three physical phantoms, including a water cylinder and two pediatric head phantoms, were scanned in axial scanning mode using a 64-slice CT scanner (Discovery CT750 HD,more » GE Healthcare, Waukesha, WI) at seven different mAs levels (5, 12.5, 25, 50, 100, 200, 300). At each mAs level, each phantom was repeatedly scanned 50 times to generate an image ensemble for noise analysis. Both the FBP method with a standard kernel and the MBIR method (Veo{sup ®}, GE Healthcare, Waukesha, WI) were used for CT image reconstruction. Three-dimensional (3D) noise power spectrum (NPS), two-dimensional (2D) NPS, and zero-dimensional NPS (noise variance) were assessed both globally and locally. Noise magnitude, noise spatial correlation, noise spatial uniformity and their dose dependence were examined for the two reconstruction methods. Results: (1) At each dose level and at each frequency, the magnitude of the NPS of MBIR was smaller than that of FBP. (2) While the shape of the NPS of FBP was dose-independent, the shape of the NPS of MBIR was strongly dose-dependent; lower dose lead to a “redder” NPS with a lower mean frequency value. (3) The noise standard deviation (σ) of MBIR and dose were found to be related through a power law of σ ∝ (dose){sup −β} with the component β ≈ 0.25, which violated the classical σ ∝ (dose){sup −0.5} power law in FBP. (4) With MBIR, noise reduction was most prominent for thin image slices. (5) MBIR lead to better noise spatial uniformity when compared with FBP. (6) A composite image generated from two MBIR images acquired at two different dose levels (D1 and D2) demonstrated lower noise than that of an image acquired at a dose level of D1+D2. Conclusions: The noise characteristics of the MBIR method are significantly different from those of the FBP method. The well known tradeoff relationship between CT image noise and radiation dose has been modified by MBIR to establish a more gradual dependence of noise on dose. Additionally, some other CT noise properties that had been well understood based on the linear system theory have also been altered by MBIR. Clinical CT scan protocols that had been optimized based on the classical CT noise properties need to be carefully re-evaluated for systems equipped with MBIR in order to maximize the method's potential clinical benefits in dose reduction and/or in CT image quality improvement.« less

Correlation between the single, high dose of ingested baclofen and clinical symptoms.

PubMed

Anand, Jacek Sein; Zając, Maciej; Waldman, Wojciech; Wojtyła, Andrzej; Biliński, Przemysław; Jaworska-Łuczak, Barbara

2017-12-23

Baclofen is a drug used mainly to treat muscle spasticity. Its overdose can lead to life-threatening clinical symptoms, including acute respiratory failure requiring mechanical ventilation. The aim of this study was to assess the prevalence of selected clinical symptoms associated with baclofen poisoning comparing to an ingested dose. 60 cases of oral baclofen poisoning were analyzed. Gender, age distribution, and correlation between the dose of ingested baclofen were studied, as well as and following clinical parameters: degree of altered consciousness, heart rate, blood pressure, presence of acute respiratory failure, duration of mechanical ventilation, and presence of psychotic symptoms. The study found statistically significant correlations between dosage of ingested baclofen and presence of acute respiratory failure, as well as duration of mechanical ventilation. No statistically significant correlations were found between the dose of ingested baclofen and presence of hypertension, bradycardia, acute psychotic symptoms, or level of consciousness disturbance. However, it was found that patients who suffered from hypertension, bradycardia, and altered mental status ingested a larger dose of baclofen. There is a statistically significant correlation between the dose of ingested baclofen and the presence of acute respiratory failure, and duration of mechanical ventilation. Patients who have taken a single dose of baclofen of 200 mg, or higher, should be managed in centres able to provide continuous monitoring of life functions. Those with a higher level of a single dose of baclofen ingestion (>500 mg), should be hospitalized in a Toxicology Unit or Intensive Care Unit able to provide airway support and mechanical ventilation.

OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

PubMed

Garton, Andrew J; Crew, Andrew P A; Franklin, Maryland; Cooke, Andrew R; Wynne, Graham M; Castaldo, Linda; Kahler, Jennifer; Winski, Shannon L; Franks, April; Brown, Eric N; Bittner, Mark A; Keily, John F; Briner, Paul; Hidden, Chris; Srebernak, Mary C; Pirrit, Carrie; O'Connor, Matthew; Chan, Anna; Vulevic, Bojana; Henninger, Dwight; Hart, Karen; Sennello, Regina; Li, An-Hu; Zhang, Tao; Richardson, Frank; Emerson, David L; Castelhano, Arlindo L; Arnold, Lee D; Gibson, Neil W

2006-01-15

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

Haloperidol Treatment with Chronically Medicated Residents: Dose Effects on Clinical Behavior and Reinforcement Contingencies.

ERIC Educational Resources Information Center

Aman, Michael G.; And Others

1989-01-01

The study of effects of haloperidol drug therapy with 20 institutionalized mentally retarded persons found clinical changes confined to a slight reduction in stereotypic behavior and an increase in gross motor activity under the high dose condition. Subjects with high initial levels of stereotypy showed the best response to the drug. (Author/DB)

Update of a comparative analysis of cost minimization following the introduction of newly available intravenous iron therapies in hospital practice

PubMed Central

Bhandari, Sunil

2011-01-01

Background The clinical need to be able to administer high doses of intravenous iron conveniently as a rapid infusion has been addressed by the recent introduction of ferric carboxymaltose and subsequently iron isomaltoside 1000. Neither requires a test dose. The maximum dose of ferric carboxymaltose is 1000 mg. The maximum dose of iron isomaltoside 1000 is based on 20 mg/kg body weight without a specified ceiling dose, thereby increasing the scope of being able to achieve total iron repletion with a single infusion. This ability to give high doses of iron is important in the context of managing iron deficiency anemia, which is associated with a number of clinical conditions where demands for iron are high. It is also an important component of the strategy as an alternative to blood transfusion. Affordability is a key issue for health services. Recent price changes affecting iron sucrose and ferric carboxymaltose, plus modifications to the manufacturers’ prescribing information, have provoked this update. Methods This study is a comparative analysis of the costs of acquiring and administering the newly available intravenous iron formulations against standard treatments in the hospital setting. The costs include the medication, nursing costs, equipment, and patient transportation. Three dosage levels (600 mg, 1000 mg, and 1600 mg) are considered. Results and conclusion The traditional standard treatments, blood and iron sucrose, cost more than the alternative intravenous iron preparations across the dose spectrum and sensitivities. Low molecular weight iron dextran is the least expensive option at the 1600 mg dose level but has the caveat of a prolonged administration time and requirement for a test dose. At 600 mg and 1000 mg dose levels, both iron isomaltoside 1000 and ferric carboxymaltose are more economical than low molecular weight iron dextran. Iron isomaltoside 1000 is less expensive than ferric carboxymaltose at all dose levels. Newly available iron preparations appear to be clinically promising, cost effective, and practical alternatives to current standards of iron repletion. PMID:22241947

TH-A-9A-01: Active Optical Flow Model: Predicting Voxel-Level Dose Prediction in Spine SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, J; Wu, Q.J.; Yin, F

2014-06-15

Purpose: To predict voxel-level dose distribution and enable effective evaluation of cord dose sparing in spine SBRT. Methods: We present an active optical flow model (AOFM) to statistically describe cord dose variations and train a predictive model to represent correlations between AOFM and PTV contours. Thirty clinically accepted spine SBRT plans are evenly divided into training and testing datasets. The development of predictive model consists of 1) collecting a sequence of dose maps including PTV and OAR (spinal cord) as well as a set of associated PTV contours adjacent to OAR from the training dataset, 2) classifying data into fivemore » groups based on PTV's locations relative to OAR, two “Top”s, “Left”, “Right”, and “Bottom”, 3) randomly selecting a dose map as the reference in each group and applying rigid registration and optical flow deformation to match all other maps to the reference, 4) building AOFM by importing optical flow vectors and dose values into the principal component analysis (PCA), 5) applying another PCA to features of PTV and OAR contours to generate an active shape model (ASM), and 6) computing a linear regression model of correlations between AOFM and ASM.When predicting dose distribution of a new case in the testing dataset, the PTV is first assigned to a group based on its contour characteristics. Contour features are then transformed into ASM's principal coordinates of the selected group. Finally, voxel-level dose distribution is determined by mapping from the ASM space to the AOFM space using the predictive model. Results: The DVHs predicted by the AOFM-based model and those in clinical plans are comparable in training and testing datasets. At 2% volume the dose difference between predicted and clinical plans is 4.2±4.4% and 3.3±3.5% in the training and testing datasets, respectively. Conclusion: The AOFM is effective in predicting voxel-level dose distribution for spine SBRT. Partially supported by NIH/NCI under grant #R21CA161389 and a master research grant by Varian Medical System.« less

Task-based image quality evaluation of iterative reconstruction methods for low dose CT using computer simulations

NASA Astrophysics Data System (ADS)

Xu, Jingyan; Fuld, Matthew K.; Fung, George S. K.; Tsui, Benjamin M. W.

2015-04-01

Iterative reconstruction (IR) methods for x-ray CT is a promising approach to improve image quality or reduce radiation dose to patients. The goal of this work was to use task based image quality measures and the channelized Hotelling observer (CHO) to evaluate both analytic and IR methods for clinical x-ray CT applications. We performed realistic computer simulations at five radiation dose levels, from a clinical reference low dose D0 to 25% D0. A fixed size and contrast lesion was inserted at different locations into the liver of the XCAT phantom to simulate a weak signal. The simulated data were reconstructed on a commercial CT scanner (SOMATOM Definition Flash; Siemens, Forchheim, Germany) using the vendor-provided analytic (WFBP) and IR (SAFIRE) methods. The reconstructed images were analyzed by CHOs with both rotationally symmetric (RS) and rotationally oriented (RO) channels, and with different numbers of lesion locations (5, 10, and 20) in a signal known exactly (SKE), background known exactly but variable (BKEV) detection task. The area under the receiver operating characteristic curve (AUC) was used as a summary measure to compare the IR and analytic methods; the AUC was also used as the equal performance criterion to derive the potential dose reduction factor of IR. In general, there was a good agreement in the relative AUC values of different reconstruction methods using CHOs with RS and RO channels, although the CHO with RO channels achieved higher AUCs than RS channels. The improvement of IR over analytic methods depends on the dose level. The reference dose level D0 was based on a clinical low dose protocol, lower than the standard dose due to the use of IR methods. At 75% D0, the performance improvement was statistically significant (p < 0.05). The potential dose reduction factor also depended on the detection task. For the SKE/BKEV task involving 10 lesion locations, a dose reduction of at least 25% from D0 was achieved.

Effect of reduced agalsidase Beta dosage in fabry patients: the Australian experience.

PubMed

Ghali, Joanna; Nicholls, Kathy; Denaro, Charles; Sillence, David; Chapman, Ian; Goldblatt, Jack; Thomas, Mark; Fletcher, Janice

2012-01-01

In Australia, enzyme replacement therapy (ERT) for Fabry Disease (FD), both Agalsidase alfa (Replagal, Shire HGT) and beta (Fabrazyme, Genzyme), is funded and monitored through a specific government program. Agalsidase beta supply has been rationed by Genzyme since 2009 due to manufacturing issues. Consequently, the Australian Fabry Disease Advisory Committee has treated patients on Agalsidase beta at 50% of their usual dose from mid-2009, with a further reduction to 30% for some patients from late 2009. To determine the clinical effect of Agalsidase beta dose reduction in the Australian FD patient cohort. A questionnaire assessing FD symptoms was administered to 40 patients on long-term ERT. Clinical data from The Fabry Registry for patients receiving Agalsidase alfa or beta, for at least 2 years prior to the time of enforced Agalsidase beta dose reduction, were reviewed. Disease burden and quality of life (QOL) were graded using the Disease Severity Scoring System, Mainz Severity Score Index, Brief Pain Inventory and Short Form 36 Health Survey at 2 years before dose reduction, at the time of dose reduction and at the most recent clinical review following dose reduction. Disease severity and QOL scores did not change between the ERT groups. Males on Agalsidase beta reported lower energy levels after dose reduction, while no change was reported by females on either product or by males on a stable dose of Agalsidase alfa. This study suggests that energy levels in male patients worsen after dose reduction of Agalsidase beta.

Use of a channelized Hotelling observer to assess CT image quality and optimize dose reduction for iteratively reconstructed images.

PubMed

Favazza, Christopher P; Ferrero, Andrea; Yu, Lifeng; Leng, Shuai; McMillan, Kyle L; McCollough, Cynthia H

2017-07-01

The use of iterative reconstruction (IR) algorithms in CT generally decreases image noise and enables dose reduction. However, the amount of dose reduction possible using IR without sacrificing diagnostic performance is difficult to assess with conventional image quality metrics. Through this investigation, achievable dose reduction using a commercially available IR algorithm without loss of low contrast spatial resolution was determined with a channelized Hotelling observer (CHO) model and used to optimize a clinical abdomen/pelvis exam protocol. A phantom containing 21 low contrast disks-three different contrast levels and seven different diameters-was imaged at different dose levels. Images were created with filtered backprojection (FBP) and IR. The CHO was tasked with detecting the low contrast disks. CHO performance indicated dose could be reduced by 22% to 25% without compromising low contrast detectability (as compared to full-dose FBP images) whereas 50% or more dose reduction significantly reduced detection performance. Importantly, default settings for the scanner and protocol investigated reduced dose by upward of 75%. Subsequently, CHO-based protocol changes to the default protocol yielded images of higher quality and doses more consistent with values from a larger, dose-optimized scanner fleet. CHO assessment provided objective data to successfully optimize a clinical CT acquisition protocol.

Fully automated treatment planning for head and neck radiotherapy using a voxel-based dose prediction and dose mimicking method

NASA Astrophysics Data System (ADS)

McIntosh, Chris; Welch, Mattea; McNiven, Andrea; Jaffray, David A.; Purdie, Thomas G.

2017-08-01

Recent works in automated radiotherapy treatment planning have used machine learning based on historical treatment plans to infer the spatial dose distribution for a novel patient directly from the planning image. We present a probabilistic, atlas-based approach which predicts the dose for novel patients using a set of automatically selected most similar patients (atlases). The output is a spatial dose objective, which specifies the desired dose-per-voxel, and therefore replaces the need to specify and tune dose-volume objectives. Voxel-based dose mimicking optimization then converts the predicted dose distribution to a complete treatment plan with dose calculation using a collapsed cone convolution dose engine. In this study, we investigated automated planning for right-sided oropharaynx head and neck patients treated with IMRT and VMAT. We compare four versions of our dose prediction pipeline using a database of 54 training and 12 independent testing patients by evaluating 14 clinical dose evaluation criteria. Our preliminary results are promising and demonstrate that automated methods can generate comparable dose distributions to clinical. Overall, automated plans achieved an average of 0.6% higher dose for target coverage evaluation criteria, and 2.4% lower dose at the organs at risk criteria levels evaluated compared with clinical. There was no statistically significant difference detected in high-dose conformity between automated and clinical plans as measured by the conformation number. Automated plans achieved nine more unique criteria than clinical across the 12 patients tested and automated plans scored a significantly higher dose at the evaluation limit for two high-risk target coverage criteria and a significantly lower dose in one critical organ maximum dose. The novel dose prediction method with dose mimicking can generate complete treatment plans in 12-13 min without user interaction. It is a promising approach for fully automated treatment planning and can be readily applied to different treatment sites and modalities.

Fully automated treatment planning for head and neck radiotherapy using a voxel-based dose prediction and dose mimicking method.

PubMed

McIntosh, Chris; Welch, Mattea; McNiven, Andrea; Jaffray, David A; Purdie, Thomas G

2017-07-06

Recent works in automated radiotherapy treatment planning have used machine learning based on historical treatment plans to infer the spatial dose distribution for a novel patient directly from the planning image. We present a probabilistic, atlas-based approach which predicts the dose for novel patients using a set of automatically selected most similar patients (atlases). The output is a spatial dose objective, which specifies the desired dose-per-voxel, and therefore replaces the need to specify and tune dose-volume objectives. Voxel-based dose mimicking optimization then converts the predicted dose distribution to a complete treatment plan with dose calculation using a collapsed cone convolution dose engine. In this study, we investigated automated planning for right-sided oropharaynx head and neck patients treated with IMRT and VMAT. We compare four versions of our dose prediction pipeline using a database of 54 training and 12 independent testing patients by evaluating 14 clinical dose evaluation criteria. Our preliminary results are promising and demonstrate that automated methods can generate comparable dose distributions to clinical. Overall, automated plans achieved an average of 0.6% higher dose for target coverage evaluation criteria, and 2.4% lower dose at the organs at risk criteria levels evaluated compared with clinical. There was no statistically significant difference detected in high-dose conformity between automated and clinical plans as measured by the conformation number. Automated plans achieved nine more unique criteria than clinical across the 12 patients tested and automated plans scored a significantly higher dose at the evaluation limit for two high-risk target coverage criteria and a significantly lower dose in one critical organ maximum dose. The novel dose prediction method with dose mimicking can generate complete treatment plans in 12-13 min without user interaction. It is a promising approach for fully automated treatment planning and can be readily applied to different treatment sites and modalities.

A Phase I Study of Triapine® in Combination with Doxorubicin in Patients with Advanced Solid Tumors

PubMed Central

Schelman, William R.; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M.; Ivy, Percy; Wilding, George; Traynor, Anne M.

2011-01-01

Purpose To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine® administered in combination with doxorubicin. Study Design Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine® IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m2 and Triapine® 25 mg/m2. PK analysis was performed at various time-points before and after treatment. Results Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m2, Triapine® 45 mg/m2), 2 patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m2) with Triapine® 45 mg/m2. The 2 patients enrolled on this level had 2 DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine® were reduced to 45 mg/m2 and 25 mg/m2, respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Conclusions Pretreated patients with advanced malignancies can tolerate the combination of Triapine® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m2 on day 1 and Triapine® 25 mg/m2 on days 1-4 of a 21 day cycle. PMID:19082825

A phase I study of Triapine in combination with doxorubicin in patients with advanced solid tumors.

PubMed

Schelman, William R; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M; Ivy, Percy; Wilding, George; Traynor, Anne M

2009-05-01

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine administered in combination with doxorubicin. Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m(2) and Triapine 25 mg/m(2). PK analysis was performed at various time-points before and after treatment. Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m(2), Triapine 45 mg/m(2)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m(2)) with Triapine 45 mg/m(2). The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine were reduced to 45 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Pretreated patients with advanced malignancies can tolerate the combination of Triapine and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m(2) on day 1 and Triapine 25 mg/m(2) on days 1-4 of a 21-day cycle.

Evidence-based algorithm for heparin dosing before cardiopulmonary bypass. Part 1: Development of the algorithm.

PubMed

McKinney, Mark C; Riley, Jeffrey B

2007-12-01

The incidence of heparin resistance during adult cardiac surgery with cardiopulmonary bypass has been reported at 15%-20%. The consistent use of a clinical decision-making algorithm may increase the consistency of patient care and likely reduce the total required heparin dose and other problems associated with heparin dosing. After a directed survey of practicing perfusionists regarding treatment of heparin resistance and a literature search for high-level evidence regarding the diagnosis and treatment of heparin resistance, an evidence-based decision-making algorithm was constructed. The face validity of the algorithm decisive steps and logic was confirmed by a second survey of practicing perfusionists. The algorithm begins with review of the patient history to identify predictors for heparin resistance. The definition for heparin resistance contained in the algorithm is an activated clotting time < 450 seconds with > 450 IU/kg heparin loading dose. Based on the literature, the treatment for heparin resistance used in the algorithm is anti-thrombin III supplement. The algorithm seems to be valid and is supported by high-level evidence and clinician opinion. The next step is a human randomized clinical trial to test the clinical procedure guideline algorithm vs. current standard clinical practice.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ke; Chen, Guang-Hong, E-mail: gchen7@wisc.edu; Garrett, John

Purpose: Statistical model based iterative reconstruction (MBIR) methods have been introduced to clinical CT systems and are being used in some clinical diagnostic applications. The purpose of this paper is to experimentally assess the unique spatial resolution characteristics of this nonlinear reconstruction method and identify its potential impact on the detectabilities and the associated radiation dose levels for specific imaging tasks. Methods: The thoracic section of a pediatric phantom was repeatedly scanned 50 or 100 times using a 64-slice clinical CT scanner at four different dose levels [CTDI{sub vol} =4, 8, 12, 16 (mGy)]. Both filtered backprojection (FBP) and MBIRmore » (Veo{sup ®}, GE Healthcare, Waukesha, WI) were used for image reconstruction and results were compared with one another. Eight test objects in the phantom with contrast levels ranging from 13 to 1710 HU were used to assess spatial resolution. The axial spatial resolution was quantified with the point spread function (PSF), while the z resolution was quantified with the slice sensitivity profile. Both were measured locally on the test objects and in the image domain. The dependence of spatial resolution on contrast and dose levels was studied. The study also features a systematic investigation of the potential trade-off between spatial resolution and locally defined noise and their joint impact on the overall image quality, which was quantified by the image domain-based channelized Hotelling observer (CHO) detectability index d′. Results: (1) The axial spatial resolution of MBIR depends on both radiation dose level and image contrast level, whereas it is supposedly independent of these two factors in FBP. The axial spatial resolution of MBIR always improved with an increasing radiation dose level and/or contrast level. (2) The axial spatial resolution of MBIR became equivalent to that of FBP at some transitional contrast level, above which MBIR demonstrated superior spatial resolution than FBP (and vice versa); the value of this transitional contrast highly depended on the dose level. (3) The PSFs of MBIR could be approximated as Gaussian functions with reasonably good accuracy. (4) Thez resolution of MBIR showed similar contrast and dose dependence. (5) Noise standard deviation assessed on the edges of objects demonstrated a trade-off with spatial resolution in MBIR. (5) When both spatial resolution and image noise were considered using the CHO analysis, MBIR led to significant improvement in the overall CT image quality for both high and low contrast detection tasks at both standard and low dose levels. Conclusions: Due to the intrinsic nonlinearity of the MBIR method, many well-known CT spatial resolution and noise properties have been modified. In particular, dose dependence and contrast dependence have been introduced to the spatial resolution of CT images by MBIR. The method has also introduced some novel noise-resolution trade-off not seen in traditional CT images. While the benefits of MBIR regarding the overall image quality, as demonstrated in this work, are significant, the optimal use of this method in clinical practice demands a thorough understanding of its unique physical characteristics.« less

A photon recycling approach to the denoising of ultra-low dose X-ray sequences.

PubMed

Hariharan, Sai Gokul; Strobel, Norbert; Kaethner, Christian; Kowarschik, Markus; Demirci, Stefanie; Albarqouni, Shadi; Fahrig, Rebecca; Navab, Nassir

2018-06-01

Clinical procedures that make use of fluoroscopy may expose patients as well as the clinical staff (throughout their career) to non-negligible doses of radiation. The potential consequences of such exposures fall under two categories, namely stochastic (mostly cancer) and deterministic risks (skin injury). According to the "as low as reasonably achievable" principle, the radiation dose can be lowered only if the necessary image quality can be maintained. Our work improves upon the existing patch-based denoising algorithms by utilizing a more sophisticated noise model to exploit non-local self-similarity better and this in turn improves the performance of low-rank approximation. The novelty of the proposed approach lies in its properly designed and parameterized noise model and the elimination of initial estimates. This reduces the computational cost significantly. The algorithm has been evaluated on 500 clinical images (7 patients, 20 sequences, 3 clinical sites), taken at ultra-low dose levels, i.e. 50% of the standard low dose level, during electrophysiology procedures. An average improvement in the contrast-to-noise ratio (CNR) by a factor of around 3.5 has been found. This is associated with an image quality achieved at around 12 (square of 3.5) times the ultra-low dose level. Qualitative evaluation by X-ray image quality experts suggests that the method produces denoised images that comply with the required image quality criteria. The results are consistent with the number of patches used, and they demonstrate that it is possible to use motion estimation techniques and "recycle" photons from previous frames to improve the image quality of the current frame. Our results are comparable in terms of CNR to Video Block Matching 3D-a state-of-the-art denoising method. But qualitative analysis by experts confirms that the denoised ultra-low dose X-ray images obtained using our method are more realistic with respect to appearance.

A comprehensive study on the relationship between the image quality and imaging dose in low-dose cone beam CT

NASA Astrophysics Data System (ADS)

Yan, Hao; Cervino, Laura; Jia, Xun; Jiang, Steve B.

2012-04-01

While compressed sensing (CS)-based algorithms have been developed for the low-dose cone beam CT (CBCT) reconstruction, a clear understanding of the relationship between the image quality and imaging dose at low-dose levels is needed. In this paper, we qualitatively investigate this subject in a comprehensive manner with extensive experimental and simulation studies. The basic idea is to plot both the image quality and imaging dose together as functions of the number of projections and mAs per projection over the whole clinically relevant range. On this basis, a clear understanding of the tradeoff between the image quality and imaging dose can be achieved and optimal low-dose CBCT scan protocols can be developed to maximize the dose reduction while minimizing the image quality loss for various imaging tasks in image-guided radiation therapy (IGRT). Main findings of this work include (1) under the CS-based reconstruction framework, image quality has little degradation over a large range of dose variation. Image quality degradation becomes evident when the imaging dose (approximated with the x-ray tube load) is decreased below 100 total mAs. An imaging dose lower than 40 total mAs leads to a dramatic image degradation, and thus should be used cautiously. Optimal low-dose CBCT scan protocols likely fall in the dose range of 40-100 total mAs, depending on the specific IGRT applications. (2) Among different scan protocols at a constant low-dose level, the super sparse-view reconstruction with the projection number less than 50 is the most challenging case, even with strong regularization. Better image quality can be acquired with low mAs protocols. (3) The optimal scan protocol is the combination of a medium number of projections and a medium level of mAs/view. This is more evident when the dose is around 72.8 total mAs or below and when the ROI is a low-contrast or high-resolution object. Based on our results, the optimal number of projections is around 90 to 120. (4) The clinically acceptable lowest imaging dose level is task dependent. In our study, 72.8 mAs is a safe dose level for visualizing low-contrast objects, while 12.2 total mAs is sufficient for detecting high-contrast objects of diameter greater than 3 mm.

Therapeutic effect of high-dose green tea extract on weight reduction: A randomized, double-blind, placebo-controlled clinical trial.

PubMed

Chen, I-Ju; Liu, Chia-Yu; Chiu, Jung-Peng; Hsu, Chung-Hua

2016-06-01

To examine the effect and safety of high-dose green tea extract (Epigallocatechin gallate, EGCG) at a daily dosage of 856.8 mg on weight reduction and changes of lipid profile and obesity-related hormone peptides in women with central obesity. We conducted a randomized, double-blind trial registered under ClinicalTrials.gov Identifier no. NCT02147041. A total of 115 women with central obesity were screened at our clinic. 102 of them with a body mass index (BMI) ≥ 27 kg/m(2) and a waist circumference (WC) ≥ 80 cm were eligible for the study. These women were randomly assigned to either a high-dose green tea group or placebo group. The total treatment time was 12 weeks. The main outcome measures were anthropometric measurements, lipid profiles, and obesity related hormone peptides including leptin, adiponectin, ghrelin, and insulin. Significant weight loss, from 76.8 ± 11.3 kg to 75.7 ± 11.5 kg (p = 0.025), as well as decreases in BMI (p = 0.018) and waist circumference (p = 0.023) were observed in the treatment group after 12 weeks of high-dose EGCG treatment. This study also demonstrated a consistent trend of decreased total cholesterol, reaching 5.33%, and decreased LDL plasma levels. There was good tolerance of the treatment among subjects without any side effects or adverse events. Significantly lower ghrelin levels and elevated adiponectin levels were detected in the study group than in the placebo group. 12 weeks of treatment with high-dose green tea extract resulted in significant weight loss, reduced waist circumference, and a consistent decrease in total cholesterol and LDL plasma levels without any side effects or adverse effects in women with central obesity. The antiobestic mechanism of high-dose green tea extract might be associated in part with ghrelin secretion inhibition, leading to increased adiponectin levels. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Auditing the Immunization Data Quality from Routine Reports in Shangyu District, East China

PubMed Central

Hu, Yu; Zhang, Xinpei; Li, Qian; Chen, Yaping

2016-01-01

Objective: To evaluate the immunization data quality in Shangyu District, East China. Methods: An audit for immunization data for the year 2014 was conducted in 20 vaccination clinics of Shangyu District. The consistency of immunization data was estimated by verification factors (VFs), which was the proportion of vaccine doses reported as being administered that could be verified by written documentation at vaccination clinics. The quality of monitoring systems was evaluated using the quality index (QI). Results: The VFs of 20 vaccine doses ranged from 0.94 to 1.04 at the district level. The VFs for the 20 vaccination clinics ranged from 0.57 to 1.07. The VFs for Shangyu District was 0.98. The mean of total QI score of the 20 vaccination clinics was 80.32%. A significant correlation between the VFs of the 3rd dose of the diphtheria–tetanus–pertussis combined vaccine (DTP) and QI scores was observed at the vaccination clinic level. Conclusions: Deficiencies in data consistency and immunization reporting practice in Shangyu District were observed. Targeted measures are suggested to improve the quality of the immunization reporting system in vaccination clinics with poor data consistency. PMID:27869729

Auditing the Immunization Data Quality from Routine Reports in Shangyu District, East China.

PubMed

Hu, Yu; Zhang, Xinpei; Li, Qian; Chen, Yaping

2016-11-18

Objective: To evaluate the immunization data quality in Shangyu District, East China. Methods: An audit for immunization data for the year 2014 was conducted in 20 vaccination clinics of Shangyu District. The consistency of immunization data was estimated by verification factors (VFs), which was the proportion of vaccine doses reported as being administered that could be verified by written documentation at vaccination clinics. The quality of monitoring systems was evaluated using the quality index (QI). Results: The VFs of 20 vaccine doses ranged from 0.94 to 1.04 at the district level. The VFs for the 20 vaccination clinics ranged from 0.57 to 1.07. The VFs for Shangyu District was 0.98. The mean of total QI score of the 20 vaccination clinics was 80.32%. A significant correlation between the VFs of the 3rd dose of the diphtheria-tetanus-pertussis combined vaccine (DTP) and QI scores was observed at the vaccination clinic level. Conclusions: Deficiencies in data consistency and immunization reporting practice in Shangyu District were observed. Targeted measures are suggested to improve the quality of the immunization reporting system in vaccination clinics with poor data consistency.

Dose Adjustment for Normal Eating (DAFNE) in routine clinical practice: who benefits?

PubMed

Keen, A J A; Duncan, E; McKillop-Smith, A; Evans, N D; Gold, A E

2012-05-01

To explore the effectiveness of Dose Adjustment for Normal Eating in routine clinical practice in the UK. Participants were 124 adults with Type 1 diabetes who had completed a Dose Adjustment for Normal Eating course. Data were collected before the course and again 1 year later on a variety of biological, psychological and social measures. There were a range of significant benefits consistent with Dose Adjustment for Normal Eating aims, including: better control among those with baseline HbA(1c) ≥ 81 mmol/mol (9.6%) (z = -2.8, P = 0.004); reduced number of participants reporting severe hypoglycaemia (χ² = 4.27, P = 0.039); total eradication of diabetic ketoacidosis (χ² = 4.17, P = 0.041) and lower diabetes-related distress (z = -4.5, P < 0.001). The most deprived of the clinic population were significantly under-represented (χ² = 17.8, P = 0.001) and the levels of clinical depression were unusually low. These results indicate that Dose Adjustment for Normal Eating delivered in routine clinical practice is associated with a range of benefits and that certain clinical and psychosocial characteristics are associated with better outcomes. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone.

PubMed

Thygesen, Peter; Andersen, Henrik Sune; Behrens, Carsten; Fels, Johannes Josef; Nørskov-Lauritsen, Leif; Rischel, Christian; Johansen, Nils Langeland

2017-08-01

Somapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys. Pharmacokinetic studies investigating exposure, absorption, clearance, and bioavailability after single intravenous (i.v.) and subcutaneous (s.c.) administration were performed in all species. A dose-response study with five dose levels and a multiple dose pharmacodynamic study with four once weekly doses was performed in hypophysectomised rats to evaluate the effect of somapacitan on growth and IGF-I production. Pharmacokinetic profiles indicated first order absorption from the subcutaneous tissue after s.c. injections for somapacitan in all three species. Apparent terminal half-lives were 5-6h in rats, 10-12h in minipigs, and 17-20h in monkeys. Somapacitan induced a dose-dependent growth in hypophysectomised rats (p<0.001) and an increase in plasma IGF-I levels in rats (p<0.01), minipigs (p<0.01), and cynomolgus monkeys (p<0.05) after single dose administration. Multiple once weekly dosing of somapacitan in hypophysectomised rats induced a step-wise increase in body weight with an initial linear phase the first 3-4days in each dosing interval (p<0.001). The nonclinical pharmacokinetic and pharmacodynamic studies of somapacitan showed similar pharmacokinetic properties, with no absorption-limited elimination, increased clearance and increased and sustained levels of IGF-I in plasma for up to 10days after a single dose administration in all three species. Somapacitan induced a dose-dependent increase in body weight and IGF-I levels in hypophysectomised rats. Multiple dosing of somapacitan in hypophysectomised rats suggested a linear growth for the first 3-4days in each weekly dosing interval, whereas daily hGH dosing showed linear growth for approximately two weeks before reaching a plateau level. Copyright © 2017 Elsevier Ltd. All rights reserved.

Review of clinical brachytherapy uncertainties: Analysis guidelines of GEC-ESTRO and the AAPM☆

PubMed Central

Kirisits, Christian; Rivard, Mark J.; Baltas, Dimos; Ballester, Facundo; De Brabandere, Marisol; van der Laarse, Rob; Niatsetski, Yury; Papagiannis, Panagiotis; Hellebust, Taran Paulsen; Perez-Calatayud, Jose; Tanderup, Kari; Venselaar, Jack L.M.; Siebert, Frank-André

2014-01-01

Background and purpose A substantial reduction of uncertainties in clinical brachytherapy should result in improved outcome in terms of increased local control and reduced side effects. Types of uncertainties have to be identified, grouped, and quantified. Methods A detailed literature review was performed to identify uncertainty components and their relative importance to the combined overall uncertainty. Results Very few components (e.g., source strength and afterloader timer) are independent of clinical disease site and location of administered dose. While the influence of medium on dose calculation can be substantial for low energy sources or non-deeply seated implants, the influence of medium is of minor importance for high-energy sources in the pelvic region. The level of uncertainties due to target, organ, applicator, and/or source movement in relation to the geometry assumed for treatment planning is highly dependent on fractionation and the level of image guided adaptive treatment. Most studies to date report the results in a manner that allows no direct reproduction and further comparison with other studies. Often, no distinction is made between variations, uncertainties, and errors or mistakes. The literature review facilitated the drafting of recommendations for uniform uncertainty reporting in clinical BT, which are also provided. The recommended comprehensive uncertainty investigations are key to obtain a general impression of uncertainties, and may help to identify elements of the brachytherapy treatment process that need improvement in terms of diminishing their dosimetric uncertainties. It is recommended to present data on the analyzed parameters (distance shifts, volume changes, source or applicator position, etc.), and also their influence on absorbed dose for clinically-relevant dose parameters (e.g., target parameters such as D90 or OAR doses). Publications on brachytherapy should include a statement of total dose uncertainty for the entire treatment course, taking into account the fractionation schedule and level of image guidance for adaptation. Conclusions This report on brachytherapy clinical uncertainties represents a working project developed by the Brachytherapy Physics Quality Assurances System (BRAPHYQS) subcommittee to the Physics Committee within GEC-ESTRO. Further, this report has been reviewed and approved by the American Association of Physicists in Medicine. PMID:24299968

Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia

PubMed Central

Fan, Yongjun; Wali, Gautam; Sutharsan, Ratneswary; Bellette, Bernadette; Crane, Denis I.; Sue, Carolyn M.; Mackay-Sim, Alan

2014-01-01

ABSTRACT Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of disorders, diagnosed by progressive gait disturbances with muscle weakness and spasticity, for which there are no treatments targeted at the underlying pathophysiology. Mutations in spastin are a common cause of HSP. Spastin is a microtubule-severing protein whose mutation in mouse causes defective axonal transport. In human patient-derived olfactory neurosphere-derived (ONS) cells, spastin mutations lead to lower levels of acetylated α-tubulin, a marker of stabilised microtubules, and to slower speed of peroxisome trafficking. Here we screened multiple concentrations of four tubulin-binding drugs for their ability to rescue levels of acetylated α-tubulin in patient-derived ONS cells. Drug doses that restored acetylated α-tubulin to levels in control-derived ONS cells were then selected for their ability to rescue peroxisome trafficking deficits. Automated microscopic screening identified very low doses of the four drugs (0.5 nM taxol, 0.5 nM vinblastine, 2 nM epothilone D, 10 µM noscapine) that rescued acetylated α-tubulin in patient-derived ONS cells. These same doses rescued peroxisome trafficking deficits, restoring peroxisome speeds to untreated control cell levels. These results demonstrate a novel approach for drug screening based on high throughput automated microscopy for acetylated α-tubulin followed by functional validation of microtubule-based peroxisome transport. From a clinical perspective, all the drugs tested are used clinically, but at much higher doses. Importantly, epothilone D and noscapine can enter the central nervous system, making them potential candidates for future clinical trials. PMID:24857849

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Pharmacokinetics of buprenorphine: a comparison of sublingual tablet versus liquid after chronic dosing.

PubMed

Compton, Peggy; Ling, Walter; Chiang, C Nora; Moody, David E; Huber, Alice; Ling, Debbie; Charuvastra, Charles

2007-06-01

Although buprenorphine is approved for use in the outpatient treatment of opioid addiction in 2 tablet formulations, a monoproduct containing buprenorphine only (Subutex) and a buprenorphine/naloxone combination product (Suboxone), much of the clinical data that support the approval by the U.S. Food and Drug Administration were generated by using a sublingual liquid. To interpret the literature in prescribing parameters for tablet buprenorphine, this study was designed to determine steady state buprenorphine plasma levels for the 2 formulations and to assess the relative bioavailability of each. A randomized, double-blind, crossover study with dose increases was conducted during a 12-week period at an outpatient treatment clinic. Of the 184 subjects initially randomized to treatment, 133 (72.3%) were evaluated for the steady-state trough plasma concentration, 16 (8.7%) for relative bioavailability, and 31 (16.8%) for dose proportionality. At steady state, differences in the trough plasma concentrations of buprenorphine between the 2 formulations were found across all the dose levels. Average plasma concentration (Cavg) of the tablet at twice the milligram dose of the liquid was twice that of the liquid; intersubject variability was greater for the tablet. At double the dose of tablet, there is no difference in steady state plasma concentrations. The bioavailability seems equivalent for the 2 formulations across all the dose levels.

Clinical radiobiology of stage T2-T3 bladder cancer.

PubMed

Majewski, Wojciech; Maciejewski, Boguslaw; Majewski, Stanislaw; Suwinski, Rafal; Miszczyk, Leszek; Tarnawski, Rafal

2004-09-01

To evaluate the relationship between total radiation dose and overall treatment time (OTT) with the treatment outcome, with adjustment for selected clinical factors, in patients with Stage T2-T3 bladder cancer treated with curative radiotherapy (RT). The analysis was based on 480 patients with Stage T2-T3 bladder cancer who were treated at the Center of Oncology in Gliwice between 1975 and 1995. The mean total radiation dose was 65.5 Gy, and the mean OTT was 51 days. In 261 patients (54%), planned and unplanned gaps occurred during RT. Four fractionation schedules were used: (1) conventional fractionation (once daily, 1.8-2.5 Gy/fraction); (2) protracted fractionation (pelvic RT, once daily, 1.6-1.7 Gy/fraction, boost RT, once daily, 2.0 Gy/fraction); (3) accelerated hyperfractionated boost (pelvic RT, once daily, 2.0 Gy/fraction; boost RT, twice daily, 1.3-1.4 Gy/fraction); and (4) accelerated hyperfractionation (pelvic and boost RT, twice daily, 1.2-1.5 Gy/fraction). In all fractionation schedules, the total radiation dose was similar (average 65.5 Gy), but the OTT was different (mean 53 days for conventional fractionation, 62 days for protracted fractionation, 45 days for accelerated hyperfractionated boost, and 41 days for accelerated hyperfractionation). A Cox proportional hazard model and maximum likelihood logistic model were used to evaluate the relationship between the treatment-related parameters (total radiation dose, dose per fraction, and OTT) and clinical factors (clinical T stage, hemoglobin level and bladder capacity before RT) and treatment outcome. With a median follow-up of 76 months, the actuarial 5-year local control rate was 47%, and the overall survival rate was 40%. The logistic analysis, which included the total dose, OTT, and T stage, revealed that all of these factors were significantly related to tumor control probability (p = 0.021 for total radiation dose, p = 0.038 for OTT, and p = 0.00068 for T stage). A multivariate Cox model, which included the treatment-related parameters and other clinical factors, revealed that the hemoglobin level and bladder capacity before RT and T-stage were statistically significant factors determining local control and overall survival. The total radiation dose was of borderline statistical significance for overall survival (p = 0.087), and OTT did not reach statistical significance. The results of our study showed that the treatment outcome after RT for bladder cancer depends mainly on clinical factors: hemoglobin level and bladder capacity before RT, and clinical T stage. An increase in the total radiation dose seemed to be associated with a better treatment outcome. The effect of the OTT was difficult to define, because it was influenced by other prognostic factors.

Multicentre dose audit for clinical trials of radiation therapy in Asia

PubMed Central

Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C.R. Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-01-01

Abstract A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. PMID:27864507

Inhalational botulism in rhesus macaques exposed to botulinum neurotoxin complex serotypes A1 and B1.

PubMed

Sanford, Daniel C; Barnewall, Roy E; Vassar, Michelle L; Niemuth, Nancy; Metcalfe, Karen; House, Robert V; Henderson, Ian; Shearer, Jeffry D

2010-09-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD(50)) and to estimate 50% lethal exposure concentrations relative to time (LCt(50)) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD(50) and LCt(50) for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

Inhalational Botulism in Rhesus Macaques Exposed to Botulinum Neurotoxin Complex Serotypes A1 and B1▿ †

PubMed Central

Sanford, Daniel C.; Barnewall, Roy E.; Vassar, Michelle L.; Niemuth, Nancy; Metcalfe, Karen; House, Robert V.; Henderson, Ian; Shearer, Jeffry D.

2010-01-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD50) and to estimate 50% lethal exposure concentrations relative to time (LCt50) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD50 and LCt50 for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication. PMID:20660138

Clinical Implementation of a Model-Based In Vivo Dose Verification System for Stereotactic Body Radiation Therapy-Volumetric Modulated Arc Therapy Treatments Using the Electronic Portal Imaging Device.

PubMed

McCowan, Peter M; Asuni, Ganiyu; Van Uytven, Eric; VanBeek, Timothy; McCurdy, Boyd M C; Loewen, Shaun K; Ahmed, Naseer; Bashir, Bashir; Butler, James B; Chowdhury, Amitava; Dubey, Arbind; Leylek, Ahmet; Nashed, Maged

2017-04-01

To report findings from an in vivo dosimetry program implemented for all stereotactic body radiation therapy patients over a 31-month period and discuss the value and challenges of utilizing in vivo electronic portal imaging device (EPID) dosimetry clinically. From December 2013 to July 2016, 117 stereotactic body radiation therapy-volumetric modulated arc therapy patients (100 lung, 15 spine, and 2 liver) underwent 602 EPID-based in vivo dose verification events. A developed model-based dose reconstruction algorithm calculates the 3-dimensional dose distribution to the patient by back-projecting the primary fluence measured by the EPID during treatment. The EPID frame-averaging was optimized in June 2015. For each treatment, a 3%/3-mm γ comparison between our EPID-derived dose and the Eclipse AcurosXB-predicted dose to the planning target volume (PTV) and the ≥20% isodose volume were performed. Alert levels were defined as γ pass rates <85% (lung and liver) and <80% (spine). Investigations were carried out for all fractions exceeding the alert level and were classified as follows: EPID-related, algorithmic, patient setup, anatomic change, or unknown/unidentified errors. The percentages of fractions exceeding the alert levels were 22.6% for lung before frame-average optimization and 8.0% for lung, 20.0% for spine, and 10.0% for liver after frame-average optimization. Overall, mean (± standard deviation) planning target volume γ pass rates were 90.7% ± 9.2%, 87.0% ± 9.3%, and 91.2% ± 3.4% for the lung, spine, and liver patients, respectively. Results from the clinical implementation of our model-based in vivo dose verification method using on-treatment EPID images is reported. The method is demonstrated to be valuable for routine clinical use for verifying delivered dose as well as for detecting errors. Copyright © 2017 Elsevier Inc. All rights reserved.

Clinical Implementation of a Model-Based In Vivo Dose Verification System for Stereotactic Body Radiation Therapy–Volumetric Modulated Arc Therapy Treatments Using the Electronic Portal Imaging Device

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCowan, Peter M., E-mail: pmccowan@cancercare.mb.ca; Asuni, Ganiyu; Van Uytven, Eric

Purpose: To report findings from an in vivo dosimetry program implemented for all stereotactic body radiation therapy patients over a 31-month period and discuss the value and challenges of utilizing in vivo electronic portal imaging device (EPID) dosimetry clinically. Methods and Materials: From December 2013 to July 2016, 117 stereotactic body radiation therapy–volumetric modulated arc therapy patients (100 lung, 15 spine, and 2 liver) underwent 602 EPID-based in vivo dose verification events. A developed model-based dose reconstruction algorithm calculates the 3-dimensional dose distribution to the patient by back-projecting the primary fluence measured by the EPID during treatment. The EPID frame-averaging was optimized in Junemore » 2015. For each treatment, a 3%/3-mm γ comparison between our EPID-derived dose and the Eclipse AcurosXB–predicted dose to the planning target volume (PTV) and the ≥20% isodose volume were performed. Alert levels were defined as γ pass rates <85% (lung and liver) and <80% (spine). Investigations were carried out for all fractions exceeding the alert level and were classified as follows: EPID-related, algorithmic, patient setup, anatomic change, or unknown/unidentified errors. Results: The percentages of fractions exceeding the alert levels were 22.6% for lung before frame-average optimization and 8.0% for lung, 20.0% for spine, and 10.0% for liver after frame-average optimization. Overall, mean (± standard deviation) planning target volume γ pass rates were 90.7% ± 9.2%, 87.0% ± 9.3%, and 91.2% ± 3.4% for the lung, spine, and liver patients, respectively. Conclusions: Results from the clinical implementation of our model-based in vivo dose verification method using on-treatment EPID images is reported. The method is demonstrated to be valuable for routine clinical use for verifying delivered dose as well as for detecting errors.« less

Positron Emission Tomography-Guided, Focal-Dose Escalation Using Intensity-Modulated Radiotherapy for Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Madani, Indira; Duthoy, Wim; Derie, Cristina R.N.

2007-05-01

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography ({sup 18}F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was appliedmore » for the remaining 22 fractions of 2.16 Gy. Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted {sup 18}F-FDG-PET-delineated region. Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.« less

Adaptive Statistical Iterative Reconstruction-V: Impact on Image Quality in Ultralow-Dose Coronary Computed Tomography Angiography.

PubMed

Benz, Dominik C; Gräni, Christoph; Mikulicic, Fran; Vontobel, Jan; Fuchs, Tobias A; Possner, Mathias; Clerc, Olivier F; Stehli, Julia; Gaemperli, Oliver; Pazhenkottil, Aju P; Buechel, Ronny R; Kaufmann, Philipp A

The clinical utility of a latest generation iterative reconstruction algorithm (adaptive statistical iterative reconstruction [ASiR-V]) has yet to be elucidated for coronary computed tomography angiography (CCTA). This study evaluates the impact of ASiR-V on signal, noise and image quality in CCTA. Sixty-five patients underwent clinically indicated CCTA on a 256-slice CT scanner using an ultralow-dose protocol. Data sets from each patient were reconstructed at 6 different levels of ASiR-V. Signal intensity was measured by placing a region of interest in the aortic root, LMA, and RCA. Similarly, noise was measured in the aortic root. Image quality was visually assessed by 2 readers. Median radiation dose was 0.49 mSv. Image noise decreased with increasing levels of ASiR-V resulting in a significant increase in signal-to-noise ratio in the RCA and LMA (P < 0.001). Correspondingly, image quality significantly increased with higher levels of ASiR-V (P < 0.001). ASiR-V yields substantial noise reduction and improved image quality enabling introduction of ultralow-dose CCTA.

Treatment Dosing Patterns and Clinical Outcomes for Patients with Type 2 Diabetes Starting or Switching to Treatment with Insulin Glargine (300 Units per Milliliter) in a Real-World Setting: A Retrospective Observational Study.

PubMed

Gupta, Shaloo; Wang, Hongwei; Skolnik, Neil; Tong, Liyue; Liebert, Ryan M; Lee, Lulu K; Stella, Peter; Cali, Anna; Preblick, Ronald

2018-01-01

Usage patterns and effectiveness of a longer-acting formulation of insulin glargine at a strength of 300 units per milliliter (Gla-300) have not been studied in real-world clinical practice. This study evaluated differences in dosing and clinical outcomes before and after Gla-300 treatment initiation in patients with type 2 diabetes starting or switching to treatment with Gla-300 to assess whether the benefits observed in clinical trials translate into real-world settings. This was a retrospective observational study using medical record data obtained by physician survey for patients starting treatment with insulin glargine at a strength of 100 units per milliliter (Gla-100) or Gla-300, or switching to treatment with Gla-300 from treatment with another basal insulin (BI). Differences in dosing and clinical outcomes before versus after treatment initiation or switching were examined by generalized linear mixed-effects models. Among insulin-naive patients starting BI treatment, no difference in the final titrated dose was observed in patients starting Gla-300 treatment versus those starting Gla-100 treatment [least-squares (LS) mean 0.43 units per kilogram vs 0.44 units per kilogram; P = 0.77]. Both groups had significant hemoglobin A 1c level reductions (LS mean 1.21 percentage points for Gla-300 and 1.12 percentage points for Gla-100 ; both P < 0.001). The relative risk of hypoglycemic events after Gla-300 treatment initiation was lower than that after Gla-100 treatment initiation [0.31, 95% confidence interval (CI) 0.12-0.81; P = 0.018] at similar daily doses. The daily dose of BI was significantly lower after switching to treatment with Gla-300 from treatment with another BI (0.73 units per kilogram before switch vs 0.58 units per kilogram after switch; P = 0.02). The mean hemoglobin A 1c level was significantly lower after switching than before switching (adjusted difference - 0.95 percentage points, 95% CI - 1.13 to - 0.78 percentage points ; P < 0.0001). Hypoglycemic events per patient-year were significantly lower (relative risk 0.17, 95% CI 0.11-0.26; P < 0.0001). Insulin-naive patients starting Gla-300 treatment had fewer hypoglycemic events, a similar hemoglobin A 1c level reduction, and no difference in insulin dose versus patients starting Gla-100 treatment. Patients switching to Gla-300 treatment from treatment with other BIs had significantly lower daily doses of BI, with fewer hypoglycemic events, without compromise of hemoglobin A 1c level reduction. These findings suggest Gla-300 in a real-world setting provides benefits in terms of dosing, with improved hemoglobin A 1c level and hypoglycemia rates. Sanofi US Inc. (Bridgewater, NJ, USA).

Comparative toxicity study on classical and modified version of Jawarish Jalinoos (a traditional Unani formulation) in rats.

PubMed

Husain, Gulam Mohammed; Ahmed, Syed Shoeb; Azhar, Misbahuddin; Siddiqui, Javed Inam; Waheed, Mohammad Abdul; Kazmi, Munawwar Husain

2017-03-01

Jawarish Jalinoos (JJ) is a classical semisolid traditional Unani formulation clinically used for the treatment of weakness of vital organs, liver, and stomach. Although JJ has been widely used clinically for several decades, no scientific report is available for its safety. JJ and its sugar-free tablet version (SFJJ; formulated to target diabetic population) were assessed for safety in rats. Ninety-day repeated dose oral toxicity study was performed as per the Organisation for Economic Co-operation and Development Guideline 408. JJ was orally administered at the dose of 2000 mg/kg bw/d, whereas SFJJ was orally administered at the doses of 506 mg/kg body weight (bw)/d, 1012 mg/kg bw/d, and 2024 mg/kg bw/d for 90 days. The animals were periodically observed for clinical signs of toxicity, mortality, morbidity, body weight changes, and feed consumption. At the end of the study, hematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight, and histological examination were performed. Treatment with SFJJ and JJ showed no significant differences in body weight gain, feed consumption, hematology, clinical biochemistry, and serum electrolytes. No gross pathological findings and differences in relative organ weights were observed between control and drug treated rats. Histological examination revealed no toxicologically significant abnormalities related with SFJJ or JJ treatment. The 90-day repeated dose oral toxicity study demonstrates that the no observed adverse effect level of SFJJ and JJ is greater than 2024 mg/kg bw/d and 2000 mg/kg bw/d (p.o.) in rats, respectively. Both formulations were found to be safe up to the tested dose levels and experimental conditions, and therefore safe for clinical use as specified in the literature.

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior

PubMed Central

Thanos, Panayotis K.; Robison, Lisa S.; Steier, Jessica; Hwang, Yu Fen; Cooper, Thomas; Swanson, James M.; Komatsu, David E.; Hadjiargyrou, Michael; Volkow, Nora D.

2015-01-01

Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (i.e. quicker and higher peak concentrations). Here, we evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic the clinical drug delivery profile. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60 mg/kg/day; as well as dual-dosages of 4 and 10 mg/kg/day, 20 and 30 mg/kg/day, or 30 and 60 mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Blood was sampled and plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60 mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30 ng/mL), while the 4/10 mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8 ng/mL). Treatment with the higher dual-dosage (HD: 30/60 mg/kg) resulted in hyperactivity, while the lower (LD: 4/10 mg/kg) had no effect. Next, chronic effects of these dual-dosages were assessed on behavior throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle; decreased exploratory behavior; and increased anxiolytic behavior. These findings suggest that this dual-dosage-drinking-paradigm can be used to examine the effects of clinically relevant pharmacokinetic doses of MP, and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes. PMID:25641666

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior.

PubMed

Thanos, Panayotis K; Robison, Lisa S; Steier, Jessica; Hwang, Yu Fen; Cooper, Thomas; Swanson, James M; Komatsu, David E; Hadjiargyrou, Michael; Volkow, Nora D

2015-04-01

Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (quicker and higher peak concentrations). We evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic clinical drug delivery. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60mg/kg/day; as well as dual-dosages of 4 and 10mg/kg/day, 20 and 30mg/kg/day, or 30 and 60mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30ng/mL), while the 4/10mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8ng/mL). Treatment with the higher dual-dosage (HD: 30/60mg/kg) resulted in hyperactivity, while the lower (LD: 4/10mg/kg) had no effect. Chronic effects of these dual-dosages were assessed throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle, decreased exploratory behavior, and increased anxiolytic behavior. Findings suggest that these dual-dosage-drinking-paradigms can be used to examine the effects of clinically relevant pharmacokinetic doses of MP and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes. Copyright © 2015 Elsevier Inc. All rights reserved.

Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B

PubMed Central

Nathwani, A.C.; Reiss, U.M.; Tuddenham, E.G.D.; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, M.; Shen, Y.-M.; Halka, K.G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K.A.; Allay, J.; Kay, M.A.; Ng, C.Y.C.; Zhou, J.; Cancio, M.; Morton, C.L.; Gray, J.T.; Srivastava, D.; Nienhuis, A.W.; Davidoff, A.M.

2014-01-01

BACKGROUND In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose–response relationship, and the level of persistent or late toxicity. METHODS We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.) PMID:25409372

Clinical Experience and Evaluation of Patient Treatment Verification With a Transit Dosimeter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ricketts, Kate, E-mail: k.ricketts@ucl.ac.uk; Department of Radiotherapy Physics, Royal Berkshire NHS Foundation Trust, Reading; Navarro, Clara

2016-08-01

Purpose: To prospectively evaluate a protocol for transit dosimetry on a patient population undergoing intensity modulated radiation therapy (IMRT) and to assess the issues in clinical implementation of electronic portal imaging devices (EPIDs) for treatment verification. Methods and Materials: Fifty-eight patients were enrolled in the study. Amorphous silicon EPIDs were calibrated for dose and used to acquire images of delivered fields. Measured EPID dose maps were back-projected using the planning computed tomographic (CT) images to calculate dose at prespecified points within the patient and compared with treatment planning system dose offline using point dose difference and point γ analysis. Themore » deviation of the results was used to inform future action levels. Results: Two hundred twenty-five transit images were analyzed, composed of breast, prostate, and head and neck IMRT fields. Patient measurements demonstrated the potential of the dose verification protocol to model dose well under complex conditions: 83.8% of all delivered beams achieved the initial set tolerance level of Δ{sub D} of 0 ± 5 cGy or %Δ{sub D} of 0% ± 5%. Importantly, the protocol was also sensitive to anatomic changes and spotted that 3 patients from 20 measured prostate patients had undergone anatomic change in comparison with the planning CT. Patient data suggested an EPID-reconstructed versus treatment planning system dose difference action level of 0% ± 7% for breast fields. Asymmetric action levels were more appropriate for inversed IMRT fields, using absolute dose difference (−2 ± 5 cGy) or summed field percentage dose difference (−6% ± 7%). Conclusions: The in vivo dose verification method was easy to use and simple to implement, and it could detect patient anatomic changes that impacted dose delivery. The system required no extra dose to the patient or treatment time delay and so could be used throughout the course of treatment to identify and limit systematic and random errors in dose delivery for patient groups.« less

Clinical Experience and Evaluation of Patient Treatment Verification With a Transit Dosimeter.

PubMed

Ricketts, Kate; Navarro, Clara; Lane, Katherine; Blowfield, Claire; Cotten, Gary; Tomala, Dee; Lord, Christine; Jones, Joanne; Adeyemi, Abiodun

2016-08-01

To prospectively evaluate a protocol for transit dosimetry on a patient population undergoing intensity modulated radiation therapy (IMRT) and to assess the issues in clinical implementation of electronic portal imaging devices (EPIDs) for treatment verification. Fifty-eight patients were enrolled in the study. Amorphous silicon EPIDs were calibrated for dose and used to acquire images of delivered fields. Measured EPID dose maps were back-projected using the planning computed tomographic (CT) images to calculate dose at prespecified points within the patient and compared with treatment planning system dose offline using point dose difference and point γ analysis. The deviation of the results was used to inform future action levels. Two hundred twenty-five transit images were analyzed, composed of breast, prostate, and head and neck IMRT fields. Patient measurements demonstrated the potential of the dose verification protocol to model dose well under complex conditions: 83.8% of all delivered beams achieved the initial set tolerance level of ΔD of 0 ± 5 cGy or %ΔD of 0% ± 5%. Importantly, the protocol was also sensitive to anatomic changes and spotted that 3 patients from 20 measured prostate patients had undergone anatomic change in comparison with the planning CT. Patient data suggested an EPID-reconstructed versus treatment planning system dose difference action level of 0% ± 7% for breast fields. Asymmetric action levels were more appropriate for inversed IMRT fields, using absolute dose difference (-2 ± 5 cGy) or summed field percentage dose difference (-6% ± 7%). The in vivo dose verification method was easy to use and simple to implement, and it could detect patient anatomic changes that impacted dose delivery. The system required no extra dose to the patient or treatment time delay and so could be used throughout the course of treatment to identify and limit systematic and random errors in dose delivery for patient groups. Copyright © 2016 Elsevier Inc. All rights reserved.

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

PubMed

Ludvigsson, Johnny; Krisky, David; Casas, Rosaura; Battelino, Tadej; Castaño, Luis; Greening, James; Kordonouri, Olga; Otonkoski, Timo; Pozzilli, Paolo; Robert, Jean-Jacques; Veeze, Henk J; Palmer, Jerry; Samuelsson, Ulf; Elding Larsson, Helena; Åman, Jan; Kärdell, Gunilla; Neiderud Helsingborg, Jan; Lundström, Göran; Albinsson, Eva; Carlsson, Annelie; Nordvall, Maria; Fors, Hans; Arvidsson, Carl-Göran; Edvardson, Stig; Hanås, Ragnar; Larsson, Karin; Rathsman, Björn; Forsgren, Henrik; Desaix, Helena; Forsander, Gun; Nilsson, Nils-Östen; Åkesson, Carl-Göran; Keskinen, Päivi; Veijola, Riitta; Talvitie, Timo; Raile, Klemens; Kapellen, Thomas; Burger, Walter; Neu, Andreas; Engelsberger, Ilse; Heidtmann, Bettina; Bechtold, Suzanne; Leslie, David; Chiarelli, Francesco; Cicognani, Alesandro; Chiumello, Giuseppe; Cerutti, Franco; Zuccotti, Gian Vincenzo; Gomez Gila, Ana; Rica, Itxaso; Barrio, Raquel; Clemente, Maria; López Garcia, Maria José; Rodriguez, Mercedes; Gonzalez, Isabel; Lopez, Juan Pedro; Oyarzabal, Mirentxu; Reeser, H M; Nuboer, Roos; Stouthart, Pauline; Bratina, Natasa; Bratanic, Nina; de Kerdanet, Marc; Weill, Jacques; Ser, Nicole; Barat, Pascal; Bertrand, Anne Marie; Carel, Jean-Claude; Reynaud, Rachel; Coutant, Regis; Baron, Sabine

2012-02-02

The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

The flame-retardant BDE-99 dose-dependently affects viral replication in CVB3-infected mice.

PubMed

Lundgren, Magnus; Darnerud, Per Ola; Ilbäck, Nils-Gunnar

2013-06-01

The flame retardant component 2,2',4,4',5-penta-BDE (BDE-99) is found in the environment and in human tissues and fluids. In mice the common human coxsackievirus B3 (CVB3) infection has been shown to change the tissue distribution of BDE-99. We now investigate how CVB3 infection in mice affects liver uptake of (14)C at two doses of radiolabelled BDE-99, and whether increased tissue levels are related to changed virus replication and gene expression of the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1). Mice were infected on day 0, orally treated either with 200μg or 20mg (14)C-BDE-99/kgbw on day 1, and euthanised on day 3. Serum and liver levels of (14)C-BDE-99, as well as virus levels and gene expressions of MCP-1 in the liver, were measured. In non-infected mice, there was a dose-dependent uptake of BDE-99 in both liver and serum, and in infected animals the liver BDE-99 levels was further increased. When comparing infected mice exposed to the two BDE-99 doses, the higher BDE dose resulted in increased virus amounts in the liver, and decreased infection-induced expression of MCP-1. Consequently, a high enough dose/tissue concentration of BDE-99 may result in a disturbed mobilisation of immune cells into infected tissues that could explain higher virus titres and a possibly altered clinical course of the disease. Moreover, the fact that CVB3 infection increased the BDE-99 levels in liver but not in serum may impair the risk assessment of polybrominated diphenyl ethers (PBDEs) in subclinical and clinically infected individuals, as serum levels is the common marker of exposure. Copyright © 2013 Elsevier Ltd. All rights reserved.

Plasma homovanillic acid levels and therapeutic outcome in schizophrenics: comparisons of neuroleptic-naive first-episode patients and patients with disease exacerbation due to neuroleptic discontinuance.

PubMed

Akiyama, K; Tsuchida, K; Kanzaki, A; Ujike, H; Hamamura, T; Kondo, K; Mutoh, S; Miyanagi, K; Kuroda, S; Otsuki, S

1995-11-15

Plasma homovanillic acid (pHVA) levels were measured and the Brief Psychiatric Rating Scale (BPRS) scores were evaluated in 26 schizophrenic patients who had either never been medicated (neuroleptic-naive, first-episode subjects) or whose condition had become exacerbated following neuroleptic discontinuance (exacerbated subjects). All the subjects received medication with a fixed dose of a neuroleptic (haloperidol or fluphenazine, both 9 mg/day) for the first week and variable doses for the subsequent 4 weeks. In the neuroleptic-naive subjects, pHVA levels increased significantly 1 week after starting the protocol; this increase correlated significantly with clinical improvement of the BPRS positive symptom scores at week 5. In the neuroleptic-naive subjects, pHVA levels had declined to the baseline level by week 5. In the exacerbated subjects, there were no significant correlations between pHVA level changes at week 1 and later improvements of the BPRS positive symptom scores. These results suggest that the rise in pHVA levels occurring within 1 week after starting a fixed neuroleptic dose may predict a favorable clinical response in neuroleptic-naive schizophrenic patients.

[Personal dose monitoring of radiation workers in medical institutions at the municipal level and below in a city from 2011 to 2014].

PubMed

Wang, C; Mo, S F; Zhang, J B; Li, J R; Huang, R L; Tan, H Y

2017-08-20

Objective: To determine the personal dose level of radiation workers in medical institutions at the municipal level and below in a city, and to provide a scientific support for strengthening the radiation protection in the city's medical institutions. Methods: Information of the successful applicants for the "Radiation Worker Permit" from 174 medical institutions at the municipal level and below was collected from October 1, 2011 to December 31, 2014. The annual effective dose was calculated based on the personal dose monitoring report, and indicators including sex, permit application time, hospital level, type of occupational radiation, length of radiation work, blood test, and micronucleated lymphocyte rate were analyzed. Results: Of the 1 143 radiation worker permit applications submitted by medical institutions the municipal level and below in this city from 2011 to 2014, 1 123 provided at least one personal dose monitoring report. The annual effective dose of the radiation workers was 0-4.76 mSv (mean 0.31±0.40 mSv) , and the collective annual effective dose was 351.96 mSv. The annual effective dose was significantly different between radiation workers with different times of permit application, hospital levels, and types of occupational radiation ( P <0.05) . Interventional radiology workers had the highest annual effective dose (0.63 mSv) , and annual effective dose was significantly different between interventional radiology workers with different lengths of radiation work ( H =10.812, P <0.05) . Conclusion: The personal radiation dose of radiation workers in medical institutions at the municipal level and below in this city is maintained at a relatively low level, suggesting that the occupational environment is relatively safe for these workers. However, more focus should be placed on clinical interventional radiology workers.

Influence of radiation dose and reconstruction algorithm in MDCT assessment of airway wall thickness: A phantom study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gomez-Cardona, Daniel; Nagle, Scott K.; Department of Radiology, University of Wisconsin-Madison School of Medicine and Public Health, 600 Highland Avenue, Madison, Wisconsin 53792

Purpose: Wall thickness (WT) is an airway feature of great interest for the assessment of morphological changes in the lung parenchyma. Multidetector computed tomography (MDCT) has recently been used to evaluate airway WT, but the potential risk of radiation-induced carcinogenesis—particularly in younger patients—might limit a wider use of this imaging method in clinical practice. The recent commercial implementation of the statistical model-based iterative reconstruction (MBIR) algorithm, instead of the conventional filtered back projection (FBP) algorithm, has enabled considerable radiation dose reduction in many other clinical applications of MDCT. The purpose of this work was to study the impact of radiationmore » dose and MBIR in the MDCT assessment of airway WT. Methods: An airway phantom was scanned using a clinical MDCT system (Discovery CT750 HD, GE Healthcare) at 4 kV levels and 5 mAs levels. Both FBP and a commercial implementation of MBIR (Veo{sup TM}, GE Healthcare) were used to reconstruct CT images of the airways. For each kV–mAs combination and each reconstruction algorithm, the contrast-to-noise ratio (CNR) of the airways was measured, and the WT of each airway was measured and compared with the nominal value; the relative bias and the angular standard deviation in the measured WT were calculated. For each airway and reconstruction algorithm, the overall performance of WT quantification across all of the 20 kV–mAs combinations was quantified by the sum of squares (SSQs) of the difference between the measured and nominal WT values. Finally, the particular kV–mAs combination and reconstruction algorithm that minimized radiation dose while still achieving a reference WT quantification accuracy level was chosen as the optimal acquisition and reconstruction settings. Results: The wall thicknesses of seven airways of different sizes were analyzed in the study. Compared with FBP, MBIR improved the CNR of the airways, particularly at low radiation dose levels. For FBP, the relative bias and the angular standard deviation of the measured WT increased steeply with decreasing radiation dose. Except for the smallest airway, MBIR enabled significant reduction in both the relative bias and angular standard deviation of the WT, particularly at low radiation dose levels; the SSQ was reduced by 50%–96% by using MBIR. The optimal reconstruction algorithm was found to be MBIR for the seven airways being assessed, and the combined use of MBIR and optimal kV–mAs selection resulted in a radiation dose reduction of 37%–83% compared with a reference scan protocol with a dose level of 1 mGy. Conclusions: The quantification accuracy of airway WT is strongly influenced by radiation dose and reconstruction algorithm. The MBIR algorithm potentially allows the desired WT quantification accuracy to be achieved with reduced radiation dose, which may enable a wider clinical use of MDCT for the assessment of airway WT, particularly for younger patients who may be more sensitive to exposures with ionizing radiation.« less

Teaching Veterinary Anesthesia: A Survey-Based Evaluation of Two High-Fidelity Models and Live-Animal Experience for Undergraduate Veterinary Students.

PubMed

Musk, Gabrielle C; Collins, Teresa; Hosgood, Giselle

In veterinary medical education, reduction, replacement, and refinement (the three Rs) must be considered. Three clinical skills in anesthesia were identified as challenging to students: endotracheal intubation, intravenous catheterization, and drug dose calculations. The aims of this project were to evaluate students' perception of their level of confidence in performing these three clinical skills in veterinary anesthesia, to document the extent of students' previous experience in performing these three tasks, and to describe students' emotional states during this training. Veterinary students completed a series of four surveys over the period of their pre-clinical training to evaluate the usefulness of high-fidelity models for skill acquisition in endotracheal intubation and intravenous catheterization. In addition, practice and ongoing assessment in drug dose calculations were performed. The curriculum during this period of training progressed from lectures and non-animal training, to anesthesia of pigs undergoing surgery from which they did not recover, and finally to anesthesia of dogs and cats in a neutering clinic. The level of confidence for each of the three clinical skills increased over the study period. For each skill, the number of students with no confidence decreased to zero and the proportion of students with higher levels of confidence increased. The high-fidelity models for endotracheal intubation and intravenous catheterization used to complement the live-animal teaching were considered a useful adjunct to the teaching of clinical skills in veterinary anesthesia. With practice, students became more confident performing drug dose calculations.

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus.

PubMed

Vajda, Eric G; Logan, Douglas; Lasseter, Kenneth; Armas, Danielle; Plotkin, Diane J; Pipkin, J D; Li, Yong-Xi; Zhou, Rong; Klein, David; Wei, Xiaoxiong; Dilzer, Stacy; Zhi, Lin; Marschke, Keith B

2017-01-01

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD-6972, in healthy subjects and subjects with type 2 diabetes (T2DM). In the single ascending dose study, LGD-6972 (2-480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia. Inhibition of glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.it; Cilla, Savino; Deodato, Francesco

Purpose: A prospective phase 1-2 clinical trial aimed at determining the recommended postoperative dose of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) in a large series of patients with high-risk and intermediate-risk endometrial cancer (HIR-EC) is presented. The study also evaluated the association between rate and severity of toxicity and comorbidities and the clinical outcomes. Methods and Materials: Two SIB-VMAT dose levels were investigated for boost to the vaginal vault, whereas the pelvic lymph nodes were always treated with 45 Gy. The first cohort received a SIB-VMAT dose of 55 Gy in 25 consecutive 2.2-Gy fractions, and the subsequent cohort receivedmore » higher doses (60 Gy in 2.4-Gy fractions). Results: Seventy consecutive HIR-EC patients, roughly half of whom were obese (47.1%) or overweight (37.1%), with Charlson Age-Comorbidity Index >2 (48.5%), were enrolled. Thirty-one patients (44.3%) were administered adjuvant chemotherapy before starting radiation therapy. All patients (n=35 per dose level) completed irradiation without any dose-limiting toxicity. Proctitis (any grade) was associated with radiation therapy dose (P=.001); not so enterocolitis. Grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity were recorded in 17 (24.3%) and 14 patients (20.0%), respectively, and were not associated with radiation dose. As for late toxicity, none of patients experienced late grade ≥3 GI or grade ≥2 GU toxicity. The 3-year late grade ≥2 GI and GU toxicity–free survival were 92.8% and 100%, respectively, with no difference between the 2 dose levels. With a median follow-up period of 25 months (range, 4-60 months), relapse/progression of disease was observed in 10 of 70 patients (14.2%). The 3-year cumulative incidence of recurrence was 1.5% (95% confidence interval (CI): 0.2-10.7), whereas the 3-year disease-free survival was 81.3% (95% CI: 65.0-90.0). Conclusions: This clinical study showed the feasibility of this technique and its good profile in terms of acute and late toxicity at the recommended doses even in aged and frail patients.« less

Lack of Response in an Autistic Population to a Low Dose Clinical Trial of Pyridoxine Plus Magnesium.

ERIC Educational Resources Information Center

Tolbert, Lelland; And Others

1993-01-01

As some therapeutic benefits for autistic persons have been reported from combined high doses of pyridoxine and magnesium, this study evaluated long-term administration of low doses (to minimize adverse effects) to 15 subjects with autism. Findings indicated that, at this dosage level, pyridoxine and magnesium had no effect on the severity of…

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

PubMed

Miyauchi, Katsumi; Kimura, Takeshi; Shimokawa, Hiroaki; Daida, Hiroyuki; Iimuro, Satoshi; Iwata, Hiroshi; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Ohashi, Yasuo; Ohtsu, Hiroshi; Saito, Yasushi; Matsuzaki, Masunori; Nagai, Ryozo

2018-03-30

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

PubMed

Shimizu, Toshio; Fukuoka, Kazuya; Takeda, Masayuki; Iwasa, Tutomu; Yoshida, Takeshi; Horobin, Joanna; Keegan, Mitchell; Vaickus, Lou; Chavan, Ajit; Padval, Mahesh; Nakagawa, Kazuhiko

2016-05-01

VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

Safety of phase I clinical trials with monoclonal antibodies in Germany--the regulatory requirements viewed in the aftermath of the TGN1412 disaster.

PubMed

Liedert, B; Bassus, S; Schneider, C K; Kalinke, U; Löwer, J

2007-01-01

This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.

High energy x-ray phase contrast CT using glancing-angle grating interferometers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sarapata, A., E-mail: adrian.sarapata@tum.de; Stayman, J. W.; Siewerdsen, J. H.

Purpose: The authors present initial progress toward a clinically compatible x-ray phase contrast CT system, using glancing-angle x-ray grating interferometry to provide high contrast soft tissue images at estimated by computer simulation dose levels comparable to conventional absorption based CT. Methods: DPC-CT scans of a joint phantom and of soft tissues were performed in order to answer several important questions from a clinical setup point of view. A comparison between high and low fringe visibility systems is presented. The standard phase stepping method was compared with sliding window interlaced scanning. Using estimated dose values obtained with a Monte-Carlo code themore » authors studied the dependence of the phase image contrast on exposure time and dose. Results: Using a glancing angle interferometer at high x-ray energy (∼45 keV mean value) in combination with a conventional x-ray tube the authors achieved fringe visibility values of nearly 50%, never reported before. High fringe visibility is shown to be an indispensable parameter for a potential clinical scanner. Sliding window interlaced scanning proved to have higher SNRs and CNRs in a region of interest and to also be a crucial part of a low dose CT system. DPC-CT images of a soft tissue phantom at exposures in the range typical for absorption based CT of musculoskeletal extremities were obtained. Assuming a human knee as the CT target, good soft tissue phase contrast could be obtained at an estimated absorbed dose level around 8 mGy, similar to conventional CT. Conclusions: DPC-CT with glancing-angle interferometers provides improved soft tissue contrast over absorption CT even at clinically compatible dose levels (estimated by a Monte-Carlo computer simulation). Further steps in image processing, data reconstruction, and spectral matching could make the technique fully clinically compatible. Nevertheless, due to its increased scan time and complexity the technique should be thought of not as replacing, but as complimentary to conventional CT, to be used in specific applications.« less

Pharmacokinetics and Bioavailability of Plant Lignan 7-Hydroxymatairesinol and Effects on Serum Enterolactone and Clinical Symptoms in Postmenopausal Women: A Single-Blinded, Parallel, Dose-Comparison Study

PubMed Central

Udani, Jay K.; Brown, Donald J.; Tan, Maria Olivia C.; Hardy, Mary

2013-01-01

Objective 7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. Methods A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 post-menopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Results Pharmacokinetic studies demonstrated 7-HMR Cmax = 757.08 ng/ml at 1 hour and ENL Cmax = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. Conclusion The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population. PMID:24606716

Pharmacokinetics and bioavailability of plant lignan 7-hydroxymatairesinol and effects on serum enterolactone and clinical symptoms in postmenopausal women: a single-blinded, parallel, dose-comparison study.

PubMed

Udani, Jay K; Brown, Donald J; Tan, Maria Olivia C; Hardy, Mary

2013-01-01

7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 postmenopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Pharmacokinetic studies demonstrated 7-HMR C max = 757.08 ng/ml at 1 hour and ENL C max = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population.

Systemic levels of local anaesthetic after intra-peritoneal application--a systematic review.

PubMed

Kahokehr, A; Sammour, T; Vather, R; Taylor, M; Stapelberg, F; Hill, A G

2010-07-01

There is a lack of cohesive reports on the systemic levels of local anaesthetic after intraperitoneal application. A comprehensive systematic review with no language restriction was conducted. Eighteen suitable articles were identified. Data were compiled and presented according to local anaesthetic agent. Intraperitoneal local anaesthetic has been studied in many different procedures, including open and laparoscopic surgery. A total of 415 patients were included for analysis. There were no cases of clinical toxicity. There were 11 (2.7%) cases with a systemic level above or close to a safe threshold (as determined by the report authors) in three trials utilising intraperitoneal local anaesthetic after laparoscopic cholecystectomy. Intraperitoneal lignocaine doses varied from 100 to 1000 mg, mean Cmax ranged from 1.01 to 4.32 microg/ml and mean Tmax ranged from 15 to 40 minutes. Intraperitoneal bupivacaine doses varied from 50 to 150 mg (weight based doses also reported), mean Cmax ranged from 0.29 to 1.14 microg/ml and mean Tmax ranged from 15 to 60 minutes. Intraperitoneal ropivacaine doses varied from 100 to 300 mg, mean Cmax ranged from 0.66 to 3.76 microg/ml and mean Tmax ranged from 15 to 35 minutes. The addition of adrenaline to intraperitoneal local anaesthetic almost halves systemic levels and prolongs Tmax. Intraperitoneal local anaesthetic results in detectable systemic levels in the perioperative setting. Despite a lack of clinical toxicity, careful attention to dose is still required to prevent potential systemic toxic levels. Clinicians should also consider the addition of adrenaline to intraperitoneal local anaesthetic solutions to further add to the systemic safety profile.

Evaluation of jojoba oil as a low-energy fat. 1. A 4-week feeding study in rats.

PubMed

Verschuren, P M

1989-01-01

The nutritional properties of jojoba oil (JO) were examined in a 4-wk feeding study of rats fed a diet with JO at dose levels of 2.2, 4.5 and 9%, supplemented with a conventional fat up to 18%. General health, survival and food intake were not adversely affected. Body-weight gains showed a dose-related decline, which amounted to 20% of the body weight in the high-dose group of both sexes. Clinical chemistry revealed significantly increased levels of various enzymes that were indicative of cell damage. Haematology showed a dose-related increase in white blood cells. On necropsy an apparent distension of the small intestine was found. Histopathological evaluation revealed marked intestinal changes characterized by massive vacuolization and lipid deposition in the enterocytes, accompanied by distension of the villi and an increased cell turnover of small intestinal cells. Faeces production and faeces lipid content were increased with increasing JO levels. The recovery of JO in the faeces also increased in a dose-related manner and was found to be correlated with the intestinal histopathological changes. The significant adverse clinical and histopathological effects observed in this study imply that JO cannot be considered as a promising alternative dietary fat with a low digestibility.

Management of testosterone therapy in adolescents and young men with hypogonadism: are we following adult clinical practice guidelines?

PubMed

Nahata, Leena; Yu, Richard N; Bhasin, Shalender; Cohen, Laurie E

2015-05-01

Male hypogonadism is a common disorder that is associated with low bone density, poor muscle mass, anemia, and sexual dysfunction. The Endocrine Society recently published a Clinical Practice Guideline for testosterone therapy in androgen-deficient men. Because treatment is frequently initiated in adolescence, the goal of this quality improvement initiative was to assess whether pediatric endocrinologists at a large tertiary care center follow these guidelines and to identify opportunities for improvement. We performed a retrospective chart review at Boston Children's Hospital. Inclusion criteria were as follows: current age ≥16 years, diagnosis of hypogonadism, and testosterone replacement therapy. Data were collected about current age, age at treatment initiation, diagnoses, pre- and on-treatment testosterone levels, route of testosterone administration and dose, bone density, hematocrit levels, and adherence with therapy. Fifty-nine patients were included. Fourteen (24%) were prescribed lower testosterone doses than those recommended in the Clinical Practice Guideline. Seven (12%) had no pre-treatment testosterone levels, and 10 (17%) had no on-treatment levels. In 49 patients with on-treatment testosterone levels, 36 had at least one value that was lower than the adult reference range. Ten (28%) of the 36 men with low testosterone levels had no dose adjustments. Thirty-seven (63%) of the 59 patients had no dual-energy X-ray absorptiometry scans, and 18 (31%) did not have hematocrit levels. Pediatric endocrinologists in this review did not consistently follow the Clinical Practice Guideline for testosterone therapy in hypogonadal adult males. Strategies that improve adherence to guidelines could help maximize the benefits of therapy and minimize treatment-associated risks.

Use of allopurinol with low-dose 6-mercaptopurine in inflammatory bowel disease to achieve optimal active metabolite levels: A review of four cases and the literature

PubMed Central

Witte, Todd N; Ginsberg, Allen L

2008-01-01

BACKGROUND: At least one-third of patients with inflammatory bowel disease do not respond or are intolerant to therapy with 6-mercaptopurine (6-MP). A subgroup fails to attain optimal levels of 6-thioguanine nucleotide (6-TGN) and instead shunts to 6-methylmercaptopurine nucleotide (6-MMPN). PATIENTS AND METHODS: A retrospective chart review was conducted, and four patients are described who had been previously unable to achieve optimal 6-TGN metabolite levels until allopurinol was added to their treatment. RESULTS: All four patients achieved optimal 6-TGN levels and undetectable 6-MMPN with a mean 6-MP dose of 0.49 mg/kg. Three achieved steroid-free clinical remission. Two of those three patients had normalization of liver enzymes; one patient had baseline normal liver enzymes despite an initial 6-MMPN level of 27,369 pmol/8×108 red blood cells. Two patients experienced reversible leukopenia. CONCLUSIONS: Combination allopurinol and low-dose 6-MP is an effective means to achieve optimal metabolite levels and steroid-free clinical remission in previously refractory patients. Caution is advised. PMID:18299738

Multicentre dose audit for clinical trials of radiation therapy in Asia.

PubMed

Mizuno, Hideyuki; Fukuda, Shigekazu; Fukumura, Akifumi; Nakamura, Yuzuru-Kutsutani; Jianping, Cao; Cho, Chul-Koo; Supriana, Nana; Dung, To Anh; Calaguas, Miriam Joy; Devi, C R Beena; Chansilpa, Yaowalak; Banu, Parvin Akhter; Riaz, Masooma; Esentayeva, Surya; Kato, Shingo; Karasawa, Kumiko; Tsujii, Hirohiko

2017-05-01

A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

The comparison of microdose flare-up and multiple dose antagonist protocols based on hCG day estradiol (E2), progesterone (P) and P/E2 ratio among poor responder patients in ICSI-ET cycles.

PubMed

Cicek, M N; Kahyaoglu, I; Kahyaoglu, S

2015-02-01

Elevated progesterone levels surpassing exact treshold values impede endometrial receptivity and decrease clinical pregnancy rates in different responder patients during assisted reproductive techniques. A progesterone (P): estradiol (E2) ratio of > 1 on the day of hCG administration has also been suggested to be a manifestation of low ovarian reserve. The clinical significance of P/E2 ratio on the day of hCG administration was investigated among poor responder patients. Based on the ESHRE Bologna consensus criteria related to poor ovarian response diagnosis, 48 poor responder patients were treated with the microdose flare-up regimen and 34 patients were treated with the multiple-dose GnRH antagonist protocol. All patients were destined to perform a ICSI-ET procedure at the end of the stimulation protocols. Progesterone levels and P/E2 ratios have been detected during controlled ovarian hyperstimulation. In the microdose flare-up group; the duration of stimulation, total gonadotropin dose used and hCG day E2 levels were significantly higher than the multiple dose antagonist group. However, the mean hCG day P/E2 rate in the microdose flare-up group was less than that in the multiple-dose antagonist group. The clinical pregnancy rates were non significantly higher in the multiple dose antagonist protocol group than in microdose flare-up group. Impaired endometrial receptivity caused by elevated P levels results with lower pregnancy rates. Regardless of the selected stimulation protocol, poor responder patients are not prone to exhibit high P and E2 secretion. Increased P/E2 ratio of > 1 on hCG day has limited value to predict cycle outcomes in poor responder patients because of ovarian follicle depletion.

Ten-year oral toxicity study with Norlestrin in rhesus monkeys.

PubMed

Fitzgerald, J; de la Iglesia, F; Goldenthal, E I

1982-12-01

The long term effects of the oral contraceptive, Norlestrin, were evaluated in sexually mature female rhesus (Macaca mulatta) monkeys over a 10 year period. Norlestrin, a combination of norethindrone acetate and ethinylestradiol (50:1) was given orally on a continuous cyclic regimen of 21 d of dosing followed by 7 d without treatment. Groups of 16 monkeys each received the drug at dose levels of 0.05, 0.51, and 2.55 mg/kg representing multiples of 1, 10, and 50 times the human dose, respectively. A comparable group of 16 animals remained untreated and served as controls. Selected clinical and laboratory parameters were monitored throughout the study and all animals were necropsied and evaluated for gross and histopathologic changes. All dose levels were well tolerated and survival was not affected. There were no consistent treatment-related alterations in coagulation or other clinical laboratory parameters. Ophthalmologically, macular pigmentary anomalies were observed in all groups. Treatment-associated pathologic findings, representing exaggerated pharmacological responses with superimposed senile changes, including ovarian and uterine atrophy and dilatation of acini and ducts in the mammary gland. Periodic vaginal cytologic examination and mammary gland palpation did not demonstrate drug related changes. A small number of neoplasms was seen in all groups and a granulosa cell carcinoma of the ovary occurred in a control animal. The benign tumors consisted of three cutaneous papillomas: one in a low dose and one in a high dose animal, a uterine leiomyoma in one high dose animal, and a pancreatic duct adenoma in one low dose animal. The results of this study indicate that Norlestrin had no significant toxic manifestations or tumorigenic potential when administered on a cyclic regimen to female rhesus monkeys at levels up to 50 times the human dose for ten yr.

Aripiprazole Lauroxil

PubMed Central

Hard, Marjie L.; Mills, Richard J.; Sadler, Brian M.; Turncliff, Ryan Z.; Citrome, Leslie

2017-01-01

Abstract Background Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Methods Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. Findings The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441–882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. Conclusions This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice. PMID:28350572

Commissioning and comprehensive evaluation of the ArcCHECK cylindrical diode array for VMAT pretreatment delivery QA.

PubMed

Chaswal, Vibha; Weldon, Michael; Gupta, Nilendu; Chakravarti, Arnab; Rong, Yi

2014-07-08

We present commissioning and comprehensive evaluation for ArcCHECK as a QA equipment for volumetric-modulated arc therapy (VMAT), using the 6 MV photon beam with and without the flattening filter, and the SNC patient software (version 6.2). In addition to commissioning involving absolute dose calibration, array calibration, and PMMA density verification, ArcCHECK was evaluated for its response dependency on linac dose rate, instantaneous dose rate, radiation field size, beam angle, and couch insertion. Scatter dose characterization, consistency and symmetry of response, and dosimetry accuracy evaluation for fixed aperture arcs and clinical VMAT patient plans were also investigated. All the evaluation tests were performed with the central plug inserted and the homogeneous PMMA density value. Results of gamma analysis demonstrated an overall agreement between ArcCHECK-measured and TPS-calculated reference doses. The diode based field size dependency was found to be within 0.5% of the reference. The dose rate-based dependency was well within 1% of the TPS reference, and the angular dependency was found to be ± 3% of the reference, as tested for BEV angles, for both beams. Dosimetry of fixed arcs, using both narrow and wide field widths, resulted in clinically acceptable global gamma passing rates on the 3%/3mm level and 10% threshold. Dosimetry of narrow arcs showed an improvement over published literature. The clinical VMAT cases demonstrated high level of dosimetry accuracy in gamma passing rates.

Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer.

PubMed

Thakur, Manish K; Heilbrun, Lance; Dobson, Kimberlee; Boerner, Julie; Stark, Karri; Li, Jing; Smith, Daryn; Heath, Elisabeth; Fontana, Joseph; Vaishampayan, Ulka

2018-06-01

Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. Chemotherapy naive mCRPC patients received docetaxel 75 mg/m 2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change. The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen. Copyright © 2018 Elsevier Inc. All rights reserved.

Safety Profile during Initiation of Propranolol for Treatment of Infantile Hemangiomas in an Ambulatory Day-Care Hospitalization Setting.

PubMed

Fogel, Itay; Ollech, Ayelet; Zvulunov, Alex; Valdman-Greenshpon, Yulia; Atar-Sagie, Vered; Friedland, Rivka; Lapidoth, Moshe; Ben-Amitai, Dan

2018-03-24

Propranolol is the mainstay of treatment for infantile hemangioma. Despite its good safety profile, it is not risk-free. Guidelines for propranolol initiation and monitoring have been suggested, but protocols vary among practitioners. This study sought to assess the prevalence of adverse events and clinically significant fluctuations in hemodynamic parameters in children with infantile hemangioma during initiation of treatment with propranolol in a day-hospitalization setting. Children with infantile hemangioma treated with propranolol in a day-hospitalization department of a tertiary pediatric medical center in 2008-2014 were identified retrospectively. The pretreatment evaluation included clinical examination by a pediatric dermatologist and electrocardiography, echocardiography, and clinical examination by a pediatric cardiologist. The propranolol dosage was escalated from 0.5mg/kg/day to 2mg/kg/day, divided into 3 doses/day, over 3 days. Heart rate, blood pressure, and blood glucose level were measured before treatment onset and 60 min after the first two doses each day. The third dose was given at home. The cohort included 220 children aged 1 month to 5 years. No severe treatment-related adverse events were documented; 27 patients had minor side effects. There was a significant decrease in heart rate each day after the first two doses (p<0.001), and in systolic blood pressure, on day 2 (1mg/kg/day) after the first dose (p=0.01). Blood glucose level remained stable. The hemodynamic changes were clinically asymptomatic and did not require intervention. Propranolol treatment (2mg/kg/day in three doses) for infantile hemangioma is well tolerated and safe and may be administered and monitored in an ambulatory setting. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies.

PubMed

Zohar, Joseph; Yahalom, Hila; Kozlovsky, Nitsan; Cwikel-Hamzany, Shlomit; Matar, Michael A; Kaplan, Zeev; Yehuda, Rachel; Cohen, Hagit

2011-11-01

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100-140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a "window of opportunity" in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

PubMed

Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Crockett, R S; Howes, John; Darpo, Borje; Zhou, Meijian; Weis, Holger; Friedhoff, Lawrence

2016-11-01

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and C max and was slowly eliminated (mean t 1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. © 2016, The American College of Clinical Pharmacology.

Initial apixaban dosing in patients with atrial fibrillation.

PubMed

Buchholz, Alexander; Ueberham, Laura; Gorczynska, Kaja; Dinov, Borislav; Hilbert, Sebastian; Dagres, Nikolaos; Husser, Daniela; Hindricks, Gerhard; Bollmann, Andreas

2018-05-01

Apixaban is a non-vitamin K oral anticoagulant approved for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). Current labeling recommends dose reduction based on patient age, weight, and renal function. The aim of this study was to analyze adherence to current labeling instructions concerning initial apixaban dosing in clinical practice and identify factors associated with inappropriate dose reduction. Patients with AF initiated on apixaban in 2016 were identified in the Heart Center Leipzig database. Records were screened to identify patient characteristics, prescribed apixaban dose, renal function, and further dosing-relevant secondary diagnoses and co-medication. We identified 569 consecutive patients with AF initiated on apixaban. In 301 (52.9%) patients, apixaban was prescribed in standard dose (5 mg b.i.d.) and in 268 (47.1%) in a reduced dose (2.5 mg b.i.d.). Of 268 patients receiving a reduced dose, 163 (60.8%) did not meet labeling criteria for dose reduction. In univariate and multivariate regression analysis, age (OR: 0.736, 95% CI: 0.664-0.816, P < 0.0001), patient weight (OR: 1.120, 95% CI: 1.076-1.166, P < 0.0001), and serum creatinine level (OR: 0.910, 95% CI: 0.881-0.940, P < 0.0001) were independent predictors for apixaban underdosage. In clinical practice, apixaban dosing is frequently inconsistent with labeling. Factors associated with inappropriate dose reduction are age, patient weight, and serum creatinine level, the same factors used as criteria for dose adjustment. However, in underdosed patients, the 3 factors did not meet the criteria for dose reduction. © 2018 Wiley Periodicals, Inc.

Fluence field modulated CT on a clinical TomoTherapy radiation therapy machine

NASA Astrophysics Data System (ADS)

Szczykutowicz, Timothy P.; Hermus, James

2015-03-01

Purpose: The multi-leaf collimator (MLC) assembly present on TomoTherapy (Accuray, Madison WI) radiation therapy (RT) and mega voltage CT machines is well suited to perform fluence field modulated CT (FFMCT). In addition, there is a demand in the RT environment for FFMCT imaging techniques, specifically volume of interest (VOI) imaging. Methods: A clinical TomoTherapy machine was programmed to deliver 30% imaging dose outside predefined VOIs. Four different size ROIs were placed at varying distances from isocenter. Projections intersecting the VOI received "full dose" while those not intersecting the VOI received 30% of the dose (i.e. the incident fluence for non VOI projections was 30% of the incident fluence for projections intersecting the VOI). Additional scans without fluence field modulation were acquired at "full" and 30% dose. The noise (pixel standard deviation) was measured inside the VOI region and compared between the three scans. Results: The VOI-FFMCT technique produced an image noise 1.09, 1.05, 1.05, and 1.21 times higher than the "full dose" scan for ROI sizes of 10 cm, 13 cm, 10 cm, and 6 cm respectively within the VOI region. Conclusions: Noise levels can be almost unchanged within clinically relevant VOIs sizes for RT applications while the integral imaging dose to the patient can be decreased, and/or the image quality in RT can be dramatically increased with no change in dose relative to non-FFMCT RT imaging. The ability to shift dose away from regions unimportant for clinical evaluation in order to improve image quality or reduce imaging dose has been demonstrated. This paper demonstrates that FFMCT can be performed using the MLC on a clinical TomoTherapy machine for the first time.

Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.

PubMed

Dósa, Edit; Heltai, Krisztina; Radovits, Tamás; Molnár, Gabriella; Kapocsi, Judit; Merkely, Béla; Fu, Rongwei; Doolittle, Nancy D; Tóth, Gerda B; Urdang, Zachary; Neuwelt, Edward A

2017-10-03

Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 ± 6.8 years) received NAC IV (N = 13) or IA (N = 15). The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3 mM concentration which seemed to be nephroprotective in previous preclinical studies. In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu . Unique identifier: 2011-000887-92.

Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

PubMed

McNally, Dayre; Amrein, Karin; O'Hearn, Katharine; Fergusson, Dean; Geier, Pavel; Henderson, Matt; Khamessan, Ali; Lawson, Margaret L; McIntyre, Lauralyn; Redpath, Stephanie; Weiler, Hope A; Menon, Kusum

2017-01-01

Clinical research has recently demonstrated that vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (PICU) and associated with worse clinical course. Multiple adult ICU trials have suggested that optimization of vitamin D status through high-dose supplementation may reduce mortality and improve other clinically relevant outcomes; however, there have been no trials of rapid normalization in the PICU setting. The objective of this study is to evaluate the safety and efficacy of an enteral weight-based cholecalciferol loading dose regimen in critically ill children with VDD. The VITdAL-PICU pilot study is designed as a multicenter placebo-controlled phase II dose evaluation pilot randomized controlled trial. We aim to randomize 67 VDD critically ill children using a 2:1 randomization schema to receive loading dose enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or a placebo solution. Participants, caregivers and outcome assessors will be blinded to allocation. Eligibility criteria include ICU patient, aged 37 weeks to 18 years, expected ICU length of stay more than 48 h, anticipated access to bloodwork at 7 days, and VDD (blood total 25 hydroxyvitamin D < 50 nmol/L). The primary objective is to determine whether the dosing protocol normalizes vitamin D status, defined as a blood total 25(OH)D concentration above 75 nmol/L. Secondary objectives include an examination of the safety of the dosing regimen (e.g. hypercalcemia, hypercalciuria, nephrocalcinosis), measures of vitamin D axis function (e.g. calcitriol levels, immune function), and protocol feasibility (eligibility criteria, protocol deviations, blinding). Despite significant observational literature suggesting VDD to be a modifiable risk factor in the PICU setting, there is no robust clinical trial evidence evaluating the benefits of rapid normalization. This phase II clinical trial will evaluate an innovative weight-based dosing regimen intended to rapidly and safely normalize vitamin D levels in critically ill children. Study findings will be used to inform the design of a multicenter phase III trial evaluating the clinical and economic benefits to rapid normalization. Recruitment for this trial was initiated in January 2016 and is expected to continue until November 30, 2017. Clinicaltrials.gov NCT02452762.

Pediatric chest HRCT using the iDose4 Hybrid Iterative Reconstruction Algorithm: Which iDose level to choose?

NASA Astrophysics Data System (ADS)

Smarda, M.; Alexopoulou, E.; Mazioti, A.; Kordolaimi, S.; Ploussi, A.; Priftis, K.; Efstathopoulos, E.

2015-09-01

Purpose of the study is to determine the appropriate iterative reconstruction (IR) algorithm level that combines image quality and diagnostic confidence, for pediatric patients undergoing high-resolution computed tomography (HRCT). During the last 2 years, a total number of 20 children up to 10 years old with a clinical presentation of chronic bronchitis underwent HRCT in our department's 64-detector row CT scanner using the iDose IR algorithm, with almost similar image settings (80kVp, 40-50 mAs). CT images were reconstructed with all iDose levels (level 1 to 7) as well as with filtered-back projection (FBP) algorithm. Subjective image quality was evaluated by 2 experienced radiologists in terms of image noise, sharpness, contrast and diagnostic acceptability using a 5-point scale (1=excellent image, 5=non-acceptable image). Artifacts existance was also pointed out. All mean scores from both radiologists corresponded to satisfactory image quality (score ≤3), even with the FBP algorithm use. Almost excellent (score <2) overall image quality was achieved with iDose levels 5 to 7, but oversmoothing artifacts appearing with iDose levels 6 and 7 affected the diagnostic confidence. In conclusion, the use of iDose level 5 enables almost excellent image quality without considerable artifacts affecting the diagnosis. Further evaluation is needed in order to draw more precise conclusions.

A random walk rule for phase I clinical trials.

PubMed

Durham, S D; Flournoy, N; Rosenberger, W F

1997-06-01

We describe a family of random walk rules for the sequential allocation of dose levels to patients in a dose-response study, or phase I clinical trial. Patients are sequentially assigned the next higher, same, or next lower dose level according to some probability distribution, which may be determined by ethical considerations as well as the patient's response. It is shown that one can choose these probabilities in order to center dose level assignments unimodally around any target quantile of interest. Estimation of the quantile is discussed; the maximum likelihood estimator and its variance are derived under a two-parameter logistic distribution, and the maximum likelihood estimator is compared with other nonparametric estimators. Random walk rules have clear advantages: they are simple to implement, and finite and asymptotic distribution theory is completely worked out. For a specific random walk rule, we compute finite and asymptotic properties and give examples of its use in planning studies. Having the finite distribution theory available and tractable obviates the need for elaborate simulation studies to analyze the properties of the design. The small sample properties of our rule, as determined by exact theory, compare favorably to those of the continual reassessment method, determined by simulation.

SU-E-T-175: Clinical Evaluations of Monte Carlo-Based Inverse Treatment Plan Optimization for Intensity Modulated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chi, Y; Li, Y; Tian, Z

2015-06-15

Purpose: Pencil-beam or superposition-convolution type dose calculation algorithms are routinely used in inverse plan optimization for intensity modulated radiation therapy (IMRT). However, due to their limited accuracy in some challenging cases, e.g. lung, the resulting dose may lose its optimality after being recomputed using an accurate algorithm, e.g. Monte Carlo (MC). It is the objective of this study to evaluate the feasibility and advantages of a new method to include MC in the treatment planning process. Methods: We developed a scheme to iteratively perform MC-based beamlet dose calculations and plan optimization. In the MC stage, a GPU-based dose engine wasmore » used and the particle number sampled from a beamlet was proportional to its optimized fluence from the previous step. We tested this scheme in four lung cancer IMRT cases. For each case, the original plan dose, plan dose re-computed by MC, and dose optimized by our scheme were obtained. Clinically relevant dosimetric quantities in these three plans were compared. Results: Although the original plan achieved a satisfactory PDV dose coverage, after re-computing doses using MC method, it was found that the PTV D95% were reduced by 4.60%–6.67%. After re-optimizing these cases with our scheme, the PTV coverage was improved to the same level as in the original plan, while the critical OAR coverages were maintained to clinically acceptable levels. Regarding the computation time, it took on average 144 sec per case using only one GPU card, including both MC-based beamlet dose calculation and treatment plan optimization. Conclusion: The achieved dosimetric gains and high computational efficiency indicate the feasibility and advantages of the proposed MC-based IMRT optimization method. Comprehensive validations in more patient cases are in progress.« less

Diagnostic accuracy at several reduced radiation dose levels for CT imaging in the diagnosis of appendicitis

NASA Astrophysics Data System (ADS)

Zhang, Di; Khatonabadi, Maryam; Kim, Hyun; Jude, Matilda; Zaragoza, Edward; Lee, Margaret; Patel, Maitraya; Poon, Cheryce; Douek, Michael; Andrews-Tang, Denise; Doepke, Laura; McNitt-Gray, Shawn; Cagnon, Chris; DeMarco, John; McNitt-Gray, Michael

2012-03-01

Purpose: While several studies have investigated the tradeoffs between radiation dose and image quality (noise) in CT imaging, the purpose of this study was to take this analysis a step further by investigating the tradeoffs between patient radiation dose (including organ dose) and diagnostic accuracy in diagnosis of appendicitis using CT. Methods: This study was IRB approved and utilized data from 20 patients who underwent clinical CT exams for indications of appendicitis. Medical record review established true diagnosis of appendicitis, with 10 positives and 10 negatives. A validated software tool used raw projection data from each scan to create simulated images at lower dose levels (70%, 50%, 30%, 20% of original). An observer study was performed with 6 radiologists reviewing each case at each dose level in random order over several sessions. Readers assessed image quality and provided confidence in their diagnosis of appendicitis, each on a 5 point scale. Liver doses at each case and each dose level were estimated using Monte Carlo simulation based methods. Results: Overall diagnostic accuracy varies across dose levels: 92%, 93%, 91%, 90% and 90% across the 100%, 70%, 50%, 30% and 20% dose levels respectively. And it is 93%, 95%, 88%, 90% and 90% across the 13.5-22mGy, 9.6-13.5mGy, 6.4-9.6mGy, 4-6.4mGy, and 2-4mGy liver dose ranges respectively. Only 4 out of 600 observations were rated "unacceptable" for image quality. Conclusion: The results from this pilot study indicate that the diagnostic accuracy does not change dramatically even at significantly reduced radiation dose.

Extrapolating theoretical efficacy of inactivated influenza A/H5N1 virus vaccine from human immunogenicity studies

PubMed Central

Feldstein, Leora R.; Matrajt, Laura; Halloran, M. Elizabeth; Keitel, Wendy A.; Longini, Ira M.

2016-01-01

Influenza A virus subtype H5N1 has been a public health concern for almost 20 years due to its potential ability to become transmissible among humans. Phase I and II clinical trials have assessed safety, reactogenicity and immunogenicity of inactivated influenza A/H5N1 virus vaccines. A shortage of vaccine is likely to occur during the first months of a pandemic. Hence, determining whether to give one dose to more people or two doses to fewer people to best protect the population is essential. We use hemagglutination-inhibition antibody titers as an immune correlate for avian influenza vaccines. Using an established relationship to obtain a theoretical vaccine efficacy from immunogenicity data from thirteen arms of six phase I and phase II clinical trials of inactivated influenza A/H5N1 virus vaccines, we assessed: 1) the proportion of theoretical vaccine efficacy achieved after a single dose (defined as primary response level), and 2) whether theoretical efficacy increases after a second dose, with and without adjuvant. Participants receiving vaccine with AS03 adjuvant had higher primary response levels (range: 0.48–0.57) compared to participants receiving vaccine with MF59 adjuvant (range: 0.32–0.47), with no observed trends in primary response levels by antigen dosage. After the first and second doses, vaccine with AS03 at dosage levels 3.75, 7.5 and 15 mcg had the highest estimated theoretical vaccine efficacy: Dose 1) 45% (95%CI: 36–57%), 53% (95%CI: 42–63%) and 55% (95%CI: 44–64%), respectively and Dose 2) 93% (95%CI: 89–96%), 97% (95%CI: 95–98%) and 97% (95%CI: 96–100%), respectively. On average, the estimated theoretical vaccine efficacy of lower dose adjuvanted vaccines (AS03 and MF59) was 17% higher than that of higher dose unadjuvanted vaccines, suggesting that including an adjuvant is dose-sparing. These data indicate adjuvanted inactivated influenza A/H5N1 virus vaccine produces high theoretical efficacy after two doses to protect individuals against a potential avian influenza pandemic. PMID:27268778

Physics must join with biology in better assessing risk from low-dose irradiation.

PubMed

Feinendegen, L E; Neumann, R D

2005-01-01

This review summarises the complex response of mammalian cells and tissues to low doses of ionising radiation. This thesis encompasses induction of DNA damage, and adaptive protection against both renewed damage and against propagation of damage from the basic level of biological organisation to the clinical expression of detriment. The induction of DNA damage at low radiation doses apparently is proportional to absorbed dose at the physical/chemical level. However, any propagation of such damage to higher levels of biological organisation inherently follows a sigmoid function. Moreover, low-dose-induced inhibition of damage propagation is not linear, but instead follows a dose-effect function typical for adaptive protection, after an initial rapid rise it disappears at doses higher than approximately 0.1-0.2 Gy to cells. The particular biological response duality at low radiation doses precludes the validity of the linear-no-threshold hypothesis in the attempt to relate absorbed dose to cancer. In fact, theory and observation support not only a lower cancer incidence than expected from the linear-no-threshold hypothesis, but also a reduction of spontaneously occurring cancer, a hormetic response, in the healthy individual.

Exercise-Induced Dose-Response Alterations in Adiponectin and Leptin Levels Are Dependent on Body Fat Changes in Women at Risk for Breast Cancer.

PubMed

Sturgeon, Kathleen; Digiovanni, Laura; Good, Jerene; Salvatore, Domenick; Fenderson, Desiré; Domchek, Susan; Stopfer, Jill; Galantino, Mary Lou; Bryan, Cathy; Hwang, Wei-Ting; Schmitz, Kathryn

2016-08-01

Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer. A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up. We observed significant linear trends for increased fitness capacity (Δ%: -2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, -2.9% low dose, -3.7% high dose), increased body fat adjusted adiponectin (Δ%: -0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, -8.2% low dose, -10.2% high dose). In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose-response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat. Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195-200. ©2016 AACR. ©2016 American Association for Cancer Research.

Dose reduction potential of iterative reconstruction algorithms in neck CTA-a simulation study.

PubMed

Ellmann, Stephan; Kammerer, Ferdinand; Allmendinger, Thomas; Brand, Michael; Janka, Rolf; Hammon, Matthias; Lell, Michael M; Uder, Michael; Kramer, Manuel

2016-10-01

This study aimed to determine the degree of radiation dose reduction in neck CT angiography (CTA) achievable with Sinogram-affirmed iterative reconstruction (SAFIRE) algorithms. 10 consecutive patients scheduled for neck CTA were included in this study. CTA images of the external carotid arteries either were reconstructed with filtered back projection (FBP) at full radiation dose level or underwent simulated dose reduction by proprietary reconstruction software. The dose-reduced images were reconstructed using either SAFIRE 3 or SAFIRE 5 and compared with full-dose FBP images in terms of vessel definition. 5 observers performed a total of 3000 pairwise comparisons. SAFIRE allowed substantial radiation dose reductions in neck CTA while maintaining vessel definition. The possible levels of radiation dose reduction ranged from approximately 34 to approximately 90% and depended on the SAFIRE algorithm strength and the size of the vessel of interest. In general, larger vessels permitted higher degrees of radiation dose reduction, especially with higher SAFIRE strength levels. With small vessels, the superiority of SAFIRE 5 over SAFIRE 3 was lost. Neck CTA can be performed with substantially less radiation dose when SAFIRE is applied. The exact degree of radiation dose reduction should be adapted to the clinical question, in particular to the smallest vessel needing excellent definition.

Safety of docosahexaenoic acid (DHA) administered as DHA ethyl ester in a 9-month toxicity study in dogs.

PubMed

Dahms, Irina; Beilstein, Paul; Bonnette, Kimberly; Salem, Norman

2016-06-01

DHA Ethyl Ester (DHA-EE) is a 90% concentrated ethyl ester of docosahexaenoic acid manufactured from the microalgal oil. The objective of the 9-month study was to evaluate safety of DHA-EE administered to beagle dogs at dose levels 150, 1000 and 2000 mg/kg bw/day by oral gavage and to determine reversibility of any findings after a 2-month recovery period. DHA-EE was well tolerated at all doses. There were observations of dry flaky skin with occasional reddened areas at doses ≥1000 mg/kg bw/day. These findings lacked any microscopic correlate and were no longer present after the recovery period. There were no toxicologically relevant findings in body weights, body weight gains, food consumption, ophthalmological examinations, and ECG measurements. Test article-related changes in hematology parameters were limited to decreases in reticulocyte count in the high-dose males and considered non-adverse. In clinical chemistry parameters, dose-related decreases in cholesterol and triglycerides levels were observed at all doses in males and females and attributed to the known lipid-lowering effects of DHA. There were no effects on other clinical chemistry, urinalysis or coagulation parameters. There were no abnormal histopathology findings attributed to test article. The No-Observable-Adverse-Effect Level of DHA-EE was established at 2000 mg/kg bw/day for both genders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Measuring Adolescent Human Papillomavirus Vaccine Coverage: A Match of Sexually Transmitted Disease Clinic and Immunization Registry Data.

PubMed

Pathela, Preeti; Jamison, Kelly; Papadouka, Vikki; Kabir, Rezaul; Markowitz, Lauri E; Dunne, Eileen F; Schillinger, Julia A

2016-12-01

Human papillomavirus (HPV) vaccine is recommended for adolescents. By the end of 2013, 64% of female and 40% of male New York City residents aged 13-18 years had received ≥1 HPV vaccine dose. Adolescents attending sexually transmitted disease (STD) clinics are at high risk for HPV exposure and could benefit from vaccination. Our objective was to estimate HPV vaccination coverage for this population. We matched records of New York City's STD clinic patients aged 13-18 years during 2010-2013 with the Citywide Immunization Registry. We assessed HPV vaccine initiation (≥1 dose) and series completion (≥3 doses among those who initiated) as of clinic visit date and by patient demographics. We compared receipt of ≥1 dose for HPV, tetanus-diphtheria-acellular pertussis, and meningococcal conjugate vaccine. Eighty-two percent of clinic attendees (13,505/16,364) had records in the Citywide Immunization Registry. Receipt of ≥1 HPV dose increased during 2010-2013 (females: 57.6%-69.7%; males: 1.5%-36.3%). Among females, ≥1-dose coverage was lowest among whites (53.4%) and highest among Hispanics (73.3%); among males, ≥1-dose coverage was lowest among whites (6.9%) and highest among Asians (20.9%). Series completion averaged 57.7% (females) and 28.0% (males), with little variation by race/ethnicity or poverty level. Receipt of ≥1 dose was 59.7% for HPV, 82% for tetanus-diphtheria-acellular pertussis, and 76% for meningococcal conjugate vaccines. HPV vaccine initiation and completion were low among adolescent STD clinic patients; coverage was lower compared with other recommended vaccines. STD clinics may be good venues for delivering HPV vaccine, thereby enhancing efforts to improve HPV vaccination. Copyright © 2016 Society for Adolescent Health and Medicine. All rights reserved.

Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism.

PubMed

Shimatsu, Akira; Teramoto, Akira; Hizuka, Naomi; Kitai, Kazuo; Ramis, Joaquim; Chihara, Kazuo

2013-01-01

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma.

PubMed

Saeki, Issei; Yamamoto, Naoki; Yamasaki, Takahiro; Takami, Taro; Maeda, Masaki; Fujisawa, Koichi; Iwamoto, Takuya; Matsumoto, Toshihiko; Hidaka, Isao; Ishikawa, Tsuyoshi; Uchida, Koichi; Tani, Kenji; Sakaida, Isao

2016-10-28

To evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies. In the basic study, the effect of DFX was investigated in three hepatoma cell lines (HepG2, Hep3B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity (according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced. Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent manner in vitro . In the murine model, DFX treatment significantly suppressed the development of liver tumors ( P < 0.01), and significantly upregulated the mRNA expression levels of hepcidin ( P < 0.05), transferrin receptor 1 ( P < 0.05), and hypoxia inducible factor-1α ( P < 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%. We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.

Effects of Epoetin Alfa Titration Practices, Implemented After Changes to Product Labeling, on Hemoglobin Levels, Transfusion Use, and Hospitalization Rates.

PubMed

Molony, Julia T; Monda, Keri L; Li, Suying; Beaubrun, Anne C; Gilbertson, David T; Bradbury, Brian D; Collins, Allan J

2016-08-01

Little is known about epoetin alfa (EPO) dosing at dialysis centers after implementation of the US Medicare prospective payment system and revision of the EPO label in 2011. Retrospective cohort study. Approximately 412,000 adult hemodialysis patients with Medicare Parts A and B as primary payer in 2009 to 2012 to describe EPO dosing and hemoglobin patterns; of these, about 70,000 patients clustered in about 1,300 dialysis facilities to evaluate facility-level EPO titration practices and patient-level outcomes in 2012. Facility EPO titration practices when hemoglobin levels were <10 and >11g/dL (grouped treatment variable) determined from monthly EPO dosing and hemoglobin level patterns. Patient mean hemoglobin levels, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates using a facility-based analysis. Monthly EPO dose and hemoglobin level, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates. Monthly EPO doses declined across all hemoglobin levels, with the greatest decline in patients with hemoglobin levels < 10g/dL (July-October 2011). In 2012, nine distinct facility titration practices were identified. Across groups, mean hemoglobin levels differed slightly (10.5-10.8g/dL) but within-patient hemoglobin standard deviations were similar (∼0.68g/dL). Patients at facilities implementing greater dose reductions and smaller dose escalations had lower hemoglobin levels and higher transfusion rates. In contrast, patients at facilities that implemented greater dose escalations (and large or small dose reductions) had higher hemoglobin levels and lower transfusion rates. There were no clinically meaningful differences in all-cause or cause-specific hospitalization events across groups. Possibly incomplete claims data; excluded small facilities and those without consistent titration patterns; hemoglobin levels reported monthly; inferred facility practice from observed dosing. Following prospective payment system implementation and labeling revisions, EPO doses declined significantly. Under the new label, facility EPO titration practices were associated with mean hemoglobin levels (but not standard deviations) and transfusion use, but not hospitalization rates. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Clinical impact of dosimetric changes for volumetric modulated arc therapy in log file-based patient dose calculations.

PubMed

Katsuta, Yoshiyuki; Kadoya, Noriyuki; Fujita, Yukio; Shimizu, Eiji; Matsunaga, Kenichi; Matsushita, Haruo; Majima, Kazuhiro; Jingu, Keiichi

2017-10-01

A log file-based method cannot detect dosimetric changes due to linac component miscalibration because log files are insensitive to miscalibration. Herein, clinical impacts of dosimetric changes on a log file-based method were determined. Five head-and-neck and five prostate plans were applied. Miscalibration-simulated log files were generated by inducing a linac component miscalibration into the log file. Miscalibration magnitudes for leaf, gantry, and collimator at the general tolerance level were ±0.5mm, ±1°, and ±1°, respectively, and at a tighter tolerance level achievable on current linac were ±0.3mm, ±0.5°, and ±0.5°, respectively. Re-calculations were performed on patient anatomy using log file data. Changes in tumor control probability/normal tissue complication probability from treatment planning system dose to re-calculated dose at the general tolerance level was 1.8% on planning target volume (PTV) and 2.4% on organs at risk (OARs) in both plans. These changes at the tighter tolerance level were improved to 1.0% on PTV and to 1.5% on OARs, with a statistically significant difference. We determined the clinical impacts of dosimetric changes on a log file-based method using a general tolerance level and a tighter tolerance level for linac miscalibration and found that a tighter tolerance level significantly improved the accuracy of the log file-based method. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Targeting MRS-Defined Dominant Intraprostatic Lesions with Inverse-Planned High Dose Rate Brachytherapy

DTIC Science & Technology

2008-06-01

brachytherapy treatment planning has been demonstrated. Using the inverse planning program IPSA , dose escalation of target regions with a higher tumor...algorithm (called IPSA ) was used to generate dose distributions for five different levels of DIL- boost, at least 110%, 120%, 130%, 140% and 150...and LDR, VI Last Generation Radiotherapy Course, São Paulo, Brazil, Oct. 19, 2006. Principles and Clinical Applications of IPSA ; Nucletron

The clinical effect and tolerability of ezetimibe in high-risk patients managed in a specialty cardiovascular risk reduction clinic

PubMed Central

Pearson, Glen J; Francis, Gordon A; Romney, Jacques S; Gilchrist, Dawna M; Opgenorth, Andrea; Gyenes, Gabor T

2006-01-01

INTRODUCTION Ezetimibe (EZ) is a selective cholesterol absorption inhibitor approved for use in Canada. The effect and tolerability of EZ among patients was evaluated in the clinical setting of a specialty cardiovascular risk reduction clinic at the University of Alberta Hospital, Edmonton, Alberta. PATIENTS AND METHODS All patients 18 years of age or older who were prescribed EZ were included, unless they failed to take EZ for a minimum of two weeks, did not have baseline and on-EZ low-density lipoprotein cholesterol (LDL-C) levels, or had concomitant lipid-lowering drugs or dosages changed within one month of starting EZ. RESULTS Eighty-four patients (mean age 57.9 years) were included. By Framingham risk calculation, 71.4% were found to be high-risk patients, 13.1% moderate-risk patients and 15.5% low-risk patients; 66.7% of patients had prior cardiovascular events. On EZ, the mean reductions were: total cholesterol level 1.11 mmol/L (16.5%); LDL-C level 1.01 mmol/L (22.3%); high-density lipoprotein cholesterol level 0.06 mmol/L (4.6%); and ratio of total cholesterol level to high-density lipoprotein cholesterol level 0.68 mmol/L (12.8%); all were statistically significant (P<0.001). Results were similar when stratified by primary (n=28) versus secondary (n=56) prevention. Patients on EZ monotherapy (n=34) had mean LDL-C reductions of 1.03 mmol/L (20.5%) compared with 1.19 mmol/L (30.1%) or 0.95 mmol/L (22.5%), where EZ was added to low-dose or high-dose statins (P<0.01 for all). On EZ, 30 patients (35.7%) achieved previously unattainable target LDL-C levels. Four patients discontinued the drug due to side effects. CONCLUSIONS EZ is safe and effective in high-risk patients treated in the clinical setting of a cardiovascular risk reduction clinic. A mean LDL-C reduction of 1 mmol/L (20% to 30%) in all patient subgroups is consistent with previous clinical trial results. The significant reduction in LDL-C (mean 22.5%) observed in the EZ plus high-dose statin subgroup provides clinical evidence for use of this medication beyond published studies. PMID:16971979

Eye dose to staff involved in interventional and procedural fluoroscopy

NASA Astrophysics Data System (ADS)

McLean, D.; Hadaya, D.; Tse, J.

2016-03-01

In 2011 the International Commission on Radiological Protection (ICRP) lowered the occupational eye dose limit from 150 to 20 mSv/yr [1]. While international jurisdictions are in a process of adopting these substantial changes, medical physicists at the clinical level have been advising medical colleagues on specific situations based on dose measurements. Commissioned and calibrated TLDs mounted in commercially available holders designed to simulate the measurement of Hp(3), were applied to staff involved in x-ray procedures for a one month period. During this period clinical procedure data was concurrently collected and subject to audit. The use or not of eye personal protective equipment (PPE) was noted for all staff. Audits were conducted in the cardiac catheterisation laboratory, the interventional angiography rooms and the procedural room where endoscopic retrograde cholangiopancreatography (ERCP) procedures are performed. Significant levels of occupational dose were recorded in the cardiac and interventional procedures, with maximum reading exceeding the new limit for some interventional radiologists. No significant eye doses were measured for staff performing ERCP procedures. One outcome of the studies was increased use of eye PPE for operators of interventional equipment with increased availability also to nursing staff, when standing in close proximity to the patient during procedures.

Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia.

PubMed

Hard, Marjie L; Mills, Richard J; Sadler, Brian M; Turncliff, Ryan Z; Citrome, Leslie

2017-06-01

Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Managing statin-induced muscle toxicity in a lipid clinic.

PubMed

Blaier, O; Lishner, M; Elis, A

2011-06-01

Muscle toxicity is the most significant adverse effect related to statins. The aim of the study was to analyse the clinical course and achievement of LDL-C target levels in patients with statin-induced muscle toxicity. All patients who were referred to the lipid clinic because of statin-induced muscle toxicity, or developed it during follow-up, or did not reach LDL-C target levels because of its previous occurrence, and attended the clinic for at least three follow-up visits, were eligible. Files were reviewed for demographic and clinical parameters, coronary heart disease risk level, the severity of muscle injury, the type of statin and dose that caused the adverse effects, the clinical approach and outcome, and whether the LDL-C target level was achieved. The study group consisted of 54 patients. Twenty-three (43%) patients complained of myalgia, 23 (43%) had asymptomatic serum creatine kinase (CK) level elevation, five (9%) had myopathy and three (5%) had rhabdomyolysis. Fifty of the patients (93%) continued statin therapy and 43 (80%) achieved the LDL-C target level. We show that for the majority of patients with statin-induced muscle toxicity, statin therapy can be safely and effectively continued. In cases of asymptomatic CK levels <3-5 upper limit of normal (ULN), statin treatment should not be interrupted. When CK levels >3-5 ULN or when various symptomatic muscle adverse reactions are present, statins rechallenge, after a recovery period, should be individualized either by a low dose of a potent statin or by a less potent statin. An additional lipid medication is advised if the target levels are not achieved. © 2011 Blackwell Publishing Ltd.

How Does Patient Radiation Exposure Compare With Low-dose O-arm Versus Fluoroscopy for Pedicle Screw Placement in Idiopathic Scoliosis?

PubMed

Su, Alvin W; McIntosh, Amy L; Schueler, Beth A; Milbrandt, Todd A; Winkler, Jennifer A; Stans, Anthony A; Larson, A Noelle

Intraoperative C-arm fluoroscopy and low-dose O-arm are both reasonable means to assist in screw placement for idiopathic scoliosis surgery. Both using pediatric low-dose O-arm settings and minimizing the number of radiographs during C-arm fluoroscopy guidance decrease patient radiation exposure and its deleterious biological effect that may be associated with cancer risk. We hypothesized that the radiation dose for C-arm-guided fluoroscopy is no less than low-dose O-arm scanning for placement of pedicle screws. A multicenter matched-control cohort study of 28 patients in total was conducted. Fourteen patients who underwent O-arm-guided pedicle screw insertion for spinal fusion surgery in 1 institution were matched to another 14 patients who underwent C-arm fluoroscopy guidance in the other institution in terms of the age of surgery, body weight, and number of imaged spine levels. The total effective dose was compared. A low-dose pediatric protocol was used for all O-arm scans with an effective dose of 0.65 mSv per scan. The effective dose of C-arm fluoroscopy was determined using anthropomorphic phantoms that represented the thoracic and lumbar spine in anteroposterior and lateral views, respectively. The clinical outcome and complications of all patients were documented. The mean total effective dose for the O-arm group was approximately 4 times higher than that of the C-arm group (P<0.0001). The effective dose for the C-arm patients had high variability based on fluoroscopy time and did not correlate with the number of imaged spine levels or body weight. The effective dose of 1 low-dose pediatric O-arm scan approximated 85 seconds of the C-arm fluoroscopy time. All patients had satisfactory clinical outcomes without major complications that required returning to the operating room. Radiation exposure required for O-arm scans can be higher than that required for C-arm fluoroscopy, but it depends on fluoroscopy time. Inclusion of more medical centers and surgeons will better account for the variability of C-arm dose due to distinct patient characteristics, surgeon's preference, and individual institution's protocol. Level III-case-control study.

On the feasibility of utilizing active personal dosimeters worn on the chest to estimate occupational eye lens dose in x-ray angiography.

PubMed

Omar, Artur; Marteinsdottir, Maria; Kadesjö, Nils; Fransson, Annette

2015-06-01

The International Commission on Radiological Protection (ICRP) has recommended that the occupational dose limit to the eye lens be substantially reduced. To ensure compliance with these recommendations, monitoring of the occupational eye lens dose is essential in certain hospital work environments. For assessment of the eye lens dose it is recommended to use a supplementary dosimeter placed at a position adjacent to the eye(s). Wearing a dosimeter at eye level can, however, be impractical and distributing and managing additional dosimeters over long periods of time is cumbersome and costly for large clinical sites. An attractive alternative is to utilize active personal dosimeters (APDs), which are routinely used by clinical staff for real-time monitoring of the personal dose equivalent rate (H(p)(10)). In this work, a formalism for the determination of eye lens dose from the response of such APD's worn on the chest is proposed and evaluated. The evaluation is based on both phantom and clinical measurements performed in an x-ray angiography suite for interventional cardiology. The main results show that the eye lens dose to the primary operator and to the assisting clinical staff can be conservatively estimated from the APD response as D(eye)(conductor) = 2.0 APD chest and D(eye)(assisting) = 1.0 APD chest, respectively. However, care should be exercised for particularly short assisting staff and if radiation protection shields are misused. These concerns can be greatly mitigated if the clinical staff are provided with adequate radiation protection training.

Dose Calculation Evolution for Internal Organ Irradiation in Humans

NASA Astrophysics Data System (ADS)

Jimenez V., Reina A.

2007-10-01

The International Commission of Radiation Units (ICRU) has established through the years, a discrimination system regarding the security levels on the prescription and administration of doses in radiation treatments (Radiotherapy, Brach therapy, Nuclear Medicine). The first level is concerned with the prescription and posterior assurance of dose administration to a point of interest (POI), commonly located at the geometrical center of the region to be treated. In this, the effects of radiation around that POI, is not a priority. The second level refers to the dose specifications in a particular plane inside the patient, mostly the middle plane of the lesion. The dose is calculated to all the structures in that plane regardless if they are tumor or healthy tissue. In this case, the dose is not represented by a point value, but by level curves called "isodoses" as in a topographic map, so you can assure the level of doses to this particular plane, but it also leave with no information about how this values go thru adjacent planes. This is why the third level is referred to the volumetrical description of doses so these isodoses construct now a volume (named "cloud") that give us better assurance about tissue irradiation around the volume of the lesion and its margin (sub clinical spread or microscopic illness). This work shows how this evolution has resulted, not only in healthy tissue protection improvement but in a rise of tumor control, quality of life, better treatment tolerance and minimum permanent secuelae.

Coenzyme Q10 and vitamin E deficiency in Friedreich's ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy.

PubMed

Cooper, J M; Korlipara, L V P; Hart, P E; Bradley, J L; Schapira, A H V

2008-12-01

A pilot study of high dose coenzyme Q(10) (CoQ(10))/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial. Fifty FRDA patients were randomly divided into high or low dose CoQ(10)/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data. At baseline serum CoQ(10) and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ(10) and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ(10) levels. A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.

Feasibility of the Utilization of BNCT in the Fast Neutron Therapy Beam at Fermilab

DOE R&D Accomplishments Database

Langen, Katja; Lennox, Arlene J.; Kroc, Thomas K.; DeLuca, Jr., Paul M.

2000-06-01

The Neutron Therapy Facility at Fermilab has treated cancer patients since 1976. Since then more than 2,300 patients have been treated and a wealth of clinical information accumulated. The therapeutic neutron beam at Fermilab is produced by bombarding a beryllium target with 66 MeV protons. The resulting continuous neutron spectrum ranges from thermal to 66 MeV in neutron energy. It is clear that this spectrum is not well suited for the treatment of tumors with boron neutron capture therapy (BNCT) only However, since this spectrum contains thermal and epithermal components the authors are investigating whether BNCT can be used in this beam to boost the tumor dose. There are clinical scenarios in which a selective tumor dose boost of 10 - 15% could be clinically significant. For these cases the principal treatment would still be fast neutron therapy but a tumor boost could be used either to deliver a higher dose to the tumor tissue or to reduce the dose to the normal healthy tissue while maintaining the absorbed dose level in the tumor tissue.

Commissioning and comprehensive evaluation of the ArcCHECK cylindrical diode array for VMAT pretreatment delivery QA

PubMed Central

Chaswal, Vibha; Weldon, Michael; Gupta, Nilendu; Chakravarti, Arnab

2014-01-01

We present commissioning and comprehensive evaluation for ArcCHECK as a QA equipment for volumetric‐modulated arc therapy (VMAT), using the 6 MV photon beam with and without the flattening filter, and the SNC patient software (version 6.2). In addition to commissioning involving absolute dose calibration, array calibration, and PMMA density verification, ArcCHECK was evaluated for its response dependency on linac dose rate, instantaneous dose rate, radiation field size, beam angle, and couch insertion. Scatter dose characterization, consistency and symmetry of response, and dosimetry accuracy evaluation for fixed aperture arcs and clinical VMAT patient plans were also investigated. All the evaluation tests were performed with the central plug inserted and the homogeneous PMMA density value. Results of gamma analysis demonstrated an overall agreement between ArcCHECK‐measured and TPS‐calculated reference doses. The diode based field size dependency was found to be within 0.5% of the reference. The dose rate‐based dependency was well within 1% of the TPS reference, and the angular dependency was found to be ± 3% of the reference, as tested for BEV angles, for both beams. Dosimetry of fixed arcs, using both narrow and wide field widths, resulted in clinically acceptable global gamma passing rates on the 3%/3 mm level and 10% threshold. Dosimetry of narrow arcs showed an improvement over published literature. The clinical VMAT cases demonstrated high level of dosimetry accuracy in gamma passing rates. PACS numbers: 87.56.Fc, 87.55.kh, 87.55.Qr PMID:25207411

Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach.

PubMed

van den Broek, M P H; Groenendaal, F; Toet, M C; van Straaten, H L M; van Hasselt, J G C; Huitema, A D R; de Vries, L S; Egberts, A C G; Rademaker, C M A

2012-10-01

Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66%. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma

PubMed Central

Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno

2017-01-01

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans’ solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas. PMID:28505195

A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity.

PubMed

Heetla, H W; Proost, J H; Molmans, B H; Staal, M J; van Laar, T

2016-01-01

Intrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations and clinical effects after administration of various ITB boluses in patients with spasticity and to create a PKPD model for ITB. Twelve patients with severe spasticity received four different bolus doses of ITB (0, 25, 50, 75 μg and an optional dose of 100 μg), administered via a catheter with the tip at thoracic level (Th) 10. After each bolus, 10 CSF samples were taken at fixed time intervals, using a catheter with the tip located at Th12. Clinical effect was assessed by measuring spasticity with the Modified Ashworth Scale (MAS). These data were used to develop a PKPD model. All patients achieved an adequate spasmolytic effect with ITB doses varying from 50 to 100 μg. No serious side effects were observed. CSF baclofen concentrations, as well as the clinical effects, correlated significantly with ITB doses. The PK model predicted a steep spinal concentration gradient of ITB along the spinal axis. The clinical effect could be predicted using a delayed-effect model. ITB is an effective and safe therapy with, however, a steep concentration gradient along the spinal axis. This means that the administered baclofen is staying mainly around the catheter tip, which stresses the importance to position the ITB catheter tip closely to the targeted spinal level. © 2015 The British Pharmacological Society.

Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brade, Anthony M., E-mail: anthony.brade@rmp.uhn.on.ca; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario; Ng, Sylvia

Purpose: To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). Methods and Materials: Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated.more » Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. Results: Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level −1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. Conclusions: Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.« less

ATG-Fresenius treatment and low-dose tacrolimus: results of a randomized controlled trial in liver transplantation.

PubMed

Benítez, C E; Puig-Pey, I; López, M; Martínez-Llordella, M; Lozano, J J; Bohne, F; Londoño, M C; García-Valdecasas, J C; Bruguera, M; Navasa, M; Rimola, A; Sánchez-Fueyo, A

2010-10-01

We report the results of a prospective randomized controlled trial in liver transplantation assessing the efficacy and safety of antithymocyte globulin (ATG-Fresenius) plus tacrolimus monotherapy at gradually decreasing doses. Patients were randomized to either: (a) standard-dose tacrolimus plus steroids;or (b) peritransplant ATG-Fresenius plus reduced-dose tacrolimus monotherapy followed by weaning of tacrolimus starting 3 months after transplantation. The primary end-point was the achievement of very low-dose tacrolimus (every-other-day or once daily dose with <5 ng/mL trough levels) at 12 months after transplantation. Acute rejection occurring during the first 3 months after transplantation was more frequent in the ATG group (52.4% vs. 25%). Moreover, late acute rejection episodes occurred in all recipients in whom weaning was attempted and no recipients reached the primary end-point. This motivated the premature termination of the trial. Tacrolimus trough levels were lower in the ATG-Fresenius group but no benefits in terms of improved renal function, lower metabolic complications or increased prevalence of tolerance-related biomarkers were observed. In conclusion, the use of ATG-Fresenius and tacrolimus at gradually decreasing doses was associated with a high rate of rejection, did not allow for the administration of very low doses of tacrolimus and failed to provide detectable clinical benefits. ClinicalTrials.gov identifier: NCT00436722. © 2010 The Authors Journal compilation © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.

SU-F-T-379: Dosimetric Impacts of Topical Agents and Dressings On Skin in Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tse, K; Morley, L; Cashell, A

Purpose: This study investigated the superficial dose enhancement in the application of topical agents, clinical materials (thermal mask and bolus) and dressings in megavoltage photon beam radiotherapy. Different topical skin agents, clinical materials and dressings were evaluated and compared for their skin dosimetric impacts on the patients during radiation treatment. Methods: Superficial dose enhancements, or percentage doses with and without the studying materials, were measured using the 6 MV (Field size = 10×10 cm{sup 2}) photon beams produced by a Varian TrueBeam linear accelerator. Twelve topical agents, five dressings (dry and wet conditions) and three clinical materials were studied. Amore » solid water phantom was used with a MOSFET dose detector (TN-1002RD, Thomson and Nielsen Electronic, Ottawa, Ontario, Canada) located under a 1-mm PMMA slab to measure the skin dose. The distance between the radiation source and phantom surface was set to 100 cm in all measurements. The topical agents were distributed evenly with 1.5 mm thickness using our specific sample holder on the phantom surface. Extrapolations were made of 0.5 mm thickness for the agents to provide meaningful clinical value. Results: By comparing surface doses without studying materials, it is found that no topical agents had superficial dose enhancement higher than the clinical materials namely, thermoplastic mask (128%), 5-mm Superflab™ bolus (158%) and 10-mm Superflab™ bolus (171%) regarding the same thickness. Superficial dose enhancement of dry dressing did not exceed 110.5%, while wet dressings produced higher dose enhancements (133% for wet Mepilex lite and 141% for wet Mepilex Ag transfer). Conclusion: It is concluded that the evaluated topical agents and dry dressings did not increase the superficial dose to a concerning level, even using excessive thickness in every fraction of radiation treatment. Wet dressings were found producing the bolus effect, but was still substantially less than applying a thin 5-mm bolus.« less

Trust, but verify - Accuracy of clinical commercial radiation Treatment Planning Systems

NASA Astrophysics Data System (ADS)

Lehmann, J.; Kenny, J.; Lye, J.; Dunn, L.; Williams, I.

2014-03-01

Computer based Treatment Planning Systems (TPS) are used worldwide to design and calculate treatment plans for treating radiation therapy patients. TPS are generally well designed and thoroughly tested by their developers and local physicists prior to clinical use. However, the wide-reaching impact of their accuracy warrants ongoing vigilance. This work reviews the findings of the Australian national audit system and provides recommendations for checks of TPS. The Australian Clinical Dosimetry Service (ACDS) has designed and implemented a national system of audits, currently in a three year test phase. The Level III audits verify the accuracy of a beam model of a facility's TPS through a comparison of measurements with calculation at selected points in an anthropomorphic phantom. The plans are prescribed by the ACDS and all measurement equipment is brought in for independent onsite measurements. In this first version of audits, plans are comparatively simple, involving asymmetric fields, wedges and inhomogeneities. The ACDS has performed 14 Level III audits to-date. Six audits returned at least one measurement at Action Level, indicating that the measured dose differed more than 3.3% (but less than 5%) from the planned dose. Two audits failed (difference >5%). One fail was caused by a data transmission error coupled with quality assurance (QA) not being performed. The second fail was investigated and reduced to Action Level with the onsite audit team finding phantom setup at treatment a contributing factor. The Action Level results are attributed to small dose calculation deviations within the TPS, which are investigated and corrected by the facilities. Small deviations exist in clinical TPS which can add up and can combine with output variations to result in unacceptable variations. Ongoing checks and independent audits are recommended.

Quantitative disease progression model of α‐1 proteinase inhibitor therapy on computed tomography lung density in patients with α‐1 antitrypsin deficiency

PubMed Central

Rogers, James A.; Vit, Oliver; Bexon, Martin; Sandhaus, Robert A.; Burdon, Jonathan; Chorostowska‐Wynimko, Joanna; Thompson, Philip; Stocks, James; McElvaney, Noel G.; Chapman, Kenneth R.; Edelman, Jonathan M.

2017-01-01

Aims Early‐onset emphysema attributed to α‐1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID‐RCT/RAPID‐OLE, the largest clinical trials of purified human α‐1 proteinase inhibitor (A1‐PI; 60 mg kg–1 week–1) therapy completed to date, demonstrated for the first time that A1‐PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response. Methods A disease progression model was constructed, utilizing observed A1‐PI exposure and lung density decline rates (measured by computed tomography) from RAPID‐RCT/RAPID‐OLE, to predict effects of population variability and higher doses on A1‐PI exposure and clinical response. Dose–exposure and exposure–response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose–exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1‐PI, forced expiratory volume in 1 s and body weight. The exposure–response model relates A1‐PI exposure to lung density decline rate at varying exposure levels. Results A dose of 60 mg kg–1 week–1 achieved trough serum levels >11 μmol l–1 (putative ‘protective threshold’) in ≥98% patients. Dose–exposure–response simulations revealed increasing separation between A1‐PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l–1 year–1 occurred more often in patients receiving A1‐PI: 63 vs. 12%. Conclusion Weight‐based A1‐PI dosing reliably raises serum levels above the 11 μmol l–1 threshold. However, our exposure–response simulations question whether this is the maximal, clinically effective threshold for A1‐PI therapy in AATD. The model suggested higher doses of A1‐PI would yield greater clinical effects. PMID:28662542

Prospective, open, multicentre Phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma.

PubMed

Ma, Hong-Bing; Di, Zheng-Li; Wen, Jiao; Ke, Yue; Sun, Xiaodong; Ren, Juan

2015-02-01

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy. Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints. Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2. Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Benchmarking pediatric cranial CT protocols using a dose tracking software system: a multicenter study.

PubMed

De Bondt, Timo; Mulkens, Tom; Zanca, Federica; Pyfferoen, Lotte; Casselman, Jan W; Parizel, Paul M

2017-02-01

To benchmark regional standard practice for paediatric cranial CT-procedures in terms of radiation dose and acquisition parameters. Paediatric cranial CT-data were retrospectively collected during a 1-year period, in 3 different hospitals of the same country. A dose tracking system was used to automatically gather information. Dose (CTDI and DLP), scan length, amount of retakes and demographic data were stratified by age and clinical indication; appropriate use of child-specific protocols was assessed. In total, 296 paediatric cranial CT-procedures were collected. Although the median dose of each hospital was below national and international diagnostic reference level (DRL) for all age categories, statistically significant (p-value < 0.001) dose differences among hospitals were observed. The hospital with lowest dose levels showed smallest dose variability and used age-stratified protocols for standardizing paediatric head exams. Erroneous selection of adult protocols for children still occurred, mostly in the oldest age-group. Even though all hospitals complied with national and international DRLs, dose tracking and benchmarking showed that further dose optimization and standardization is possible by using age-stratified protocols for paediatric cranial CT. Moreover, having a dose tracking system revealed that adult protocols are still applied for paediatric CT, a practice that must be avoided. • Significant differences were observed in the delivered dose between age-groups and hospitals. • Using age-adapted scanning protocols gives a nearly linear dose increase. • Sharing dose-data can be a trigger for hospitals to reduce dose levels.

Multidetector CT radiation dose optimisation in adults: short- and long-term effects of a clinical audit.

PubMed

Tack, Denis; Jahnen, Andreas; Kohler, Sarah; Harpes, Nico; De Maertelaer, Viviane; Back, Carlo; Gevenois, Pierre Alain

2014-01-01

To report short- and long-term effects of an audit process intended to optimise the radiation dose from multidetector row computed tomography (MDCT). A survey of radiation dose from all eight MDCT departments in the state of Luxembourg performed in 2007 served as baseline, and involved the most frequently imaged regions (head, sinus, cervical spine, thorax, abdomen, and lumbar spine). CT dose index volume (CTDIvol), dose-length product per acquisition (DLP/acq), and DLP per examination (DLP/exa) were recorded, and their mean, median, 25th and 75th percentiles compared. In 2008, an audit conducted in each department helped to optimise doses. In 2009 and 2010, two further surveys evaluated the audit's impact on the dose delivered. Between 2007 and 2009, DLP/exa significantly decreased by 32-69 % for all regions (P < 0.001) except the lumbar spine (5 %, P = 0.455). Between 2009 and 2010, DLP/exa significantly decreased by 13-18 % for sinus, cervical and lumbar spine (P ranging from 0.016 to less than 0.001). Between 2007 and 2010, DLP/exa significantly decreased for all regions (18-75 %, P < 0.001). Collective dose decreased by 30 % and the 75th percentile (diagnostic reference level, DRL) by 20-78 %. The audit process resulted in long-lasting dose reduction, with DRLs reduced by 20-78 %, mean DLP/examination by 18-75 %, and collective dose by 30 %. • External support through clinical audit may optimise default parameters of routine CT. • Reduction of 75th percentiles used as reference diagnostic levels is 18-75 %. • The effect of this audit is sustainable over time. • Dose savings through optimisation can be added to those achievable through CT.

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

PubMed

Guan, Xi-ting; Shao, Feng; Xie, Xi; Chen, Lin; Wang, Weiwen

2014-09-01

Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant-like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro-inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-α in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-α levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-α levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6 mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect. Copyright © 2014 Elsevier Inc. All rights reserved.

A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells

PubMed Central

Rosenthal, Mark; McArthur, Grant A.; Pattison, Scott T.; Pattison, Stacey L.; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Scott, Andrew M.

2015-01-01

Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000672257 PMID:26659127

Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.

PubMed

Nader, Ahmed; Zahran, Noran; Alshammaa, Aya; Altaweel, Heba; Kassem, Nancy; Wilby, Kyle John

2017-04-01

Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice. A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII ® . A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics. Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c ) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively). Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization.

PubMed

Kim, Edwin H; Bird, J Andrew; Kulis, Michael; Laubach, Susan; Pons, Laurent; Shreffler, Wayne; Steele, Pamela; Kamilaris, Janet; Vickery, Brian; Burks, A Wesley

2011-03-01

There are no treatments currently available for peanut allergy. Sublingual immunotherapy (SLIT) is a novel approach to the treatment of peanut allergy. We sought to investigate the safety, clinical effectiveness, and immunologic changes with SLIT in children with peanut allergy. In this double-blind, placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind, placebo-controlled food challenge. Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge. Dosing side effects were primarily oropharyngeal and uncommonly required treatment. During the double-blind, placebo-controlled food challenge, the treatment group safely ingested 20 times more peanut protein than the placebo group (median, 1,710 vs 85 mg; P = .011). Mechanistic studies demonstrated a decrease in skin prick test wheal size (P = .020) and decreased basophil responsiveness after stimulation with 10(-2) μg/mL (P = .009) and 10(-3) μg/mL (P = .009) of peanut. Peanut-specific IgE levels increased over the initial 4 months (P = .002) and then steadily decreased over the remaining 8 months (P = .003), whereas peanut-specific IgG4 levels increased during the 12 months (P = .014). Lastly, IL-5 levels decreased after 12 months (P = .015). No statistically significant changes were found in IL-13 levels, the percentage of regulatory T cells, or IL-10 and IFN-γ production. Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy, with evidence of immunologic changes suggesting a significant change in the allergic response. Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Pathology, Organ Distribution, and Immune Response after Single and Repeated Intravenous Injection of Rats with Clinical-Grade Parvovirus H1

PubMed Central

Geletneky, Karsten; Leoni, Anne-Laure; Pohlmeyer-Esch, Gabriele; Loebhard, Stephanie; Baetz, Andrea; Leuchs, Barbara; Roscher, Mandy; Hoefer, Constance; Jochims, Karin; Dahm, Michael; Huber, Bernard; Rommelaere, Jean; Krebs, Ottheinz; Hajda, Jacek

2015-01-01

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. PMID:25730754

In situ delivery of allogeneic natural killer cell (NK) combined with Cetuximab in liver metastases of gastrointestinal carcinoma: A phase I clinical trial.

PubMed

Adotevi, O; Godet, Y; Galaine, J; Lakkis, Z; Idirene, I; Certoux, J M; Jary, M; Loyon, R; Laheurte, C; Kim, S; Dormoy, A; Pouthier, F; Barisien, C; Fein, F; Tiberghien, P; Pivot, X; Valmary-Degano, S; Ferrand, C; Morel, P; Delabrousse, E; Borg, C

2018-01-01

Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.10 6 , 8.10 6 and 12.10 6 NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3 + regulatory T cells and PD-1 + T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses.

A CONCEPTUAL FRAMEWORK FOR MANAGING RADIATION DOSE TO PATIENTS IN DIAGNOSTIC RADIOLOGY USING REFERENCE DOSE LEVELS.

PubMed

Almén, Anja; Båth, Magnus

2016-06-01

The overall aim of the present work was to develop a conceptual framework for managing radiation dose in diagnostic radiology with the intention to support optimisation. An optimisation process was first derived. The framework for managing radiation dose, based on the derived optimisation process, was then outlined. The outset of the optimisation process is four stages: providing equipment, establishing methodology, performing examinations and ensuring quality. The optimisation process comprises a series of activities and actions at these stages. The current system of diagnostic reference levels is an activity in the last stage, ensuring quality. The system becomes a reactive activity only to a certain extent engaging the core activity in the radiology department, performing examinations. Three reference dose levels-possible, expected and established-were assigned to the three stages in the optimisation process, excluding ensuring quality. A reasonably achievable dose range is also derived, indicating an acceptable deviation from the established dose level. A reasonable radiation dose for a single patient is within this range. The suggested framework for managing radiation dose should be regarded as one part of the optimisation process. The optimisation process constitutes a variety of complementary activities, where managing radiation dose is only one part. This emphasises the need to take a holistic approach integrating the optimisation process in different clinical activities. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Infusion dose requirement of rocuronium in patients on phenytoin therapy - A prospective comparative study.

PubMed

Sheshadri, Veena; Radhakrishnan, Arathi; Halemani, Kusuma; Keshavan, Venkatesh H

2017-10-01

Patients with intracranial tumour are usually on anticonvulsants. Patients on phenytoin therapy demonstrate rapid metabolism of nondepolarising muscle relaxants secondary to enzyme induction. Infusion dose requirement of rocuronium in such patients has been sparingly studied. We studied the continuous infusion dose requirement of rocuronium bromide in patients on phenytoin therapy and its correlation with serum levels of phenytoin. Seventy-five patients scheduled for supratentorial tumour surgery were included in the study. Patients not on phenytoin were taken as control. The primary outcome variable studied was the infusion dose requirement of rocuronium in patients on phenytoin. Based on pre-operative serum phenytoin levels, study group patients were divided into two groups: sub-therapeutic level group (phenytoin level <10 μg/mL) and therapeutic level group (phenytoin level >10 μg/mL). Following anaesthesia induction, rocuronium bromide 0.6 mg/kg was administered to achieve tracheal intubation. Rocuronium infusion was titrated to maintain zero response on the train-of-four response. Demographic data were comparable. Patients receiving phenytoin required higher infusion dose compared to the control group (0.429 ± 0.2 mg/kg/h vs. 0.265 ± 0.15 mg/kg/h, P < 0.001). The serum phenytoin level had no correlation to infusion dose requirement of rocuronium (0.429 ± 0.205 mg/kg/h vs. 0.429 ± 0.265 mg/kg/h ( P = 0.815). The recovery was faster in the phenytoin group compared to the control group. Haowever, it was not clinically significant. The infusion dose requirement of rocuronium bromide in patients on phenytoin is higher and the serum levels of phenytoin does not influence the dose required.

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM

PubMed Central

Koopmeiners, Joseph S.; Wey, Andrew

2017-01-01

The primary object of a phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose-finding. Recently, it was shown that the CRM has a tendency to get “stuck” on a dose-level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable trade-off with respect to the average number treated at the MTD. PMID:28340333

The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM.

PubMed

Koopmeiners, Joseph S; Wey, Andrew

2017-01-01

The primary object of a Phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose finding. Recently, it was shown that the CRM has a tendency to get "stuck" on a dose level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable tradeoff with respect to the average number treated at the MTD.

Mebendazole paste as an anthelmintic in random source research cats.

PubMed

Bradley, R E; Peters, L J

1982-10-01

Mebendazole paste, administered per os daily for 3 days, at dose levels of 22 mg/kg and 33 mg/kg was highly effective in removing Ancylostoma tubaeforme from naturally infected cats. The 22 mg/kg dose gave the highest efficacy (95.5% critical and 98% controlled). The same product at 11 mg/kg, 22 mg/kg, or 33 mg/kg was 100% effective in removing Toxocara cati from naturally infected cats. Both 11 mg/kg and 22 mg/kg dose levels were highly efficacious against the common tapeworm, Dipylidium caninum. No toxic side effects or clinical illness were observed in any of the cats used in this study.

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

PubMed

Stein, Eytan M; Garcia-Manero, Guillermo; Rizzieri, David A; Tibes, Raoul; Berdeja, Jesus G; Savona, Michael R; Jongen-Lavrenic, Mojca; Altman, Jessica K; Thomson, Blythe; Blakemore, Stephen J; Daigle, Scott R; Waters, Nigel J; Suttle, A Benjamin; Clawson, Alicia; Pollock, Roy; Krivtsov, Andrei; Armstrong, Scott A; DiMartino, Jorge; Hedrick, Eric; Löwenberg, Bob; Tallman, Martin S

2018-05-03

Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m 2 /day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m 2 /day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as no. NCT01684150. Copyright © 2018 American Society of Hematology.

A randomized, double-blind, placebo-controlled clinical trial on the treatment of vitamin D insufficiency in postmenopausal women

PubMed Central

Hansen, Karen E.; Johnson, R. Erin; Chambers, Kaitlin R.; Johnson, Michael G.; Lemon, Christina C.; Thuy Vo, Tien Nguyen; Marvdashti, Sheeva

2015-01-01

Importance Experts debate optimal 25(OH)D levels for musculoskeletal health. Objective To compare effects of placebo, low-dose and high-dose vitamin D on one-year changes in total fractional calcium absorption, bone mineral density, Timed-Up-and-Go and 5-sit-to-stand tests and muscle mass in postmenopausal women with vitamin D insufficiency. Design Randomized, double-blind, placebo-controlled, clinical trial conducted from May 2010 to August 2014. Setting Single-center trial conducted in Madison, Wisconsin. Participants 230 postmenopausal women ≤75 years old with baseline 25(OH)D levels 14-27 ng/mL and no osteoporosis. Intervention Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=76), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels ≥30 ng/mL. Main Outcome Measures One year change in total fractional calcium absorption using two stable isotopes, bone mineral density and muscle mass using dual energy x-ray absorptiometry, Timed-Up-and-Go and 5-Sit-to-Stand tests, functional status (Health Assessment Questionnaire) and physical activity (Physical Activity Scale for the Elderly), with Benjamini-Hochberg correction of p-values to control the false discovery rate. Results After controlling for baseline absorption, calcium absorption increased 1% (10 mg/day) in the high-dose arm, but decreased by 2% in low-dose (p=0.005 vs. high-dose) and by 1.3% placebo (p=0.03 vs. high-dose) arms. We found no between-arm changes in spine, mean total hip, mean femoral neck or total body bone mineral density, trabecular bone score, muscle mass, 5-sit-to-stand or Timed-Up-and-Go test scores. Likewise, we found no between-arm differences for numbers of falls, number of fallers, physical activity or functional status. Conclusion and Relevance High-dose vitamin D therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass or falls. We found no data to support experts’ recommendations to maintain serum 25(OH)D levels ≥30 ng/mL in postmenopausal women. Instead, we found that low and high-dose vitamin D were equivalent to placebo, in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels <30 ng/mL. ClinicalTrials.gov.Identifier:NCT00933244 PMID:26237520

A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer.

PubMed

Parker, Christopher C; Pascoe, Sarah; Chodacki, Aleš; O'Sullivan, Joe M; Germá, Josep R; O'Bryan-Tear, Charles Gillies; Haider, Trond; Hoskin, Peter

2013-02-01

Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n=41), 50 kBq/kg (n=39), or 80 kBq/kg (n=42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥ 50% in baseline prostate-specific antigen (PSA) levels. Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. The study met its primary end point with a statistically significant dose-response relationship in confirmed ≥ 50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p=0.0297). A ≥ 50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p<0.0001). The most common treatment-related AEs (≥ 10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline. Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses. ClinicalTrials.gov: NCT00337155. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Preclinical safety assessment of the 5-HT2A receptor agonist PET radioligand [ 11C]Cimbi-36.

PubMed

Ettrup, Anders; Holm, Søren; Hansen, Martin; Wasim, Muhammad; Santini, Martin Andreas; Palner, Mikael; Madsen, Jacob; Svarer, Claus; Kristensen, Jesper Langgaard; Knudsen, Gitte Moos

2013-08-01

[11C]Cimbi-36 was recently developed as an agonist radioligand for brain imaging of serotonin 2A receptors (5-HT2A) with positron emission tomography (PET). This may be used to quantify the high-affinity state of 5-HT2A receptors and may have the potential to quantify changes in cerebral 5-HT levels in vivo. We here investigated safety aspects related to clinical use of [11C]Cimbi-36, including radiation dosimetry and in vivo pharmacology. [11C]Cimbi-36 was injected in rats or pigs, and radiation dosimetry was examined by ex vivo dissection or with PET scanning, respectively. Based on animal data, the Organ Level INternal Dose Assessment software was used to estimate extrapolated human dosimetry for [11C]Cimbi-36. The 5-HT2A receptor agonist actions of [11C]Cimbi-36 in vivo pharmacological effects in mice elicited by increasing doses of Cimbi-36 were assessed with the head-twitch response (HTR). The effective dose as extrapolated from both rat and pig data was low, 7.67 and 4.88 μSv/MBq, respectively. In addition, the estimated absorbed radiation dose to human target organs did not exceed safety levels. Administration of 0.5 mg/kg Cimbi-36 leads to significant HTR compared to saline, whereas 0.05 mg/kg Cimbi-36 (doses much larger than those given in conjunction with a PET scan) did not elicit a significant HTR. Administration of tracer doses of [11C]Cimbi-36 does not seem to be associated with unusual radiation burden or adverse clinical effects.

Are Evidence Standards Different for Genomic- vs. Clinical-Based Precision Medicine? A Quantitative Analysis of Individualized Warfarin Therapy.

PubMed

Dhanda, D S; Guzauskas, G F; Carlson, J J; Basu, A; Veenstra, D L

2017-11-01

Evidence requirements for implementation of precision medicine (PM), whether informed by genomic or clinical data, are not well defined. Evidence requirements are driven by uncertainty and its attendant consequences; these aspects can be quantified by a novel technique in health economics: value of information analysis (VOI). We utilized VOI analysis to compare the evidence levels over time for warfarin dosing based on pharmacogenomic vs. amiodarone-warfarin drug-drug interaction information. The primary outcome was the expected value of perfect information (EVPI), which is an estimate of the upper limit of the societal value of conducting future research. Over the past decade, the EVPI for the pharmacogenomic strategy decreased from $1,550 to $140 vs. $1,220 to $280 per patient for the drug-interaction strategy. Evidence levels thus appear to be higher for pharmacogenomic-guided vs. drug-interaction-guided warfarin dosing. Clinical guidelines and reimbursement policies for warfarin PM could be informed by these findings. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Head-and-neck IMRT treatments assessed with a Monte Carlo dose calculation engine.

PubMed

Seco, J; Adams, E; Bidmead, M; Partridge, M; Verhaegen, F

2005-03-07

IMRT is frequently used in the head-and-neck region, which contains materials of widely differing densities (soft tissue, bone, air-cavities). Conventional methods of dose computation for these complex, inhomogeneous IMRT cases involve significant approximations. In the present work, a methodology for the development, commissioning and implementation of a Monte Carlo (MC) dose calculation engine for intensity modulated radiotherapy (MC-IMRT) is proposed which can be used by radiotherapy centres interested in developing MC-IMRT capabilities for research or clinical evaluations. The method proposes three levels for developing, commissioning and maintaining a MC-IMRT dose calculation engine: (a) development of a MC model of the linear accelerator, (b) validation of MC model for IMRT and (c) periodic quality assurance (QA) of the MC-IMRT system. The first step, level (a), in developing an MC-IMRT system is to build a model of the linac that correctly predicts standard open field measurements for percentage depth-dose and off-axis ratios. Validation of MC-IMRT, level (b), can be performed in a rando phantom and in a homogeneous water equivalent phantom. Ultimately, periodic quality assurance of the MC-IMRT system is needed to verify the MC-IMRT dose calculation system, level (c). Once the MC-IMRT dose calculation system is commissioned it can be applied to more complex clinical IMRT treatments. The MC-IMRT system implemented at the Royal Marsden Hospital was used for IMRT calculations for a patient undergoing treatment for primary disease with nodal involvement in the head-and-neck region (primary treated to 65 Gy and nodes to 54 Gy), while sparing the spinal cord, brain stem and parotid glands. Preliminary MC results predict a decrease of approximately 1-2 Gy in the median dose of both the primary tumour and nodal volumes (compared with both pencil beam and collapsed cone). This is possibly due to the large air-cavity (the larynx of the patient) situated in the centre of the primary PTV and the approximations present in the dose calculation.

Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for Clostridium difficile.

PubMed

Early, C R; Park, J M; Dorsch, M P; Pogue, K T; Hanigan, S M

2016-10-01

Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

PubMed

Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

2017-09-01

Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met 5 ]-enkephalin or β-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.

[Rosiglitazone (BRL-49653)].

PubMed

Kameda, N; Okuya, S; Oka, Y

2000-02-01

Rosiglitazone, a thiazolidinedion antidiabetic agent, improves insulin resistance in patients with type 2 diabetes mellitus. Rosiglitazone binds to PPAR-gamma with high affinity and the in vivo antidiabetic potency of rosiglitazone is correlated with its high biding affinity. In animal models of insulin resistence, rosiglitazone decreased plasma glucose, triglyceride and insulin levels and also prevented diabetic nephropathy and pancreatic islet cell degeneration. In clinical trials in patients with type 2 diabetes mellitus, rosiglitazone, 2 to 12 mg/day (as a single daily dose or 2 divided daily doses), improved glycemic control as demonstrated, by decreases in fasting plasma glucose and HbA1C levels. Rosiglitazone did not appear to increase the risk of hypoglycemia and there was no evidence of hepatotoxicity in pre-clinical trials.

SU-E-P-10: Establishment of Local Diagnostic Reference Levels of Routine Exam in Computed Tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yeh, M; Wang, Y; Weng, H

Introduction National diagnostic reference levels (NDRLs) can be used as a reference dose of radiological examination can provide radiation dose as the basis of patient dose optimization. Local diagnostic reference levels (LDRLs) by periodically view and check doses, more efficiency to improve the way of examination. Therefore, the important first step is establishing a diagnostic reference level. Computed Tomography in Taiwan had been built up the radiation dose limit value,in addition, many studies report shows that CT scan contributed most of the radiation dose in different medical. Therefore, this study was mainly to let everyone understand DRL’s international status. Formore » computed tomography in our hospital to establish diagnostic reference levels. Methods and Materials: There are two clinical CT scanners (a Toshiba Aquilion and a Siemens Sensation) were performed in this study. For CT examinations the basic recommended dosimetric quantity is the Computed Tomography Dose Index (CTDI). Each exam each different body part, we collect 10 patients at least. Carried out the routine examinations, and all exposure parameters have been collected and the corresponding CTDIv and DLP values have been determined. Results: The majority of patients (75%) were between 60–70 Kg of body weight. There are 25 examinations in this study. Table 1 shows the LDRL of each CT routine examination. Conclusions: Therefore, this study would like to let everyone know DRL’s international status, but also establishment of computed tomography of the local reference levels for our hospital, and providing radiation reference, as a basis for optimizing patient dose.« less

A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom.

PubMed

Lye, Jessica; Kenny, John; Lehmann, Joerg; Dunn, Leon; Kron, Tomas; Alves, Andrew; Cole, Andrew; Williams, Ivan

2014-10-01

The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantoms are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%-8%. The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.

Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, D.W. Nathan; Cho, L. Chinsoo; Straka, Christopher

2014-07-01

Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% ofmore » patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.« less

How to emerge from the conservatism in clinical research methodology?

PubMed

Kotecki, Nuria; Penel, Nicolas; Awada, Ahmad

2017-09-01

Despite recent changes in clinical research methodology, many challenges remain in drug development methodology. Advances in molecular biology and cancer treatments have changed the clinical research landscape. Thus, we moved from empirical clinical oncology to molecular and immunological therapeutic approaches. Along with this move, adapted dose-limiting toxicities definitions, endpoints, and dose escalation methods have been proposed. Moreover, the classical frontier between phase I, phase II, and phase III has become unclear in particular for immunological approaches. So, investigators are facing major challenges in drug development methodology. We propose to individualize clinical research using innovative approaches to significantly improve patient outcomes and targeting what is considered unmet need. Integrating high level of translational research and performing well designed biomarker studies with great potential for clinical practice are of utmost importance. This could be performed within new models of clinical research networks and by building a strong collaboration between academic, cooperative groups, on-site investigators, and pharma.

A Population Pharmacokinetic and Pharmacodynamic Analysis of Abemaciclib in a Phase I Clinical Trial in Cancer Patients.

PubMed

Tate, Sonya C; Sykes, Amanda K; Kulanthaivel, Palaniappan; Chan, Edward M; Turner, P Kellie; Cronier, Damien M

2018-03-01

Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels. A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model. The pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (F rel ) adequately described the pharmacokinetics of abemaciclib. Serum albumin and alkaline phosphatase were the only significant covariates identified in the model, the inclusion of which reduced inter-individual variability in F rel by 10.3 percentage points. By combining the clinical popPK model with the previously developed pre-clinical pharmacokinetic/pharmacodynamic model, the extent of target engagement in skin in cancer patients was successfully predicted. The proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight. NCT01394016 (ClinicalTrials.gov).

Evidence for single-dose protection by the bivalent HPV vaccine-Review of the Costa Rica HPV vaccine trial and future research studies.

PubMed

Kreimer, Aimée R; Herrero, Rolando; Sampson, Joshua N; Porras, Carolina; Lowy, Douglas R; Schiller, John T; Schiffman, Mark; Rodriguez, Ana Cecilia; Chanock, Stephen; Jimenez, Silvia; Schussler, John; Gail, Mitchell H; Safaeian, Mahboobeh; Kemp, Troy J; Cortes, Bernal; Pinto, Ligia A; Hildesheim, Allan; Gonzalez, Paula

2018-01-20

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. Published by Elsevier Ltd.

WE-D-18A-04: How Iterative Reconstruction Algorithms Affect the MTFs of Variable-Contrast Targets in CT Images

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dodge, C.T.; Rong, J.; Dodge, C.W.

2014-06-15

Purpose: To determine how filtered back-projection (FBP), adaptive statistical (ASiR), and model based (MBIR) iterative reconstruction algorithms affect the measured modulation transfer functions (MTFs) of variable-contrast targets over a wide range of clinically applicable dose levels. Methods: The Catphan 600 CTP401 module, surrounded by an oval, fat-equivalent ring to mimic patient size/shape, was scanned on a GE HD750 CT scanner at 1, 2, 3, 6, 12 and 24 mGy CTDIvol levels with typical patient scan parameters: 120kVp, 0.8s, 40mm beam width, large SFOV, 2.5mm thickness, 0.984 pitch. The images were reconstructed using GE's Standard kernel with FBP; 20%, 40% andmore » 70% ASiR; and MBIR. A task-based MTF (MTFtask) was computed for six cylindrical targets: 2 low-contrast (Polystyrene, LDPE), 2 medium-contrast (Delrin, PMP), and 2 high-contrast (Teflon, air). MTFtask was used to compare the performance of reconstruction algorithms with decreasing CTDIvol from 24mGy, which is currently used in the clinic. Results: For the air target and 75% dose savings (6 mGy), MBIR MTFtask at 5 lp/cm measured 0.24, compared to 0.20 for 70% ASiR and 0.11 for FBP. Overall, for both high-contrast targets, MBIR MTFtask improved with increasing CTDIvol and consistently outperformed ASiR and FBP near the system's Nyquist frequency. Conversely, for Polystyrene at 6 mGy, MBIR (0.10) and 70% ASiR (0.07) MTFtask was lower than for FBP (0.18). For medium and low-contrast targets, FBP remains the best overall algorithm for improved resolution at low CTDIvol (1–6 mGy) levels, whereas MBIR is comparable at higher dose levels (12–24 mGy). Conclusion: MBIR improved the MTF of small, high-contrast targets compared to FBP and ASiR at doses of 50%–12.5% of those currently used in the clinic. However, for imaging low- and mediumcontrast targets, FBP performed the best across all dose levels. For assessing MTF from different reconstruction algorithms, task-based MTF measurements are necessary.« less

The Australian radiation protection and nuclear safety agency megavoltage photon thermoluminescence dosimetry postal audit service 2007-2010.

PubMed

Oliver, C P; Butler, D J; Webb, D V

2012-03-01

The Australian radiation protection and nuclear safety agency (ARPANSA) has continuously provided a level 1 mailed thermoluminescence dosimetry audit service for megavoltage photons since 2007. The purpose of the audit is to provide an independent verification of the reference dose output of a radiotherapy linear accelerator in a clinical environment. Photon beam quality measurements can also be made as part of the audit in addition to the output measurements. The results of all audits performed between 2007 and 2010 are presented. The average of all reference beam output measurements calculated as a clinically stated dose divided by an ARPANSA measured dose is 0.9993. The results of all beam quality measurements calculated as a clinically stated quality divided by an ARPANSA measured quality is 1.0087. Since 2011 the provision of all auditing services has been transferred from the Ionizing Radiation Standards section to the Australian Clinical Dosimetry Service (ACDS) which is currently housed within ARPANSA.

Tuberculosis in Newborns: The Lessons of the “Lübeck Disaster” (1929–1933)

PubMed Central

Fox, Gregory J.; Orlova, Marianna; Schurr, Erwin

2016-01-01

In an accident later known as the Lübeck disaster, 251 neonates were orally given three doses of the new Bacille Calmette–Guérin (BCG) antituberculosis (TB) vaccine contaminated with Mycobacterium tuberculosis. A total of 173 infants developed clinical or radiological signs of TB but survived the infection, while 72 died from TB. While some blamed the accident on BCG itself by postulating reversion to full virulence, such a possibility was conclusively disproven. Rather, by combining clinical, microbiological, and epidemiological data, the chief public health investigator Dr. A. Moegling concluded that the BCG vaccine had been contaminated with variable amounts of fully virulent M. tuberculosis. Here, we summarize the conclusions drawn by Moegling and point out three lessons that can be learned. First, while mortality was high (approximately 29%), the majority of neonates inoculated with M. tuberculosis eventually overcame TB disease. This shows the high constitutional resistance of humans to the bacillus. Second, four semiquantitative levels of contamination were deduced by Moegling from the available data. While at low levels of M. tuberculosis there was a large spread of clinical phenotypes reflecting a good degree of innate resistance to TB, at the highest dose, the majority of neonates were highly susceptible to TB. This shows the dominating role of dose for innate resistance to TB. Third, two infants inoculated with the lowest dose nevertheless died of TB, and their median time from inoculation to death was substantially shorter than for those who died after inoculation with higher doses. This suggests that infants who developed disease after low dose inoculation are those who are most susceptible to the disease. We discuss some implications of these lessons for current study of genetic susceptibility to TB. PMID:26794678

Postoperative Intensity-Modulated Radiotherapy in Low-Risk Endometrial Cancers: Final Results of a Phase I Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.i; Cilla, Savino M.P.; Ferrandina, Gabriella

2010-04-15

Purpose: To determine the maximum tolerated dose of short-course radiotherapy (intensity-modulated radiotherapy technique) to the upper two thirds of the vagina in endometrial cancers with low risk of local recurrence. Patients and Methods: A Phase I clinical trial was performed. Eligible patients had low-risk resected primary endometrial adenocarcinomas. Radiotherapy was delivered in 5 fractions over 1 week. The planning target volume was the clinical target volume plus 5 mm. The clinical target volume was defined as the upper two thirds of the vagina as evidenced at CT simulation by a vaginal radio-opaque device. The planning target volume was irradiated bymore » a seven-field intensity-modulated radiotherapy technique, planned by the Plato Sunrise inverse planning system. A first cohort of 6 patients received 25 Gy (5-Gy fractions), and a subsequent cohort received 30 Gy (6-Gy fractions). The Common Toxicity Criteria scale, version 3.0, was used to score toxicity. Results: Twelve patients with endometrial cancer were enrolled. Median age was 58 years (range, 49-74 years). Pathologic stage was IB (83.3%) and IC (16.7%). Median tumor size was 30 mm (range, 15-50 mm). All patients completed the prescribed radiotherapy. No patient experienced a dose-limiting toxicity at the first level, and the radiotherapy dose was escalated from 25 to 30 Gy. No patients at the second dose level experienced dose-limiting toxicity. The most common Grade 2 toxicity was gastrointestinal, which was tolerable and manageable. Conclusions: The maximum tolerated dose of short-course radiotherapy was 30 Gy at 6 Gy per fraction. On the basis of this result, we are conducting a Phase II study with radiotherapy delivered at 30 Gy.« less

SU-F-P-45: Clinical Experience with Radiation Dose Reduction of CT Examinations Using Iterative Reconstruction Algorithms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weir, V; Zhang, J

2016-06-15

Purpose: Iterative reconstruction (IR) algorithms have been adopted by medical centers in the past several years. IR has a potential to substantially reduce patient dose while maintaining or improving image quality. This study characterizes dose reductions in clinical settings for CT examinations using IR. Methods: We retrospectively analyzed dose information from patients who underwent abdomen/pelvis CT examinations with and without contrast media in multiple locations of our Healthcare system. A total of 743 patients scanned with ASIR on 64 slice GE lightspeed VCTs at three sites, and 30 patients scanned with SAFIRE on a Siemens 128 slice Definition Flash inmore » one site was retrieved. For comparison, patient data (n=291) from a GE scanner and patient data (n=61) from two Siemens scanners where filtered back-projection (FBP) was used was collected retrospectively. 30% and 10% ASIR, and SAFIRE Level 2 was used. CTDIvol, Dose-length-product (DLP), weight and height from all patients was recorded. Body mass index (BMI) was calculated accordingly. To convert CTDIvol to SSDE, AP and lateral dimensions at the mid-liver level was measured for each patient. Results: Compared with FBP, 30% ASIR reduces dose by 44.1% (SSDE: 12.19mGy vs. 21.83mGy), while 10% ASIR reduced dose by 20.6% (SSDE 17.32mGy vs. 21.83). Use of SAFIRE reduced dose by 61.4% (SSDE: 8.77mGy vs. 22.7mGy). The geometric mean for patients scanned with ASIR was larger than for patients scanned with FBP (geometric mean is 297.48 mmm vs. 284.76 mm). The same trend was observed for the Siemens scanner where SAFIRE was used (geometric mean: 316 mm with SAFIRE vs. 239 mm with FBP). Patient size differences suggest that further dose reduction is possible. Conclusion: Our data confirmed that in clinical practice IR can significantly reduce dose to patients who undergo CT examinations, while meeting diagnostic requirements for image quality.« less

First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors

PubMed Central

Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A.; Raynaud, Florence I.; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S.; Kaye, Stan B.; Derynck, Mika K.; Workman, Paul; de Bono, Johann S.

2014-01-01

Purpose This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics, pharmacodynamics and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent and selective inhibitor of the Class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450mg once-daily, initially on days 1-21 every 28 days and later, utilizing continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma and tumor tissue. Results Pictilisib was well-tolerated. The most common toxicities were grade 1-2 nausea, rash and fatigue while the DLT was grade 3 maculopapular rash (450mg, 2 of 3 patients; 330mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in platelet rich plasma at 3 hours post-dose at the MTD and in tumor at pictilisib doses associated with AUC >20uM.hr. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100mg and signs of antitumor activity. The recommended Phase II dose was continuous dosing at 330mg once-daily. PMID:25370471

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

PubMed

Sarker, Debashis; Ang, Joo Ern; Baird, Richard; Kristeleit, Rebecca; Shah, Krunal; Moreno, Victor; Clarke, Paul A; Raynaud, Florence I; Levy, Gallia; Ware, Joseph A; Mazina, Kathryn; Lin, Ray; Wu, Jenny; Fredrickson, Jill; Spoerke, Jill M; Lackner, Mark R; Yan, Yibing; Friedman, Lori S; Kaye, Stan B; Derynck, Mika K; Workman, Paul; de Bono, Johann S

2015-01-01

This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. ©2014 American Association for Cancer Research.

Prasugrel Results in Higher Decrease in High-Sensitivity C-Reactive Protein Level in Patients Undergoing Percutaneous Coronary Intervention Comparing to Clopidogrel.

PubMed

Hajsadeghi, Shokoufeh; Chitsazan, Mandana; Chitsazan, Mitra; Salehi, Negar; Amin, Ahmad; Bidokhti, Arash Amin; Babaali, Nima; Bordbar, Armin; Hejrati, Maral; Moghadami, Samar

2016-01-01

A growing body of clinical and laboratory evidence indicates that inflammation plays a crucial role in atherosclerosis. In the present study, we compared the effects of clopidogrel and prasugrel on high-sensitivity C-reactive protein (hs-CRP) in patients undergoing percutaneous coronary intervention (PCI). The present randomized, double-blind clinical trial included 120 patients who underwent PCI. Eligible patients were randomly assigned 2:1 to one of the two groups: 80 patients in the first group received clopidogrel (Plavix(®); loading dose and maintenance dose of 300 and 75 mg daily, respectively) and 40 patients in the second group received prasugrel (Effient(®); loading dose and maintenance dose of 60 and 10 mg, respectively) for 12 weeks. The hs-CRP levels between baseline and 12th week were compared. Of the 120 patients, 69 patients (57.5%) were male. Pretreatment hs-CRP level was statistically comparable in clopidogrel (median, 15.10 mg/dL; interquartile range [IQR], 9.62-23.75 mg/dL) and prasugrel groups (median, 18 mg/dL; IQR, 14.25-22 mg/dL; P = 0.06). Patients taking clopidogrel showed a significant reduction in hs-CRP level compared with the baseline values (P < 0.001). Prasugrel administration also resulted in a significant reduction in hs-CRP level (P < 0.001). A significant 73% overall reduction in the hs-CRP level was seen with prasugrel compared with 39% overall reduction in hs-CRP level with clopidogrel (P = 0.002). Prasugrel seems to be superior to clopidogrel in the reduction of hs-CRP in patients undergoing PCI.

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

PubMed Central

Fitzgerald, Kevin; White, Suellen; Borodovsky, Anna; Bettencourt, Brian R.; Strahs, Andrew; Clausen, Valerie; Wijngaard, Peter; Horton, Jay D.; Taubel, Jorg; Brooks, Ashley; Fernando, Chamikara; Kauffman, Robert S.; Kallend, David; Vaishnaw, Akshay; Simon, Amy

2018-01-01

BACKGROUND Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.) PMID:27959715

Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes.

PubMed

Strange, P; Schwartz, S L; Graf, R J; Polvino, W; Weston, I; Marbury, T C; Huang, W C; Goldberg, R B

1999-01-01

The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes. Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean). Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events. These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.

Outcomes using exhaled nitric oxide measurements as an adjunct to primary care asthma management.

PubMed

Hewitt, Richard S; Modrich, Catherine M; Cowan, Jan O; Herbison, G Peter; Taylor, D Robin

2009-12-01

Exhaled nitric oxide (FENO) measurements may help to highlight when inhaled corticosteroid (ICS) therapy should or should not be adjusted in asthma. This is often difficult to judge. Our aim was to evaluate a decision-support algorithm incorporating FENO measurements in a nurse-led asthma clinic. Asthma management was guided by an algorithm based on high (>45ppb), intermediate (30-45ppb), or low (<30ppb) FENO levels and asthma control status. This provided for one of eight possible treatment options, including diagnosis review and ICS dose adjustment. Well controlled asthma increased from 41% at visit 1 to 68% at visit 5 (p=0.001). The mean fluticasone dose decreased from 312 mcg/day at visit 2 to 211mcg/day at visit 5 (p=0.022). There was a high level of protocol deviations (25%), often related to concerns about reducing the ICS dose. The % fall in FENO associated with a change in asthma status from poor control to good control was 35%. An FENO-based algorithm provided for a reduction in ICS doses without compromising asthma control. However, the results may have been influenced by the education and support which patients received. Reluctance to reduce ICS dose was an issue which may have influenced the overall results. Australian Clinical Trials Registry # 012605000354684.

High brachytherapy doses can counteract hypoxia in cervical cancer—a modelling study

NASA Astrophysics Data System (ADS)

Lindblom, Emely; Dasu, Alexandru; Beskow, Catharina; Toma-Dasu, Iuliana

2017-01-01

Tumour hypoxia is a well-known adverse factor for the outcome of radiotherapy. For cervical tumours in particular, several studies indicate large variability in tumour oxygenation. However, clinical evidence shows that the management of cervical cancer including brachytherapy leads to high rate of success. It was the purpose of this study to investigate whether the success of brachytherapy for cervical cancer, seemingly regardless of oxygenation status, could be explained by the characteristics of the brachytherapy dose distributions. To this end, a previously used in silico model of tumour oxygenation and radiation response was further developed to simulate the treatment of cervical cancer employing a combination of external beam radiotherapy and intracavitary brachytherapy. Using a clinically-derived brachytherapy dose distribution and assuming a homogeneous dose delivered by external radiotherapy, cell survival was assessed on voxel level by taking into account the variation of sensitivity with oxygenation as well as the effects of repair, repopulation and reoxygenation during treatment. Various scenarios were considered for the conformity of the brachytherapy dose distribution to the hypoxic region in the target. By using the clinically-prescribed brachytherapy dose distribution and varying the total dose delivered with external beam radiotherapy in 25 fractions, the resulting values of the dose for 50% tumour control, D 50, were in agreement with clinically-observed values for high cure rates if fast reoxygenation was assumed. The D 50 was furthermore similar for the different degrees of conformity of the brachytherapy dose distribution to the tumour, regardless of whether the hypoxic fraction was 10%, 25%, or 40%. To achieve 50% control with external RT only, a total dose of more than 70 Gy in 25 fractions would be required for all cases considered. It can thus be concluded that the high doses delivered in brachytherapy can counteract the increased radioresistance caused by hypoxia if fast reoxygenation is assumed.

SU-E-I-10: Automatic Monitoring of Accumulated Dose Indices From DICOM RDSR to Improve Radiation Safety in X-Ray Angiography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Omar, A; Bujila, R; Nowik, P

2014-06-01

Purpose: To investigate the potential benefits of automatic monitoring of accumulated patient and staff dose indicators, i.e., CAK and KAP, from DICOM Radiation Dose Structured Reports (RDSR) in x-ray angiography (XA). Methods: Recently RDSR has enabled the convenient aggregation of dose indices and technique parameters for XA procedures. The information contained in RDSR objects for three XA systems, dedicated to different types of clinical procedures, has been collected and aggregated in a database for over one year using a system developed with open-source software at the Karolinska University Hospital. Patient weight was complemented to the RDSR data via an interfacemore » with the Hospital Information System (HIS). Results: The linearly approximated trend in KAP over a time period of a year for cerebrovascular, pelvic/peripheral vascular, and cardiovascular procedures showed a decrease of 12%, 20%, and 14%, respectively. The decrease was mainly due to hardware/software upgrades and new low-dose imaging protocols, and partially due to ongoing systematic radiation safety education of the clinical staff. The CAK was in excess of 3 Gy for 15 procedures, and exceeded 5 Gy for 3 procedures. The dose indices have also shown a significant dependence on patient weight for cardiovascular and pelvic/peripheral vascular procedures; a 10 kg shift in mean patient weight can result in a dose index increase of 25%. Conclusion: Automatic monitoring of accumulated dose indices can be utilized to notify the clinical staff and medical physicists when the dose index has exceeded a predetermined action level. This allows for convenient and systematic follow-up of patients in risk of developing deterministic skin injuries. Furthermore, trend analyses of dose indices over time is a valuable resource for the identification of potential positive or negative effects (dose increase/decrease) from changes in hardware, software, and clinical work habits.« less

The value of fixed rasburicase dosing versus weight-based dosing in the treatment and prevention of tumor lysis syndrome.

PubMed

Boutin, Alyssa; Blackman, Alison; O'Sullivan, David M; Forcello, Nicholas

2018-01-01

Background Rasburicase is a recombinant urate oxidase enzyme used for the treatment and prevention of tumor lysis syndrome. Our objective was to assess the efficacy of indication-based, low-dose rasburicase administration compared to the Food and Drug Administration-approved weight-based dosing. Methods This was a retrospective cohort study utilizing data from a tertiary medical center including patients admitted from 2012 to 2016, who received at least one dose of rasburicase. The primary outcome was achieving a uric acid level less than 7.5 mg/dl after a single dose of rasburicase in the preprotocol (Food and Drug Administration-approved weight-based dosing) and postprotocol (indication-based, low-dose) groups. Secondary outcomes included the change in uric acid levels between the pre- and postprotocol groups, adherence to the new institutional protocol, need for repeat rasburicase doses, and a cost analysis. Results Sixty-four patients received at least one dose of rasburicase between 1 January 2012 and 1 December 2016. Twenty-seven (79.4%) doses in the preprotocol group and 28 (82.4%) doses in the postprotocol group successfully achieved a uric acid level less than 7.5 mg/dl after a single dose of rasburicase (p=1.000). The average total monthly cost of rasburicase was reduced by 59.9% after adoption of the new protocol. Conclusions Indication-based, low-dose rasburicase displayed significantly more value when compared to weight-based dosing as shown by achieving cost savings without compromising clinical efficacy.

Impact of high-dose atorvastatin therapy and clinical risk factors on incident aortic valve stenosis in patients with cardiovascular disease (from TNT, IDEAL, and SPARCL).

PubMed

Arsenault, Benoit J; Boekholdt, S Matthijs; Mora, Samia; DeMicco, David A; Bao, Weihang; Tardif, Jean-Claude; Amarenco, Pierre; Pedersen, Terje; Barter, Philip; Waters, David D

2014-04-15

Clinical trials have not provided evidence for a role of statin therapy in reducing aortic valve stenosis (AVS) severity in patients with documented AVS. However, whether statin therapy could prevent the onset of AVS is unknown. Our objectives were (1) to compare the incidence rates of AVS among patients treated with high-dose versus usual-dose statin or placebo and (2) to identify clinical risk factors associated with the development of AVS. We conducted post hoc analyses in 23,508 participants from 3 large-scale multicenter atorvastatin randomized blinded clinical trials: Treating to New Targets, the Incremental Decrease in End Points Through Aggressive Lipid Lowering, and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels. The main outcome measure was the incidence of clinical AVS over a median follow-up of 4.9 years (82 cases). Among patients who developed AVS, 39 (47.6%) were treated with atorvastatin 80 mg and 43 (52.4%) were treated with lower dose statin (atorvastatin 10 mg in Treating to New Targets, simvastatin 20 to 40 mg in Incremental Decrease in End Points Through Aggressive Lipid Lowering, or placebo in Stroke Prevention by Aggressive Reduction in Cholesterol Levels; hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.59 to 1.41, p=0.67). In multivariate analyses forcing treatment, sex, and race into the model, factors that were significantly associated with AVS included age (HR 2.17, 95% CI 1.61 to 2.93, p<0.0001 per 1-SD increment), diabetes (HR 1.67, 95% CI 1.00 to 2.80, p=0.05), vitamin K antagonist use (HR 3.25, 95% CI 2.06 to 5.16, p<0.0001), and previous statin use (HR 2.65, 95% CI 1.54 to 4.60, p=0.0008). In conclusion, random allocation to high-dose versus usual-dose statin therapy or placebo did not impact the incidence of AVS among patients without known AVS. Age, diabetes, vitamin K antagonists, and previous statin use were significant predictors of incident AVS in these high-risk patients. Copyright © 2014 Elsevier Inc. All rights reserved.

TH-CD-207A-12: Impacts of Inter- and Intra-Fractional Organ Motion for High-Risk Prostate Cancer Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hassan Rezaeian, N; Chi, Y; Zhou, Y

2016-06-15

Purpose: We are conducting a clinical trial on stereotactic body radiation therapy (SBRT) for high-risk prostate cancer. Doses to three targets, prostate, intra-prostatic lesion, and pelvic lymph node (PLN) region, are escalated to three different levels via simultaneous integrated boost technique. Inter-/intra-fractional organ motions deteriorate planned dose distribution. This study aims at developing a dose reconstruction system to comprehensively understand the impacts of organ motion in our clinical trial. Methods: A 4D dose reconstruction system has been developed for this study. Using a GPU-based Monte-Carlo dose engine and delivery log file, the system is able to reconstruct dose on staticmore » or dynamic anatomy. For prostate and intra-prostatic targets, intra-fractional motion is the main concern. Motion trajectory acquired from Calypso in previously treated SBRT patients were used to perform 4D dose reconstructions. For pelvic target, inter-fractional motion is one concern. Eight patients, each with four cone beam CTs, were used to derive fractional motion. The delivered dose was reconstructed on the deformed anatomy. Dosimetric parameters for delivered dose distributions of the three targets were extracted and compared with planned levels. Results: For prostate intra-fractional motion, the mean 3D motion amplitude during beam delivery ranged from 1.5mm to 5.0mm and the average among all patients was 2.61mm. Inter-fractional motion for the PLN target was more significant. The average amplitude among patients was 4mm with the largest amplitude up to 9.6mm. The D95% deviation from planned level for prostate PTVs and GTVs are on average less than<0.1% and this deviation for intra-prostatic lesion PTVs and GTVs were more prominent. The dose at PLN was significantly affected with D{sub 95}% reduced by up to 44%. Conclusion: Intra-/inter-fractional organ motion is a concern for high-risk prostate SBRT, particularly for the PLN target. Our dose reconstruction approach can also serve as the basis to guide treatment adaptation.« less

An Approach to Mitigate Particle Formation on the Dilution of a Monoclonal Antibody Drug Product in an IV Administration Fluid.

PubMed

Zheng, Songyan; Adams, Monica; Mantri, Rao V

2016-03-01

To support dose reduction, low dose of a monoclonal antibody (mAb) was required to be administered via IV infusion at a concentration of 0.1 mg/mL. To achieve the target protein concentration, the infusion solution was prepared by diluting the drug product containing 10-mg/mL mAb with normal saline, a 0.9% sodium chloride injection solution. However, particles were observed in the diluted solution. Particle formation must be avoided to administer the low dose using the existing drug product. To mitigate the particle formation, an unconventional compounding approach was used. With this approach, a stabilizing vehicle containing polysorbate-80 was added to saline before drug-product dilution to maintain suitable surfactant level to prevent precipitation of the mAb. In this way, use of the stabilizing vehicle to support low doses ensured suitable quality across a wider range of mAb concentrations, thereby allowing additional flexibility to the clinical trial. Such an approach may be useful for broader application in early-stage clinical trials where there is an uncertainty regarding doses or the need to revise to lower doses based on clinical observations or other drivers. Copyright © 2016. Published by Elsevier Inc.

Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.

PubMed

Sandborn, W J; Bhandari, B R; Fogel, R; Onken, J; Yen, E; Zhao, X; Jiang, Z; Ge, D; Xin, Y; Ye, Z; French, D; Silverman, J A; Kanwar, B; Subramanian, G M; McHutchison, J G; Lee, S D; Shackelton, L M; Pai, R K; Levesque, B G; Feagan, B G

2016-07-01

Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Characterization of a new generation of computed radiography system based on line scanning and phosphor needles

NASA Astrophysics Data System (ADS)

Dragusin, Octavian; Rogge, Frank; Pauwels, Herman; Marchal, Guy; Bosmans, Hilde

2006-03-01

A new generation CR system that is based on phosphor needles and that uses a digitizer with line scan technology was compared to a clinically used CR system. Purely technical and more clinically related tests were run on both systems. This included the calculation of the DQE, signal-to-noise and contrast to noise ratios from Aluminum inserts, contrast detail analysis with the CDRAD phantom and the use of anthropomorphic phantoms (wrist, chest and skull) with scoring by a radiologist. X-ray exposures with various dose levels and 50kV, 70kV and 125kV were acquired. For detector doses above 0.8 μGy, all noise related measurements showed the superiority of the new technology. The MTF confirmed the improvement in sharpness: between 1 and 3 lp/mm increases ranged from 20 to 50%. Further work should be devoted to the determination of the required dose levels in the plate for the different radiological applications.

A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload.

PubMed

Rienhoff, Hugh Young; Viprakasit, Vip; Tay, Lay; Harmatz, Paul; Vichinsky, Elliott; Chirnomas, Deborah; Kwiatkowski, Janet L; Tapper, Amy; Kramer, William; Porter, John B; Neufeld, Ellis J

2011-04-01

There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (C(max)) was reached within 60-90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t(1/2)) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419).

EVALUATION OF EYE LENS DOSES OF INTERVENTIONAL CARDIOLOGISTS.

PubMed

Yokoyama, Sumi; Suzuki, Shoichi; Toyama, Hiroshi; Arakawa, Shinji; Inoue, Satoshi; Kinomura, Yutaka; Kobayashi, Ikuo

2017-04-01

The effective dose of medical staff members, especially interventional radiologists and cardiologists, is classified as a relatively high level. We measured the dose for interventional cardiologists by using optically stimulated luminescence dosimeters (OSLDs). However, this quantity is not the same as Hp (3). In experiments, the dose at the eye-lens position of a phantom were measured using OSLDs and thermoluminescence dosimeters (TLDs). A conversion factor from dose measured by using TLDs to OSLDs was estimated from these results. In addition, the eye doses of interventional cardiologists in clinical situations were measured, and the effect of eyewear on the eye-lens dose was discussed. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of high-dose rosuvastatin loading before percutaneous coronary intervention in Chinese patients with acute coronary syndrome: A systematic review and meta-analysis

PubMed Central

Su, Qiang; Guo, Wenqin; Dai, Weiran; Li, Hongqing; Yang, Huafeng; Li, Lang

2017-01-01

Background Acute coronary syndrome (ACS) is an important disease threatening human life and health. Many studies have shown that the loading dose of atorvastatin can significantly improve the prognosis of patients with ACS, and reduce the mortality. However, this conclusion is not consistent. Thus, we aimed to evaluate the effect of high-dose rosuvastatin loading before percutaneous coronary intervention (PCI) in Chinese patients with ACS using a meta-analysis based on a systematic review of published articles. Methods We systematically reviewed published studies, evaluating the effect of high-dose rosuvastatin loading before percutaneous coronary intervention in Chinese patients with ACS. The retrieval time is limited from inception to 2 November 2016, and the retrieved databases included PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, the VIP database and the Wang Fang database. Two researchers independently assessed the quality of the included studies and then extracted the data. Stata 11.0 was used for data analysis. Results In total, 11 articles, which included 802 patients, were included in our meta-analysis. Among these patients, 398 patients were in the high-dose group (20 mg/day) and 404 patients were in the conventional dose group (10 mg/day). Meta-analysis results showed that compared with the conventional dose group: 1) The loading dose of rosuvastatin can significantly reduce the hs-CRP level after PCI, including at 24 hours (SMD = -0.65, 95%CI -0.84 ~ -0.47, P = 0.000), 48 hours (SMD = -0.40, 95%CI -0.68 ~ -0.11, P = 0.006), and four weeks (SMD = -1.64, 95%CI -2.01 ~ -1.26, P = 0.000). 2) The loading dose of rosuvastatin can significantly reduce the levels of LDL-C and cTnT, including the level of LDL-C at 30 d after PCI (SMD = -0.89, 95%CI -1.10 ~ -0.69, P = 0.000), and the level of cTnT at 24 h after PCI (SMD = -1.93, 95%CI -2.28 ~ -1.59, P = 0.000), and increase the level of HDL-C at 48 h after PCI (SMD = 0.61, 95%CI 0.34 ~ 0.88, P = 0.000). 3) The loading dose of rosuvastatin can significantly reduce the levels of TG and TC, including the level of TG at 30 d after PCI (SMD = -0.94, 95%CI -1.17 ~ -0.71, P = 0.000), the level of TC at 48 h after PCI (SMD = -0.35, 95%CI -0.68 ~ -0.01, P = 0.043), and the level of TC at 30 d after PCI (SMD = -0.77, 95%CI -0.98 ~ -0.56, P = 0.000). Conclusions Our systematic review and meta-analysis showed that, compared with the conventional dose, the loading dose of rosuvastatin was more beneficial to patients with ACS in China and is suitable for clinical application. Due to the limitations of the quality and quantity of included articles, this conclusion still needs to be confirmed by multicenter clinical trials. PMID:28231287

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Influence of low-level resistance to vancomycin on efficacy of teicoplanin and vancomycin for treatment of experimental endocarditis due to Enterococcus faecium.

PubMed Central

Fantin, B; Leclercq, R; Arthur, M; Duval, J; Carbon, C

1991-01-01

Emergence of vancomycin-resistant strains among enterococci raises a new clinical challenge. Rabbits with aortic endocarditis were infected with Enterococcus faecium BM4172, a clinical strain resistant to low levels of vancomycin (MIC, 16 micrograms/ml) and susceptible to teicoplanin (MIC, 1 micrograms/ml), and against its susceptible variant E. faecium BM4172S obtained in vitro by insertional mutagenesis (MICs, 2 and 0.5 micrograms/ml, respectively). Control animals retained 8 to 10.5 log10 CFU/g of vegetation. We evaluated in this model the efficacy of vancomycin (30 mg/kg of body weight; mean peak and trough serum levels, 27 and 5 micrograms/ml, respectively), teicoplanin (standard dose, 10 mg/kg; mean peak and trough levels, 23 and 9 micrograms/ml, respectively; and high dose, 20 mg/kg; mean peak and trough levels, 63 and 25 micrograms/ml, respectively), gentamicin (6 mg/kg; mean peak and trough levels, 8.6 and less than 0.1 micrograms/ml, respectively), alone or in combination, given every 12 h intramuscularly for 5 days. Teicoplanin standard dose was as active as vancomycin against both strains. Vancomycin was not effective against E. faecium BM4172 but was highly effective against E. faecium BM4172S (7.5 +/- 1.1 log10 CFU/g of vegetation versus 4.9 +/- 1.0 log10 CFU/g of vegetation for vancomycin against E. faecium BM4172 and E. faecium BM4172S, respectively; P = 0.0012). A high dose of teicoplanin was more effective than vancomycin against E. faecium BM4172 (4.4 +/- 1.8 log10 CFU/g of vegetation versus 7.5 +/- 1.1 log10 CFU/g of vegetation for teicoplanin high dose and vancomycin, respectively; P less than 0.05). Against E. faecium BM4172 glycopeptide-gentamicin combinations were the most effective regimens in vitro and in vivo (2.8 +/- 0.7 and 3.5 +/- 1.3 log10 CFU/g of vegetation for vancomycin plus gentamicin and teicoplanin standard dose plus gentamicin, respectively; P < 0.05 versus single-drug regimens). We concluded that high-dose teicoplanin or the combination of a glycopeptide antibiotic plus gentamicin was effective against experimental infection due to E. faecium with low-level resistance to vancomycin. PMID:1834013

Importance of a Patient Dosimetry and Clinical Follow-up Program in the Detection of Radiodermatitis After Long Percutaneous Coronary Interventions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vano, Eliseo, E-mail: eliseov@med.ucm.es; Escaned, Javier; Vano-Galvan, Sergio

Complex percutaneous interventions often require high radiation doses likely to produce skin radiation injuries. We assessed the methodology used to select patients with potential skin injuries in cardiac procedures and in need of clinical follow-up. We evaluated peak skin dose and clinical follow-up in a case of radiodermatitis produced during a total occlusion recanalization. This prospective study followed CIRSE and ACC/AHA/SCAI recommendations for patient radiation dose management in interventional procedures carried out in a university hospital with a workload of 4200 interventional cardiac procedures per year. Patient dose reports were automatically transferred to a central database. Patients exceeding trigger levelsmore » for air kerma area product (500 Gy cm{sup 2}) and cumulative skin dose (5 Gy) were counseled and underwent follow-up for early detection of skin injuries, with dermatologic support. The Ethical Committee and the Quality Assurance and Radiation Safety Committee approved the program. During 2010, a total of 13 patients (3.0/1,000 that year) received dose values exceeding trigger levels in the cardiovascular institute. Only one patient, who had undergone two consecutive procedures resulting in 970 Gy cm{sup 2} and 13.0 Gy as cumulative skin dose, showed signs of serious radiodermatitis that resolved in 3.7 months. The remaining patients did not manifest skin lesions during follow-up, and whenever patient examination was not feasible as part of the follow-up, neither patients nor families reported any skin injuries. Peak skin dose calculation and close clinical follow-up were feasible and appropriate, with a moderate additional workload for the staff and satisfaction for the patient.« less

Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study.

PubMed

Schulz, Craig A; Mehta, Minesh P; Badie, Benham; McGinn, Cornelius J; Robins, H Ian; Hayes, Lori; Chappell, Rick; Volkman, Jen; Binger, Kim; Arzoomanian, Rhoda; Simon, Kris; Alberti, Dona; Feierabend, Christine; Tutsch, Kendra D; Kunugi, Keith A; Wilding, George; Kinsella, Timothy J

2004-07-15

To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma. Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used. Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM). In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.

Development and Validation of a Novel Vancomycin Dosing Nomogram for Achieving High-Target Trough Levels at 2 Canadian Teaching Hospitals

PubMed Central

Thalakada, Rosanne; Legal, Michael; Lau, Tim T Y; Luey, Tiffany; Batterink, Josh; Ensom, Mary H H

2012-01-01

Background: Recent guidelines recommend a vancomycin trough (predose) level between 15 and 20 mg/L in the treatment of invasive gram-positive infections, but most initial dosing nomograms are designed to achieve lower targets (5–15 mg/L). Clinicians need guidance about appropriate initial dosing to achieve the higher target. Objective: To develop and validate a high-target vancomycin dosing nomogram to achieve trough levels of 15–20 mg/L. Methods: A retrospective study was conducted at 2 teaching hospitals, St Paul’s Hospital and Vancouver General Hospital in Vancouver, British Columbia. Patients who were treated with vancomycin between January 2008 and June 2010 and who had achieved a trough level of 14.5–20.5 mg/L were identified. Demographic and clinical data were collected. Multiple linear regression was used to develop a vancomycin dosing nomogram for each hospital site. An integrated nomogram was constructed by merging the data from the 2 hospitals. A unique set of patients at each institution was used for validating their respective nomograms and a pooled group of patients for validating the integrated nomogram. Predictive success was evaluated, and a nomogram was deemed significantly different from another nomogram if p < 0.05 via “χ2 testing. Results: Data from 78 patients at one hospital and 91 patients at the other were used in developing the respective institutional nomograms. For each hospital’s data set, both age and initial serum creatinine were significantly associated with the predicted dosing interval (p < 0.001). Validation in a total of 105 test patients showed that the integrated nomogram had a predictive success rate of 56%. Conclusions: A novel vancomycin dosing nomogram was developed and validated at 2 Canadian teaching hospitals. This integrated nomogram is a tool that clinicians can use in selecting appropriate initial vancomycin regimens on the basis of age and serum creatinine, to achieve high-target levels of 15–20 mg/L. The nomogram should not replace clinical judgment for patients with unstable and/or reduced renal function. PMID:22783028

SU-E-I-57: Estimating the Occupational Eye Lens Dose in Interventional Radiology Using Active Personal Dosimeters Worn On the Chest

DOE Office of Scientific and Technical Information (OSTI.GOV)

Omar, A; Marteinsdottir, M; Kadesjo, N

Purpose: To provide a general formalism for determination of occupational eye lens dose based on the response of an active personal dosimeter (APD) worn at chest level above the radiation protection apron. Methods: The formalism consists of three factors: (1) APD conversion factor converting the reading at chest level (APDchest) to the corresponding personal dose equivalent at eye level, (2) Dose conversion factor transferring the measured dose quantity, Hp(10), into a dose quantity relevant for the eye lens dose, (3) Correction factor accounting for differences in exposure of the eye(s) compared to the exposure at chest level (e.g., due tomore » protective lead glasses).The different factors were investigated and evaluated based on phantom and clinical measurements performed in an x-ray angiography suite for interventional cardiology. Results: The eye lens dose can be conservatively estimated by assigning an appropriate numerical value to each factor entering the formalism that in most circumstances overestimates the dose. Doing so, the eye lens dose to the primary operator and assisting staff was estimated in this work as D-eye,primary = 2.0 APDchest and D-eye,assisting = 1.0 APDchest, respectively.The annual eye lens dose to three nurses and one cardiologist was estimated to be 2, 2, 2, and 13 mSv (Hp(0.07)), respectively, using a TLD dosimeter worn at eye level. In comparison, using the formalism and APDchest measurements, the respective doses were 2, 2, 2, and 16 mSv (Hp(3)). Conclusion: The formalism outlined in this work can be used to estimate the occupational eye lens dose from the response of an APD worn on the chest. The formalism is general and could be applied also to other types of dosimeters. However, the numerical value of the different factors may differ from those obtained with the APD’s used in this work due to differences in dosimeter properties.« less

Cognitive style, alprazolam plasma levels, and treatment response in panic disorder.

PubMed

Uhlenhuth, E H; Starcevic, Vladan; Qualls, Clifford; Antal, Edward J; Matuzas, William; Javaid, Javaid I; Barnhill, Jamie

2008-01-01

This study investigated an anxiety-prone cognitive style (measured by the Anxious Thoughts and Tendencies Questionnaire, AT&T) as a predictor of the acute response to increasing alprazolam plasma levels in panic disorder. Panic disorder patients (n=26) were treated with escalating doses of alprazolam for 4 weeks, then a fixed dose of 1 mg four times a day for 4 weeks. At 0, 1, 2, 3, 4, 6, and 8 weeks, trough alprazolam plasma levels; clinical, self-report, and performance measures; and vital signs were assessed. Panic attack data were from daily diaries. The repeated response measures were analyzed in relation to alprazolam plasma levels using SAS GENMOD, with patients classified as high or low on the baseline AT&T. Panic attacks, anticipatory anxiety, fear, avoidance, overall agoraphobia, the Hamilton Anxiety Rating Scale, and clinicians' global ratings improved with increasing alprazolam plasma levels. Hopkins Symptom Checklist-90 Anger-Hostility; Profile of Mood States Vigor, Confusion, and Friendliness; and speed and accuracy of performance worsened. Patients with high AT&T scores were worse throughout the study on situational panics, fear, avoidance, overall agoraphobia, the Hamilton Anxiety Rating Scale, the Hamilton Rating Scale for Depression, and Clinical Global Improvement; most Hopkins Symptom Checklist-90 clusters; Profile of Mood States Anxiety, Depression, and Confusion; and Continuous Performance Task omissions. We conclude that in panic disorder: (1) alprazolam has a broad spectrum of clinical activity related to plasma levels in individual patients; (2) sedation, disinhibition, and performance deficits may persist for at least a month after dose escalation ends; (3) marked anxiety-prone cognitions predict more symptoms throughout treatment, but do not modify the response to alprazolam and therefore should not influence the choice of alprazolam as treatment. Published 2007 Wiley-Liss, Inc.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.

PubMed

Creelan, Ben C; Gabrilovich, Dmitry I; Gray, Jhanelle E; Williams, Charles C; Tanvetyanon, Tawee; Haura, Eric B; Weber, Jeffrey S; Gibney, Geoffrey T; Markowitz, Joseph; Proksch, Joel W; Reisman, Scott A; McKee, Mark D; Chin, Melanie P; Meyer, Colin J; Antonia, Scott J

2017-01-01

Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

Progressive cone beam CT dose control in image-guided radiation therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yan Hao; Cervino, Laura; Jiang, Steve B.

2013-06-15

Purpose: Cone beam CT (CBCT) in image-guided radiotherapy (IGRT) offers a tremendous advantage for treatment guidance. The associated imaging dose is a clinical concern. One unique feature of CBCT-based IGRT is that the same patient is repeatedly scanned during a treatment course, and the contents of CBCT images at different fractions are similar. The authors propose a progressive dose control (PDC) scheme to utilize this temporal correlation for imaging dose reduction. Methods: A dynamic CBCT scan protocol, as opposed to the static one in the current clinical practice, is proposed to gradually reduce the imaging dose in each treatment fraction.more » The CBCT image from each fraction is processed by a prior-image based nonlocal means (PINLM) module to enhance its quality. The increasing amount of prior information from previous CBCT images prevents degradation of image quality due to the reduced imaging dose. Two proof-of-principle experiments have been conducted using measured phantom data and Monte Carlo simulated patient data with deformation. Results: In the measured phantom case, utilizing a prior image acquired at 0.4 mAs, PINLM is able to improve the image quality of a CBCT acquired at 0.2 mAs by reducing the noise level from 34.95 to 12.45 HU. In the synthetic patient case, acceptable image quality is maintained at four consecutive fractions with gradually decreasing exposure levels of 0.4, 0.1, 0.07, and 0.05 mAs. When compared with the standard low-dose protocol of 0.4 mAs for each fraction, an overall imaging dose reduction of more than 60% is achieved. Conclusions: PINLM-PDC is able to reduce CBCT imaging dose in IGRT utilizing the temporal correlations among the sequence of CBCT images while maintaining the quality.« less

High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097.

PubMed

He, Wei; Luistro, Leopoldo; Carvajal, Daisy; Smith, Melissa; Nevins, Tom; Yin, Xuefeng; Cai, James; Higgins, Brian; Kolinsky, Kenneth; Rizzo, Christine; Packman, Kathryn; Heimbrook, David; Boylan, John F

2011-06-01

Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the γ-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

The adaptive statistical iterative reconstruction-V technique for radiation dose reduction in abdominal CT: comparison with the adaptive statistical iterative reconstruction technique.

PubMed

Kwon, Heejin; Cho, Jinhan; Oh, Jongyeong; Kim, Dongwon; Cho, Junghyun; Kim, Sanghyun; Lee, Sangyun; Lee, Jihyun

2015-10-01

To investigate whether reduced radiation dose abdominal CT images reconstructed with adaptive statistical iterative reconstruction V (ASIR-V) compromise the depiction of clinically competent features when compared with the currently used routine radiation dose CT images reconstructed with ASIR. 27 consecutive patients (mean body mass index: 23.55 kg m(-2) underwent CT of the abdomen at two time points. At the first time point, abdominal CT was scanned at 21.45 noise index levels of automatic current modulation at 120 kV. Images were reconstructed with 40% ASIR, the routine protocol of Dong-A University Hospital. At the second time point, follow-up scans were performed at 30 noise index levels. Images were reconstructed with filtered back projection (FBP), 40% ASIR, 30% ASIR-V, 50% ASIR-V and 70% ASIR-V for the reduced radiation dose. Both quantitative and qualitative analyses of image quality were conducted. The CT dose index was also recorded. At the follow-up study, the mean dose reduction relative to the currently used common radiation dose was 35.37% (range: 19-49%). The overall subjective image quality and diagnostic acceptability of the 50% ASIR-V scores at the reduced radiation dose were nearly identical to those recorded when using the initial routine-dose CT with 40% ASIR. Subjective ratings of the qualitative analysis revealed that of all reduced radiation dose CT series reconstructed, 30% ASIR-V and 50% ASIR-V were associated with higher image quality with lower noise and artefacts as well as good sharpness when compared with 40% ASIR and FBP. However, the sharpness score at 70% ASIR-V was considered to be worse than that at 40% ASIR. Objective image noise for 50% ASIR-V was 34.24% and 46.34% which was lower than 40% ASIR and FBP. Abdominal CT images reconstructed with ASIR-V facilitate radiation dose reductions of to 35% when compared with the ASIR. This study represents the first clinical research experiment to use ASIR-V, the newest version of iterative reconstruction. Use of the ASIR-V algorithm decreased image noise and increased image quality when compared with the ASIR and FBP methods. These results suggest that high-quality low-dose CT may represent a new clinical option.

The adaptive statistical iterative reconstruction-V technique for radiation dose reduction in abdominal CT: comparison with the adaptive statistical iterative reconstruction technique

PubMed Central

Cho, Jinhan; Oh, Jongyeong; Kim, Dongwon; Cho, Junghyun; Kim, Sanghyun; Lee, Sangyun; Lee, Jihyun

2015-01-01

Objective: To investigate whether reduced radiation dose abdominal CT images reconstructed with adaptive statistical iterative reconstruction V (ASIR-V) compromise the depiction of clinically competent features when compared with the currently used routine radiation dose CT images reconstructed with ASIR. Methods: 27 consecutive patients (mean body mass index: 23.55 kg m−2 underwent CT of the abdomen at two time points. At the first time point, abdominal CT was scanned at 21.45 noise index levels of automatic current modulation at 120 kV. Images were reconstructed with 40% ASIR, the routine protocol of Dong-A University Hospital. At the second time point, follow-up scans were performed at 30 noise index levels. Images were reconstructed with filtered back projection (FBP), 40% ASIR, 30% ASIR-V, 50% ASIR-V and 70% ASIR-V for the reduced radiation dose. Both quantitative and qualitative analyses of image quality were conducted. The CT dose index was also recorded. Results: At the follow-up study, the mean dose reduction relative to the currently used common radiation dose was 35.37% (range: 19–49%). The overall subjective image quality and diagnostic acceptability of the 50% ASIR-V scores at the reduced radiation dose were nearly identical to those recorded when using the initial routine-dose CT with 40% ASIR. Subjective ratings of the qualitative analysis revealed that of all reduced radiation dose CT series reconstructed, 30% ASIR-V and 50% ASIR-V were associated with higher image quality with lower noise and artefacts as well as good sharpness when compared with 40% ASIR and FBP. However, the sharpness score at 70% ASIR-V was considered to be worse than that at 40% ASIR. Objective image noise for 50% ASIR-V was 34.24% and 46.34% which was lower than 40% ASIR and FBP. Conclusion: Abdominal CT images reconstructed with ASIR-V facilitate radiation dose reductions of to 35% when compared with the ASIR. Advances in knowledge: This study represents the first clinical research experiment to use ASIR-V, the newest version of iterative reconstruction. Use of the ASIR-V algorithm decreased image noise and increased image quality when compared with the ASIR and FBP methods. These results suggest that high-quality low-dose CT may represent a new clinical option. PMID:26234823

Dietary supplementation with low-dose omega-3 fatty acids reduces salivary tumor necrosis factor-α levels in patients with chronic periodontitis: a randomized controlled clinical study.

PubMed

Keskiner, I; Saygun, I; Bal, V; Serdar, M; Kantarci, A

2017-08-01

Recent studies have demonstrated the beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) on physiological processes and on a variety of chronic inflammatory diseases, including periodontal diseases. In this study, we evaluated the impact of omega-3 PUFAs in conjunction with scaling and root planing (SRP) on salivary markers in patients with chronic periodontitis. Thirty systemically healthy subjects with chronic periodontitis were enrolled and randomly allocated into two groups. The control group (n = 15) was treated with SRP + placebo whereas the test group was treated with SRP and dietary supplementation of low-dose omega-3 PUFAs (6.25 mg eicosapentaenoic acid and 19.19 mg docosahexaenoic acid). Clinical parameters were taken at baseline, 1, 3 and 6 mo following therapy. Saliva samples were obtained at the same time intervals and analyzed for tumor necrosis factor-α (TNF-α) and superoxide dismutase (SOD). Both groups showed significant changes in clinical parameters in response to treatment compared to baseline with no significant difference between groups. Salivary TNF-α levels showed a statistically significant decrease in the test group at 6 mo compared to the control group. Salivary SOD levels increased significantly at 3 and 6 mo in the test group and at 6 mo in placebo groups compared to baseline with no statistically significant differences between the groups. The results demonstrated that dietary supplementation with low-dose omega-3 PUFAs improves salivary TNF-α without any significant impact on clinical parameters in patients with chronic periodontitis, suggesting that the systemic benefits of dietary omega-3 PUFAs may not be translated to periodontal health. (ClinicalTrials.gov ID NCT02719587). © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Subchronic toxicity studies of t-butyl alcohol in rats and mice.

PubMed

Lindamood, C; Farnell, D R; Giles, H D; Prejean, J D; Collins, J J; Takahashi, K; Maronpot, R R

1992-07-01

The purpose of this study was to evaluate the toxicity of t-butyl alcohol, an important commodity chemical, an additive to unleaded gasoline, and a contaminant of drinking water. Ninety-day toxicity studies were conducted in B6C3F1 mice and Fischer 344 (F344) rats of both sexes using dosed water. Dose levels of t-butyl alcohol were 0, 0.25, 0.5, 1, 2, and 4% (w/v). Lethality was observed at the 4% level of both sexes and species. Weight-gain depression was present in all dose levels of male rats; 4% female rats; 1, 2, and 4% male mice; and 2 and 4% female mice. Water consumption was increased at lower dose levels in male rats and decreased in the higher dose levels of both sexes of rats and female mice. Clinical signs in rats were ataxia in both sexes and hypoactivity in males. Clinical signs in mice were ataxia, abnormal posture, and hypoactivity. In rats, urine volumes were reduced, in association with crystalluria. Gross lesions at necropsy were urinary tract calculi, renal pelvic and ureteral dilatation, and thickening of the urinary bladder mucosa. Microscopic lesions were hyperplasia of transitional epithelia and inflammation of the urinary bladder. In male rats treated with t-butyl alcohol, microscopic renal changes were suggestive of alpha-2 mu-globulin nephropathy. No-effect levels for the urinary tract lesions were 1% in male rats and mice (803.7 mg/kg/day for the male rats and 1565.8 mg/kg/day for the male mice) and 2% in female rats and mice (1451.5 mg/kg/day for the female rats and 4362.9 mg/kg/day for the female mice). The results indicate that in rodents the urinary tract is the target organ for t-butyl alcohol toxicity, and males are more sensitive to t-butyl alcohol toxicity than females.

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

PubMed

Martinez, Alvaro A; Gustafson, Gary; Gonzalez, José; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

2002-06-01

To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Comparison of 2-Dose and 3-Dose 9-Valent Human Papillomavirus Vaccine Schedules in the United States: A Cost-effectiveness Analysis.

PubMed

Laprise, Jean-François; Markowitz, Lauri E; Chesson, Harrell W; Drolet, Mélanie; Brisson, Marc

2016-09-01

A recent clinical trial using the 9-valent human papillomavirus virus (HPV) vaccine has shown that antibody responses after 2 doses are noninferior to those after 3 doses, suggesting that 2 and 3 doses may have comparable vaccine efficacy. We used an individual-based transmission-dynamic model to compare the population-level effectiveness and cost-effectiveness of 2- and 3-dose schedules of 9-valent HPV vaccine in the United States. Our model predicts that if 2 doses of 9-valent vaccine protect for ≥20 years, the additional benefits of a 3-dose schedule are small as compared to those of 2-dose schedules, and 2-dose schedules are likely much more cost-efficient than 3-dose schedules. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.

PubMed

Dellinger, Ryan W; Santos, Santiago Roel; Morris, Mark; Evans, Mal; Alminana, Dan; Guarente, Leonard; Marcotulli, Eric

2017-01-01

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD +) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD + in whole blood demonstrated that NRPT significantly increases the concentration of NAD + in a dose-dependent manner. NAD + levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD + levels was sustained throughout the entire 8-week trial. NAD + levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD + levels sustainably.

Evaluation of a 12-week targeted vitamin D supplementation regimen in patients with active inflammatory bowel disease.

PubMed

Garg, Mayur; Rosella, Ourania; Rosella, Gennaro; Wu, Yunqiu; Lubel, John S; Gibson, Peter R

2017-06-15

Vitamin D at serum 25(OH)D concentrations above 100 nmol/L is associated with disease remission in patients with IBD, suggesting targeted dosing might be anti-inflammatory. This study aimed to assess the effectiveness, safety and predictors of a 12-week regimen of vitamin D supplementation to achieve such a target in patients with active disease. In a pilot study, patients with active colitis and a serum 25(OH)D concentration <75 nmol/L were prescribed oral liquid vitamin D supplementation over 12 weeks using a specific protocol with dose adjusted 4-weekly to aim for a target level of 100-125 nmol/L. Five patients each with Crohn's colitis or ulcerative colitis (UC) had mean 25(OH)D concentration 52 (range 27-73 nmol/L). Five reached the targeted level and four 89-95 nmol/L. One withdrew after 4 weeks (88 nmol/L). Target dose was met only in those with BMI <30 kg/m 2 and total dose inversely correlated with initial serum 25(OH)D. One patient had developed a high level at 8 weeks (146 nmol/L) and another new hypercalciuria. There were no serious adverse events attributable to the therapy. Clinical disease activity consistently declined, but faecal calprotectin and circulating markers of inflammation did not. A specified oral vitamin D regimen successfully and safely achieved target or near-target levels, improved symptom-based activity scores, but did not alter objective measures of intestinal or systemic inflammation. A modified version of this dose-escalating regimen would be suitable for a randomised placebo-controlled trial, but does require regular safety monitoring. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Radiosynthesis of clinical doses of 68Ga-DOTATATE (GalioMedix™) and validation of organic-matrix-based 68Ge/68Ga generators

PubMed Central

Tworowska, Izabela; Ranganathan, David; Thamake, Sanjay; Delpassand, Ebrahim; Mojtahedi, Alireza; Schultz, Michael K.; Zhernosekov, Konstantin; Marx, Sebastian

2017-01-01

Introduction 68Ga-DOTATATE is a radiolabeled peptide-based agonist that targets somatostatin receptors overexpressed in neuroendocrine tumors. Here, we present our results on validation of organic matrix 68Ge/68Ga generators (ITG GmbH) applied for radiosynthesis of the clinical doses of 68Ga-DOTATATE (GalioMedixTM). Methods The clinical grade of DOTATATE (25 µg±5µg) compounded in 1MNaOAc at pH=5.5 was labeled manually with 514±218MBq (13.89±5.9 mCi) of 68Ga eluate in 0.05 N HCl at 95 °C for 10 min. The radiochemical purity of the final dose was validated using radio-TLC. The quality control of clinical doses included tests of their osmolarity, endotoxin level, radionuclide identity, filter integrity, pH, sterility and 68Ge breakthrough. Results The final dose of 272±126MBq (7.35±3.4 mCi) of 68Ga-DOTATATE was produced with a radiochemical yield (RCY) of 99%±1%. The total time required for completion of radiolabeling and quality control averaged approximately 35 min. This resulted in delivery of 50% ± 7% of 68Ga-DOTATATE at the time of calibration (not decay corrected). Conclusions 68Ga eluted from the generator was directly applied for labeling of DOTA-peptide with no additional pre-concentration or pre-purification of isotope. The low acidity of 68Ga eluate allows for facile synthesis of clinical doses with radiochemical and radionuclide purity higher than 98% and average activity of 272 ± 126 MBq (7.3 ± 3 mCi). There is no need for post-labeling C18 Sep-Pak purification of final doses of radiotracer. Advances in knowledge and implications for patient care. The clinical interest in validation of 68Galabeled agents has increased in the past years due to availability of generators from different vendors (Eckert-Ziegler, ITG, iThemba), favorable approach of U.S. FDA agency to initiate clinical trials, and collaboration of U.S. centers with leading EU clinical sites. The list of 68Ga-labeled tracers evaluated in clinical studies should growth because of the sensitivity of PET technique, the simplicity of the shakebake approach for the dose preparation and reliability of 68Ge/68Ga generators. Our studies have confirmed the reproducible elution profile, and high reliability of ITG GmbH generators required for routine doses preparation according to FDA recommendations. PMID:26702783

Radiosynthesis of clinical doses of ⁶⁸Ga-DOTATATE (GalioMedix™) and validation of organic-matrix-based ⁶⁸Ge/⁶⁸Ga generators.

PubMed

Tworowska, Izabela; Ranganathan, David; Thamake, Sanjay; Delpassand, Ebrahim; Mojtahedi, Alireza; Schultz, Michael K; Zhernosekov, Konstantin; Marx, Sebastian

2016-01-01

68Ga-DOTATATE is a radiolabeled peptide-based agonist that targets somatostatin receptors overexpressed in neuroendocrine tumors. Here, we present our results on validation of organic matrix 68Ge/68Ga generators (ITG GmbH) applied for radiosynthesis of the clinical doses of 68Ga-DOTATATE (GalioMedixTM). The clinical grade of DOTATATE (25 μg±5 μg) compounded in 1 M NaOAc at pH=5.5 was labeled manually with 514±218 MBq (13.89±5.9 mCi) of 68Ga eluate in 0.05 N HCl at 95°C for 10 min. The radiochemical purity of the final dose was validated using radio-TLC. The quality control of clinical doses included tests of their osmolarity, endotoxin level, radionuclide identity, filter integrity, pH, sterility and 68Ge breakthrough. The final dose of 272±126 MBq (7.35±3.4 mCi) of 68Ga-DOTATATE was produced with a radiochemical yield (RCY) of 99%±1%. The total time required for completion of radiolabeling and quality control averaged approximately 35 min. This resulted in delivery of 50%±7% of 68Ga-DOTATATE at the time of calibration (not decay corrected). 68Ga eluted from the generator was directly applied for labeling of DOTA-peptide with no additional pre-concentration or pre-purification of isotope. The low acidity of 68Ga eluate allows for facile synthesis of clinical doses with radiochemical and radionuclide purity higher than 98% and average activity of 272±126 MBq (7.3±3 mCi). There is no need for post-labeling C18 Sep-Pak purification of final doses of radiotracer. Advances in knowledge and implications for patient care. The clinical interest in validation of 68Galabeled agents has increased in the past years due to availability of generators from different vendors (Eckert-Ziegler, ITG, iThemba), favorable approach of U.S. FDA agency to initiate clinical trials, and collaboration of U.S. centers with leading EU clinical sites. The list of 68Ga-labeled tracers evaluated in clinical studies should growth because of the sensitivity of PET technique, the simplicity of the shakebake approach for the dose preparation and reliability of 68Ge/68Ga generators. Our studies have confirmed the reproducible elution profile, and high reliability of ITG GmbH generators required for routine doses preparation according to FDA recommendations. Copyright © 2015 Elsevier Inc. All rights reserved.

Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside.

PubMed

Capizzi, R L

1996-01-01

In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C x t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c x T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c x T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1-3 gm/m2) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C x t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.

Validation of the Oncentra Brachy Advanced Collapsed cone Engine for a commercial (192)Ir source using heterogeneous geometries.

PubMed

Ma, Yunzhi; Lacroix, Fréderic; Lavallée, Marie-Claude; Beaulieu, Luc

2015-01-01

To validate the Advanced Collapsed cone Engine (ACE) dose calculation engine of Oncentra Brachy (OcB) treatment planning system using an (192)Ir source. Two levels of validation were performed, conformant to the model-based dose calculation algorithm commissioning guidelines of American Association of Physicists in Medicine TG-186 report. Level 1 uses all-water phantoms, and the validation is against TG-43 methodology. Level 2 uses real-patient cases, and the validation is against Monte Carlo (MC) simulations. For each case, the ACE and TG-43 calculations were performed in the OcB treatment planning system. ALGEBRA MC system was used to perform MC simulations. In Level 1, the ray effect depends on both accuracy mode and the number of dwell positions. The volume fraction with dose error ≥2% quickly reduces from 23% (13%) for a single dwell to 3% (2%) for eight dwell positions in the standard (high) accuracy mode. In Level 2, the 10% and higher isodose lines were observed overlapping between ACE (both standard and high-resolution modes) and MC. Major clinical indices (V100, V150, V200, D90, D50, and D2cc) were investigated and validated by MC. For example, among the Level 2 cases, the maximum deviation in V100 of ACE from MC is 2.75% but up to ~10% for TG-43. Similarly, the maximum deviation in D90 is 0.14 Gy between ACE and MC but up to 0.24 Gy for TG-43. ACE demonstrated good agreement with MC in most clinically relevant regions in the cases tested. Departure from MC is significant for specific situations but limited to low-dose (<10% isodose) regions. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)-6, IL-8 and tumour necrosis factor-α.

PubMed

Schmittner, M D; Faulhaber, J; Kemler, B; Koenen, W; Thumfart, J O; Weiss, C; Neumaier, M; Beck, G C

2010-12-01

Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro-inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. This prospective study examines the influence of MHb on serum interleukin (IL)-6, IL-8 and tumour necrosis tumour necrosis (TNF)-α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880-4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 μg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL-6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF-α and IL-8 release were not found significantly increased. Three patients developed MHb concentrations >15%. This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL-6 but not of IL-8 and TNF-α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia. © 2010 The Authors. Journal compilation © 2010 European Academy of Dermatology and Venereology.

Estimations of the lethal and exposure doses for representative methanol symptoms in humans.

PubMed

Moon, Chan-Seok

2017-01-01

The aim of this review was to estimate the lethal and exposure doses of a representative symptom (blindness) of methanol exposure in humans by reviewing data from previous articles. Available articles published from 1970 to 2016 that investigated the dose-response relationship for methanol exposure (i.e., the exposure concentration and the biological markers/clinical symptoms) were evaluated; the MEDLINE and RISS (Korean search engine) databases were searched. The available data from these articles were carefully selected to estimate the range and median of a lethal human dose. The regression equation and correlation coefficient (between the exposure level and urinary methanol concentration as a biological exposure marker) were assumed from the previous data. The lethal human dose of pure methanol was estimated at 15.8-474 g/person as a range and as 56.2 g/person as the median. The dose-response relationship between methanol vapor in ambient air and urinary methanol concentrations was thought to be correlated. An oral intake of 3.16-11.85 g/person of pure methanol could cause blindness. The lethal dose from respiratory intake was reported to be 4000-13,000 mg/l. The initial concentration of optic neuritis and blindness were shown to be 228.5 and 1103 mg/l, respectively, for a 12-h exposure. The concentration of biological exposure indices and clinical symptoms for methanol exposure might have a dose-response relationship according to previous articles. Even a low dose of pure methanol through oral or respiratory exposure might be lethal or result in blindness as a clinical symptom.

SU-F-18C-01: Minimum Detectability Analysis for Comprehensive Sized Based Optimization of Image Quality and Radiation Dose Across CT Protocols

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smitherman, C; Chen, B; Samei, E

2014-06-15

Purpose: This work involved a comprehensive modeling of task-based performance of CT across a wide range of protocols. The approach was used for optimization and consistency of dose and image quality within a large multi-vendor clinical facility. Methods: 150 adult protocols from the Duke University Medical Center were grouped into sub-protocols with similar acquisition characteristics. A size based image quality phantom (Duke Mercury Phantom) was imaged using these sub-protocols for a range of clinically relevant doses on two CT manufacturer platforms (Siemens, GE). The images were analyzed to extract task-based image quality metrics such as the Task Transfer Function (TTF),more » Noise Power Spectrum, and Az based on designer nodule task functions. The data were analyzed in terms of the detectability of a lesion size/contrast as a function of dose, patient size, and protocol. A graphical user interface (GUI) was developed to predict image quality and dose to achieve a minimum level of detectability. Results: Image quality trends with variations in dose, patient size, and lesion contrast/size were evaluated and calculated data behaved as predicted. The GUI proved effective to predict the Az values representing radiologist confidence for a targeted lesion, patient size, and dose. As an example, an abdomen pelvis exam for the GE scanner, with a task size/contrast of 5-mm/50-HU, and an Az of 0.9 requires a dose of 4.0, 8.9, and 16.9 mGy for patient diameters of 25, 30, and 35 cm, respectively. For a constant patient diameter of 30 cm, the minimum detected lesion size at those dose levels would be 8.4, 5, and 3.9 mm, respectively. Conclusion: The designed CT protocol optimization platform can be used to evaluate minimum detectability across dose levels and patient diameters. The method can be used to improve individual protocols as well as to improve protocol consistency across CT scanners.« less

Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711.

PubMed

Lindström, Erik; Rizoska, Biljana; Henderson, Ian; Terelius, Ylva; Jerling, Markus; Edenius, Charlotte; Grabowska, Urszula

2018-05-09

Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man. The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3-30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg. MIV-711 was a potent inhibitor of human cathepsin K (K i : 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC 50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data. MIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA. Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011.

TU-EF-204-03: Task-Based KV and MAs Optimization for Radiation Dose Reduction in CT: From FBP to Statistical Model-Based Iterative Reconstruction (MBIR)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gomez-Cardona, D; Li, K; Lubner, M G

Purpose: The introduction of the highly nonlinear MBIR algorithm to clinical CT systems has made CNR an invalid metric for kV optimization. The purpose of this work was to develop a task-based framework to unify kV and mAs optimization for both FBP- and MBIR-based CT systems. Methods: The kV-mAs optimization was formulated as a constrained minimization problem: to select kV and mAs to minimize dose under the constraint of maintaining the detection performance as clinically prescribed. To experimentally solve this optimization problem, exhaustive measurements of detectability index (d’) for a hepatic lesion detection task were performed at 15 different mAmore » levels and 4 kV levels using an anthropomorphic phantom. The measured d’ values were used to generate an iso-detectability map; similarly, dose levels recorded at different kV-mAs combinations were used to generate an iso-dose map. The iso-detectability map was overlaid on top of the iso-dose map so that for a prescribed detectability level d’, the optimal kV-mA can be determined from the crossing between the d’ contour and the dose contour that corresponds to the minimum dose. Results: Taking d’=16 as an example: the kV-mAs combinations on the measured iso-d’ line of MBIR are 80–150 (3.8), 100–140 (6.6), 120–150 (11.3), and 140–160 (17.2), where values in the parentheses are measured dose values. As a Result, the optimal kV was 80 and optimal mA was 150. In comparison, the optimal kV and mA for FBP were 100 and 500, which corresponded to a dose level of 24 mGy. Results of in vivo animal experiments were consistent with the phantom results. Conclusion: A new method to optimize kV and mAs selection has been developed. This method is applicable to both linear and nonlinear CT systems such as those using MBIR. Additional dose savings can be achieved by combining MBIR with this method. This work was partially supported by an NIH grant R01CA169331 and GE Healthcare. K. Li, D. Gomez-Cardona, M. G. Lubner: Nothing to disclose. P. J. Pickhardt: Co-founder, VirtuoCTC, LLC Stockholder, Cellectar Biosciences, Inc. G.-H. Chen: Research funded, GE Healthcare; Research funded, Siemens AX.« less

Effect of inhaled corticosteroids on salival composition: a cross-sectional study in patients with bronchial asthma.

PubMed

Navarrete, Bernardino Alcázar; Palacios, Pedro José Romero; Aguilar-Salvatierra, Antonio; Guardia, Javier; Gómez-Moreno, Gerardo

2015-09-01

To date, no evidence exists in the literature as to the effects of inhaled corticosteroids (ICs) on salivary composition in patients with bronchial asthma. The aim of this study was to assess the effect of ICs on salival composition. Adult patients attending an outpatient respiratory clinic who were classified into two groups (controls and patients with bronchial asthma receiving ICs), were recruited in this cross-sectional study. For each participant, data of clinical records, baseline history of asthma, and regular IC dose were recorded. A sample of stimulated saliva was collected and processed for investigation of mucin 5B (MUC5B), lipoxygenase (LPO), total antioxidant capacity, and 8-hydroxydeoxyguanosine (8-OHdG) levels. Overall, 103 patients (49 controls and 54 patients receiving regular treatment with ICs) were recruited. No differences in comorbidities or smoking habits were observed. Patients treated with high-doses of ICs showed lower levels of salival MUC5B compared with those treated with medium IC doses or those not treated with ICs (1.60 vs. 2.20 vs. 2.53 ng/mL; p = 0.042). In patients with asthma, treatment with high-doses of ICs is associated with reduced levels of salivary MUC5B. This effect can explain some of the effects of ICs on oral health.

Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial.

PubMed

Bakris, George L; Pitt, Bertram; Weir, Matthew R; Freeman, Mason W; Mayo, Martha R; Garza, Dahlia; Stasiv, Yuri; Zawadzki, Rezi; Berman, Lance; Bushinsky, David A

2015-07-14

Hyperkalemia is a potentially life-threatening condition predominantly seen in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both. To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia. Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m2 and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment. Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower. The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks. A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P < .001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients. Among patients with hyperkalemia and diabetic kidney disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks. clinicaltrials.gov Identifier:NCT01371747.

Leflunomide is equally efficacious and safe compared to low dose rituximab in refractory rheumatoid arthritis given in combination with methotrexate: results from a randomized double blind controlled clinical trial.

PubMed

Wijesinghe, Harindu; Galappatthy, Priyadharshini; de Silva, Rajiva; Seneviratne, Suranjith L; Saravanamuttu, Ushagowry; Udagama, Preethi; Hart, Melanie; Kelleher, Peter; Senerath, Upul; Fernandopulle, Rohini; Weerasekera, Lilani P; Wijayaratne, Lalith S

2017-07-19

The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination. Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). Leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient's refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).

Influence of CT contrast agent on dose calculation of intensity modulated radiation therapy plan for nasopharyngeal carcinoma.

PubMed

Lee, F K-H; Chan, C C-L; Law, C-K

2009-02-01

Contrast enhanced computed tomography (CECT) has been used for delineation of treatment target in radiotherapy. The different Hounsfield unit due to the injected contrast agent may affect radiation dose calculation. We investigated this effect on intensity modulated radiotherapy (IMRT) of nasopharyngeal carcinoma (NPC). Dose distributions of 15 IMRT plans were recalculated on CECT. Dose statistics for organs at risk (OAR) and treatment targets were recorded for the plain CT-calculated and CECT-calculated plans. Statistical significance of the differences was evaluated. Correlations were also tested, among magnitude of calculated dose difference, tumor size and level of enhancement contrast. Differences in nodal mean/median dose were statistically significant, but small (approximately 0.15 Gy for a 66 Gy prescription). In the vicinity of the carotid arteries, the difference in calculated dose was also statistically significant, but only with a mean of approximately 0.2 Gy. We did not observe any significant correlation between the difference in the calculated dose and the tumor size or level of enhancement. The results implied that the calculated dose difference was clinically insignificant and may be acceptable for IMRT planning.

Neuroactive steroids and PTSD treatment.

PubMed

Rasmusson, Ann M; Marx, Christine E; Pineles, Suzanne L; Locci, Andrea; Scioli-Salter, Erica R; Nillni, Yael I; Liang, Jennifer J; Pinna, Graziano

2017-05-10

This review highlights early efforts to translate pre-clinical and clinical findings regarding the role of neuroactive steroids in stress adaptation and PTSD into new therapeutics for PTSD. Numerous studies have demonstrated PTSD-related alterations in resting levels or the reactivity of neuroactive steroids and their targets. These studies also have demonstrated substantial variability in the dysfunction of specific neuroactive steroid systems among PTSD subpopulations. These variabilities have been related to the developmental timing of trauma, severity and type of trauma, genetic background, sex, reproductive state, lifestyle influences such as substance use and exercise, and the presence of comorbid conditions such as depression and chronic pain. Nevertheless, large naturalistic studies and a small placebo-controlled interventional study have revealed generally positive effects of glucocorticoid administration in preventing PTSD after trauma, possibly mediated by glucocorticoid receptor-mediated effects on other targets that impact PTSD risk, including other neuroactive steroid systems. In addition, clinical and preclinical studies show that administration of glucocorticoids, 17β-estradiol, and GABAergic neuroactive steroids or agents that enhance their synthesis can facilitate extinction and extinction retention, depending on dose and timing of dose in relation to these complex PTSD-relevant recovery processes. This suggests that clinical trials designed to test neuroactive steroid therapeutics in PTSD may benefit from such considerations; typical continuous dosing regimens may not be optimal. In addition, validated and clinically accessible methods for identifying specific neuroactive steroid system abnormalities at the individual level are needed to optimize both clinical trial design and precision medicine based treatment targeting. Copyright © 2017. Published by Elsevier B.V.

Safety of fluralaner chewable tablets (BravectoTM), a novel systemic antiparasitic drug, in dogs after oral administration

PubMed Central

2014-01-01

Background Fluralaner is a novel systemic insecticide and acaricide that provides long acting efficacy in dogs after a single oral treatment. This study investigated the safety of oral administration of fluralaner in chewable tablets to dogs at the highest recommended treatment dose and at multiples of this dose. Methods Thirty-two (16 male and 16 female) healthy 8-week old Beagle dogs weighing 2.0 - 3.6 kg at first administration were included in the study. Fluralaner was administered on three occasions at 8-week intervals at doses of up to 56, 168, and 280 mg fluralaner/kg body weight, equivalent to 1, 3, and 5 times the highest recommended treatment dose of fluralaner; sham dosed dogs served as controls. During the study, all dogs were clinically observed, and their health was carefully monitored including body weight development, food consumption and measurement of hematology, coagulation, clinical chemistry (including measurement of levels of ACTH and C-reactive protein) and urinalysis. Following euthanasia of the dogs, complete gross post mortem examination, including organ weight determination, and histopathological examination of multiple tissues were conducted. Results There were no clinical findings related to fluralaner treatment. Statistically significant differences between the treated groups and the control group were observed for some clinical pathology parameters and organ weights; none of these findings were considered to be of clinical relevance. Conclusions Oral administration of fluralaner at the highest recommended treatment dose (56 mg/kg) at 8-week intervals is well tolerated and has a safety margin of more than five in healthy dogs eight weeks of age or older and weighing at least 2 kg. PMID:24606886

Evaluation of lens dose from anterior electron beams: comparison of Pinnacle and Gafchromic EBT3 film.

PubMed

Sonier, Marcus; Wronski, Matt; Yeboah, Collins

2015-03-08

Lens dose is a concern during the treatment of facial lesions with anterior electron beams. Lead shielding is routinely employed to reduce lens dose and minimize late complications. The purpose of this work is twofold: 1) to measure dose pro-files under large-area lead shielding at the lens depth for clinical electron energies via film dosimetry; and 2) to assess the accuracy of the Pinnacle treatment planning system in calculating doses under lead shields. First, to simulate the clinical geometry, EBT3 film and 4 cm wide lead shields were incorporated into a Solid Water phantom. With the lead shield inside the phantom, the film was positioned at a depth of 0.7 cm below the lead, while a variable thickness of solid water, simulating bolus, was placed on top. This geometry was reproduced in Pinnacle to calculate dose profiles using the pencil beam electron algorithm. The measured and calculated dose profiles were normalized to the central-axis dose maximum in a homogeneous phantom with no lead shielding. The resulting measured profiles, functions of bolus thickness and incident electron energy, can be used to estimate the lens dose under various clinical scenarios. These profiles showed a minimum lead margin of 0.5 cm beyond the lens boundary is required to shield the lens to ≤ 10% of the dose maximum. Comparisons with Pinnacle showed a consistent overestimation of dose under the lead shield with discrepancies of ~ 25% occur-ring near the shield edge. This discrepancy was found to increase with electron energy and bolus thickness and decrease with distance from the lead edge. Thus, the Pinnacle electron algorithm is not recommended for estimating lens dose in this situation. The film measurements, however, allow for a reasonable estimate of lens dose from electron beams and for clinicians to assess the lead margin required to reduce the lens dose to an acceptable level.

Method for simulating dose reduction in digital mammography using the Anscombe transformation.

PubMed

Borges, Lucas R; Oliveira, Helder C R de; Nunes, Polyana F; Bakic, Predrag R; Maidment, Andrew D A; Vieira, Marcelo A C

2016-06-01

This work proposes an accurate method for simulating dose reduction in digital mammography starting from a clinical image acquired with a standard dose. The method developed in this work consists of scaling a mammogram acquired at the standard radiation dose and adding signal-dependent noise. The algorithm accounts for specific issues relevant in digital mammography images, such as anisotropic noise, spatial variations in pixel gain, and the effect of dose reduction on the detective quantum efficiency. The scaling process takes into account the linearity of the system and the offset of the detector elements. The inserted noise is obtained by acquiring images of a flat-field phantom at the standard radiation dose and at the simulated dose. Using the Anscombe transformation, a relationship is created between the calculated noise mask and the scaled image, resulting in a clinical mammogram with the same noise and gray level characteristics as an image acquired at the lower-radiation dose. The performance of the proposed algorithm was validated using real images acquired with an anthropomorphic breast phantom at four different doses, with five exposures for each dose and 256 nonoverlapping ROIs extracted from each image and with uniform images. The authors simulated lower-dose images and compared these with the real images. The authors evaluated the similarity between the normalized noise power spectrum (NNPS) and power spectrum (PS) of simulated images and real images acquired with the same dose. The maximum relative error was less than 2.5% for every ROI. The added noise was also evaluated by measuring the local variance in the real and simulated images. The relative average error for the local variance was smaller than 1%. A new method is proposed for simulating dose reduction in clinical mammograms. In this method, the dependency between image noise and image signal is addressed using a novel application of the Anscombe transformation. NNPS, PS, and local noise metrics confirm that this method is capable of precisely simulating various dose reductions.

General equations for optimal selection of diagnostic image acquisition parameters in clinical X-ray imaging.

PubMed

Zheng, Xiaoming

2017-12-01

The purpose of this work was to examine the effects of relationship functions between diagnostic image quality and radiation dose on the governing equations for image acquisition parameter variations in X-ray imaging. Various equations were derived for the optimal selection of peak kilovoltage (kVp) and exposure parameter (milliAmpere second, mAs) in computed tomography (CT), computed radiography (CR), and direct digital radiography. Logistic, logarithmic, and linear functions were employed to establish the relationship between radiation dose and diagnostic image quality. The radiation dose to the patient, as a function of image acquisition parameters (kVp, mAs) and patient size (d), was used in radiation dose and image quality optimization. Both logistic and logarithmic functions resulted in the same governing equation for optimal selection of image acquisition parameters using a dose efficiency index. For image quality as a linear function of radiation dose, the same governing equation was derived from the linear relationship. The general equations should be used in guiding clinical X-ray imaging through optimal selection of image acquisition parameters. The radiation dose to the patient could be reduced from current levels in medical X-ray imaging.

High Dose Atorvastatin Decreases Cellular Markers of Immune Activation Without Affecting HIV-1 RNA Levels: Results of a Double-Blind Randomized Placebo Controlled Clinical Trial

DTIC Science & Technology

2011-02-15

M A J O R A R T I C L E High Dose Atorvastatin Decreases Cellular Markers of Immune Activation without Affecting HIV-1 RNA Levels: Results of a... atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving...antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4–6 week washout phase, participants

Dose planning management of patients undergoing salvage whole brain radiation therapy after radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saw, Cheng B., E-mail: cheng.saw@aol.com; Battin, Frank; McKeague, Janice

2016-01-01

Dose or treatment planning management is necessary for the re-irradiation of intracranial relapses after focal irradiation, radiosurgery, or stereotactic radiotherapy. The current clinical guidelines for metastatic brain tumors are the use of focal irradiation if the patient presents with 4 lesions or less. Salvage treatments with the use of whole brain radiation therapy (WBRT) can then be used to limit disease progression if there is an intracranial relapse. However, salvage WBRT poses a number of challenges in dose planning to limit disease progression and preserve neurocognitive function. This work presents the dose planning management that addresses a method of delineatingmore » previously treated volumes, dose level matching, and the dose delivery techniques for WBRT.« less

Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

PubMed

Egan, Sean; Murphy, Philip G; Fennell, Jerome P; Kelly, Sinead; Hickey, Mary; McLean, Carolyn; Pate, Muriel; Kirke, Ciara; Whiriskey, Annette; Wall, Niall; McCullagh, Eddie; Murphy, Joan; Delaney, Tim

2012-12-01

Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg/kg to 4.78 mg/kg/day. Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.

Effective and safe mannitol administration in patients undergoing supratentorial tumor surgery: A prospective, randomized and double blind study.

PubMed

Akcil, Eren Fatma; Dilmen, Ozlem Korkmaz; Karabulut, Esra Sultan; Koksal, Serdar Selcuk; Altindas, Fatis; Tunali, Yusuf

2017-08-01

Although osmotic diuresis with mannitol is commonly used to provide brain relaxation, there is no consensus regarding its optimal dose and combination with loop diuretics. The aim of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity in patients undergoing supratentorial tumor surgery. This prospective, randomized, double blind, placebo-controlled study included 51 patients (ASA I-III) scheduled for elective supratentorial craniotomy. Different doses and combinations of diuretics were administered after the bone flap removal. The Group 1 received mannitol at 0.5gkg -1 and furosemide at 0.5mgkg -1 , the Group 2 received mannitol at 1gkg -1 and furosemide at 0.5mgkg -1 , and the Group 3 received mannitol at 0.5gkg -1 and placebo. The primary end-point of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and the secondary end-points are to evaluate their effects on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity. This study shows that mannitol alone (0.5gkg -1 ), and the combinations of furosemide (0.5mgkg -1 ) with different doses of mannitol (0.5gkg -1 -1gkg -1 ) provides adequate brain relaxation. However, administration of furosemide with low or high doses of mannitol may cause reduction in the sodium and chloride levels as well as rise in the lactate level. Moreover it may cause high urine output and negative intra-operative fluid balance. Administration of 0.5gkg -1 mannitol provides adequate brain relaxation without causing systemic side effects in patients undergoing supratentorial tumor surgery. This study is registered to clinical trials (Clinical Trials.gov identifier NCT02712476). Copyright © 2017 Elsevier B.V. All rights reserved.

Assessing sensor accuracy for non-adjunct use of continuous glucose monitoring.

PubMed

Kovatchev, Boris P; Patek, Stephen D; Ortiz, Edward Andrew; Breton, Marc D

2015-03-01

The level of continuous glucose monitoring (CGM) accuracy needed for insulin dosing using sensor values (i.e., the level of accuracy permitting non-adjunct CGM use) is a topic of ongoing debate. Assessment of this level in clinical experiments is virtually impossible because the magnitude of CGM errors cannot be manipulated and related prospectively to clinical outcomes. A combination of archival data (parallel CGM, insulin pump, self-monitoring of blood glucose [SMBG] records, and meals for 56 pump users with type 1 diabetes) and in silico experiments was used to "replay" real-life treatment scenarios and relate sensor error to glycemic outcomes. Nominal blood glucose (BG) traces were extracted using a mathematical model, yielding 2,082 BG segments each initiated by insulin bolus and confirmed by SMBG. These segments were replayed at seven sensor accuracy levels (mean absolute relative differences [MARDs] of 3-22%) testing six scenarios: insulin dosing using sensor values, threshold, and predictive alarms, each without or with considering CGM trend arrows. In all six scenarios, the occurrence of hypoglycemia (frequency of BG levels ≤50 mg/dL and BG levels ≤39 mg/dL) increased with sensor error, displaying an abrupt slope change at MARD =10%. Similarly, hyperglycemia (frequency of BG levels ≥250 mg/dL and BG levels ≥400 mg/dL) increased and displayed an abrupt slope change at MARD=10%. When added to insulin dosing decisions, information from CGM trend arrows, threshold, and predictive alarms resulted in improvement in average glycemia by 1.86, 8.17, and 8.88 mg/dL, respectively. Using CGM for insulin dosing decisions is feasible below a certain level of sensor error, estimated in silico at MARD=10%. In our experiments, further accuracy improvement did not contribute substantively to better glycemic outcomes.

Assessing Sensor Accuracy for Non-Adjunct Use of Continuous Glucose Monitoring

PubMed Central

Patek, Stephen D.; Ortiz, Edward Andrew; Breton, Marc D.

2015-01-01

Abstract Background: The level of continuous glucose monitoring (CGM) accuracy needed for insulin dosing using sensor values (i.e., the level of accuracy permitting non-adjunct CGM use) is a topic of ongoing debate. Assessment of this level in clinical experiments is virtually impossible because the magnitude of CGM errors cannot be manipulated and related prospectively to clinical outcomes. Materials and Methods: A combination of archival data (parallel CGM, insulin pump, self-monitoring of blood glucose [SMBG] records, and meals for 56 pump users with type 1 diabetes) and in silico experiments was used to “replay” real-life treatment scenarios and relate sensor error to glycemic outcomes. Nominal blood glucose (BG) traces were extracted using a mathematical model, yielding 2,082 BG segments each initiated by insulin bolus and confirmed by SMBG. These segments were replayed at seven sensor accuracy levels (mean absolute relative differences [MARDs] of 3–22%) testing six scenarios: insulin dosing using sensor values, threshold, and predictive alarms, each without or with considering CGM trend arrows. Results: In all six scenarios, the occurrence of hypoglycemia (frequency of BG levels ≤50 mg/dL and BG levels ≤39 mg/dL) increased with sensor error, displaying an abrupt slope change at MARD =10%. Similarly, hyperglycemia (frequency of BG levels ≥250 mg/dL and BG levels ≥400 mg/dL) increased and displayed an abrupt slope change at MARD=10%. When added to insulin dosing decisions, information from CGM trend arrows, threshold, and predictive alarms resulted in improvement in average glycemia by 1.86, 8.17, and 8.88 mg/dL, respectively. Conclusions: Using CGM for insulin dosing decisions is feasible below a certain level of sensor error, estimated in silico at MARD=10%. In our experiments, further accuracy improvement did not contribute substantively to better glycemic outcomes. PMID:25436913

Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population.

PubMed

Stumpf, Janice L; Skyles, Amy J; Alaniz, Cesar; Erickson, Steven R

2007-01-01

To evaluate the knowledge of appropriate doses and potential toxicities of acetaminophen and assess the ability to recognize products containing acetaminophen in an adult outpatient setting. Cross-sectional, prospective study. University adult general internal medicine (AGIM) clinic. 104 adult patients presenting to the clinic over consecutive weekdays in December 2003. Three-page, written questionnaire. Ability of patients to identify maximum daily doses and potential toxicities of acetaminophen and recognize products that contain acetaminophen. A large percentage of participants (68.3%) reported pain on a daily or weekly basis, and 78.9% reported use of acetaminophen in the past 6 months. Only 2 patients correctly identified the maximum daily dose of regular acetaminophen, and just 3 correctly identified the maximum dose of extra-strength acetaminophen. Furthermore, 28 patients were unsure of the maximum dose of either product. Approximately 63% of participants either had not received or were unsure whether information on the possible danger of high doses of acetaminophen had been previously provided to them. When asked to identify potential problems associated with high doses of acetaminophen, 43.3% of patients noted the liver would be affected. The majority of the patients (71.2%) recognized Tylenol as containing acetaminophen, but fewer than 15% correctly identified Vicodin, Darvocet, Tylox, Percocet, and Lorcet as containing acetaminophen. Although nearly 80% of this AGIM population reported recent acetaminophen use, their knowledge of the maximum daily acetaminophen doses and potential toxicities associated with higher doses was poor and appeared to be independent of education level, age, and race. This indicates a need for educational efforts to all patients receiving acetaminophen-containing products, especially since the ability to recognize multi-ingredient products containing acetaminophen was likewise poor.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

PubMed

Chan, Noel; Sager, Philip T; Lawrence, Jack; Ortel, Thomas's; Reilly, Paul; Berkowitz, Scott; Kubitza, Dagmar; Eikelboom, John; Florian, Jeffry; Stockbridge, Norman; Rose, Martin; Temple, Robert; Seltzer, Jonathan H

2018-05-01

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. Copyright © 2017. Published by Elsevier Inc.

Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

PubMed

Mukai, Hirofumi; Saeki, Toshiaki; Aogi, Kenjiro; Naito, Yoichi; Matsubara, Nobuaki; Shigekawa, Takashi; Ueda, Shigeto; Takashima, Seiki; Hara, Fumikata; Yamashita, Tomonari; Ohwada, Shoichi; Sasaki, Yasutsuna

2016-10-01

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open-label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non-life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI-121772.). © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels.

PubMed

Crespo, M; Mir, M; Marin, M; Hurtado, S; Estadella, C; Gurí, X; Rap, O; Moral, R; Puig, J M; Lloveras, J

2009-01-01

Advagraf is a new modified-release once-daily formulation of tacrolimus with a similar efficacy and safety profile to twice-daily tacrolimus (Prograf) according to clinical trials. Few data are published about its use in clinical practice, outside of sponsored clinical trials. We compared efficacy and basic pharmacokinetics of once-daily and twice-daily tacrolimus in de novo renal transplantation. The Advagraf group included 26 de novo renal cases who had received initial immunosuppression with once-daily tacrolimus (0.2 mg/kg from day 1 posttransplantation) combined with mycophenolic acid, steroids, and anti-CD25 monoclonal antibodies (2 doses). We compared them with a Prograf group of 26 transplants performed immediately before, who received equivalent immunosuppression with twice-daily tacrolimus (0.2 mg/kg from day 1). We did not observe significant differences between groups in demographics, efficacy, and basic pharmacokinetics, namely, tacrolimus trough levels at 7, 15, 30, 60, or 90 days. We found that recipients on Advagraf needed significantly higher tacrolimus doses per kg up to 6 months post-transplantation than those on Prograf: 0.16 vs 0.11; 0.14 vs 0.08; and 0.12 vs 0.08 mg/kg at 1, 3, and 6 months. No patient suffered severe liver dysfunction. There were no differences between groups in the administration of drugs interacting with CYP3A4 or prokinetics, which could alter tacrolimus pharmacokinetics. Among de novo renal cases, the new once-daily formulation of tacrolimus offered a similar short-term efficacy profile as the twice-daily tacrolimus. But it was necessary to use up to a 50% higher dose of Advagraf than Prograf to achieve similar trough levels during the first 6 months.

Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.

PubMed

McGuire, Brendan M; Zupanets, Igor A; Lowe, Mark E; Xiao, Xunjun; Syplyviy, Vasyliy A; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F

2010-06-01

Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.

Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy Adults and Adults with Cirrhosis

PubMed Central

MCGuire, Brendan M.; Zupanets, Igor A.; Lowe, Mark E.; Xiao, Xunjun; Syplyviy, Vasyliy A.; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F.

2013-01-01

Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. Conclusion GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted. PMID:20512995

Toxic effects of Tripterygium wilfordii Hook F on the reproductive system of adolescent male rats.

PubMed

Jing, Xiaoping; Cheng, Weiwei; Guo, Sheng; Zou, Ya; Zhang, Ting; He, Li

2017-11-01

Tripterygium wilfordii Hook F. (TWHF) is a compound extracted from Lei Gong Teng (Thunder God Vine) that has been used to treat a variety of immune-related diseases in clinical practice, particularly in pediatrics. Nevertheless, clinical data indicated that glycosides from Tripterygium wilfordii Hook F (GTW) are toxic to the male reproductive system, but the mechanism is unknown. Here, the administration of a high dose of GTW for 4 weeks and a low dose for 12 weeks can reduce the body weights and testes weights in adolescent male rats. This effect is accompanied by a significantly reduction in the serum testosterone levels. Notably, short-term use of high-dose GTW or long-term use of low-dose GTW leads to testicular damage in adolescent male rats. Furthermore, the expression of the steroidogenic acute regulatory protein (StAR), P450 side chain cleavage enzyme (P450scc), cytochrome P450 17-hydroxylase (P450c17), 3β-hydroxysteroid dehydrogenase (3β-HSD), and 17β-hydroxysteroid dehydrogenase (17β-HSD) mRNAs and proteins in the testes was down-regulated by a short-term treatment with high-dose GTW and a long-term treatment with low-dose GTW. Therefore, GTW exhibit male reproductive toxicity in a concentration-and time-dependent manner by inhibiting the expression of the key enzymes and total cholesterol level involved in testosterone synthesis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The effect of electronic monitoring feedback on medication adherence and clinical outcomes: A systematic review

PubMed Central

van den Ende, Cornelia H. M.; Houterman, Anne E. J.; Heemskerk, Charlotte P. M.; van Dulmen, Sandra; van den Bemt, Bart J. F.

2017-01-01

Objective This study aims to assess the efficacy of Electronic Monitoring Feedback (EMF) as an intervention to improve medication adherence (i.e. dose- or full adherence) and clinical outcomes in adult patients. Methods A systematic search was performed in Medline, EMBASE, PsycINFO and Web of Science and reported according to the PRISMA guidelines. Randomised controlled trials (RCTs) comparing EMF with usual care were identified to systematically summarise the evidence for use of EMF in improving medication adherence and clinical outcomes. The GRADE approach was used to assess the quality of the body of evidence. Results Of 9,993 initially-identified studies, ten studies (four of high-quality and six of low-quality) were included. The sample size of the studies included varied from 18 to 205 patients. Four of the six studies (66.7%) reported a significant positive effect of EMF on mean dose adherence levels, whereas a significant positive effect of EMF on mean full adherence levels was found in all of the included studies (100%, five out of five of the studies included). A significant positive effect of EMF on clinical outcomes was reported in one of the seven studies included. The overall effect of EMF on mean dose- and full adherence was positive and the overall effect of EMF on clinical outcomes was inconclusive. Conclusion Considering the positive effect of EMF on medication adherence, EMF might be a promising intervention to enhance medication adherence. However, the effect of EMF on clinical outcomes was inconclusive. Prior to implementing EMF in clinical practice, future research with high-quality studies (e.g. adequate sample sizes, follow-up periods and no interfering co-interventions) is required to examine the (long-term) efficacy of EMF. PMID:28991903

The effect of electronic monitoring feedback on medication adherence and clinical outcomes: A systematic review.

PubMed

van Heuckelum, Milou; van den Ende, Cornelia H M; Houterman, Anne E J; Heemskerk, Charlotte P M; van Dulmen, Sandra; van den Bemt, Bart J F

2017-01-01

This study aims to assess the efficacy of Electronic Monitoring Feedback (EMF) as an intervention to improve medication adherence (i.e. dose- or full adherence) and clinical outcomes in adult patients. A systematic search was performed in Medline, EMBASE, PsycINFO and Web of Science and reported according to the PRISMA guidelines. Randomised controlled trials (RCTs) comparing EMF with usual care were identified to systematically summarise the evidence for use of EMF in improving medication adherence and clinical outcomes. The GRADE approach was used to assess the quality of the body of evidence. Of 9,993 initially-identified studies, ten studies (four of high-quality and six of low-quality) were included. The sample size of the studies included varied from 18 to 205 patients. Four of the six studies (66.7%) reported a significant positive effect of EMF on mean dose adherence levels, whereas a significant positive effect of EMF on mean full adherence levels was found in all of the included studies (100%, five out of five of the studies included). A significant positive effect of EMF on clinical outcomes was reported in one of the seven studies included. The overall effect of EMF on mean dose- and full adherence was positive and the overall effect of EMF on clinical outcomes was inconclusive. Considering the positive effect of EMF on medication adherence, EMF might be a promising intervention to enhance medication adherence. However, the effect of EMF on clinical outcomes was inconclusive. Prior to implementing EMF in clinical practice, future research with high-quality studies (e.g. adequate sample sizes, follow-up periods and no interfering co-interventions) is required to examine the (long-term) efficacy of EMF.

RBE, reference RBE and clinical RBE: applications of these concepts in hadron therapy.

PubMed

Wambersie, A

1999-06-01

Introduction of heavy particles (hadrons) into radiation therapy aims at improving the physical selectivity of the irradiation (e.g. proton beams), or the radiobiological differential effect (e.g. fast neutrons), or both (e.g. heavy-ion beams). Each of these new therapy modalities requires several types of information before prescribing safely the doses to patients, as well as for recording and reporting the treatments: (i) absorbed dose measured in a homogeneous phantom in reference conditions; (ii) dose distribution computed at the level of the target volume(s) and the normal tissues at risk; (iii) radiation quality from which a RBE evaluation could be predicted and (iv) RBE measured on biological systems or derived from clinical observation. In hadron therapy, the RBE of the different beams raises specific problems. For fast neutrons, the RBE varies within wide limits (about 2 to 5) depending on the neutron energy spectrum, dose, and biological system. For protons, the RBE values range between smaller limits (about 1.0 to 1.2). A clinical benefit can thus not be expected from RBE differences. However, the proton RBE problem cannot be ignored since dose differences of about 5% can be detected clinically in some cases. The situation is most complex with heavy ions since RBE variations are at least as large as for fast neutrons, as a function of particle type and energy, dose and biological system. In addition, RBE varies with depth. Radiation quality thus has to be taken into account when prescribing and reporting a treatment. This can be done in different ways: (a) description of the method of beam production; (b) computed LET spectra and/or measured microdosimetric spectra at the points clinically relevant; (c) RBE determination. The most relevant RBE data are those obtained for late tolerance of normal tissues at 2 Gy per fraction ("reference RBE"). The "clinical RBE" selected by the radiation oncologist when prescribing the treatment will be close to the reference RBE, but other factors (such as heterogeneity in dose distribution) may influence the selection of the clinical RBE. Combination of microdosimetric data and experimental RBE values improves the confidence in both sets of data.

A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study.

PubMed

Chung, Hyewon; Oh, Jaeseong; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Chung, Jae-Yong

2018-01-01

The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated. The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms. This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin. ClinicalTrials.gov NCT02712619.

Estimation of absorbed dose in clinical radiotherapy linear accelerator beams: Effect of ion chamber calibration and long-term stability

PubMed Central

Ravichandran, Ramamoorthy; Binukumar, Johnson Pichy; Davis, Cheriyathmanjiyil Antony

2013-01-01

The measured dose in water at reference point in phantom is a primary parameter for planning the treatment monitor units (MU); both in conventional and intensity modulated/image guided treatments. Traceability of dose accuracy therefore still depends mainly on the calibration factor of the ion chamber/dosimeter provided by the accredited Secondary Standard Dosimetry Laboratories (SSDLs), under International Atomic Energy Agency (IAEA) network of laboratories. The data related to Nd,water calibrations, thermoluminescent dosimetry (TLD) postal dose validation, inter-comparison of different dosimeter/electrometers, and validity of Nd,water calibrations obtained from different calibration laboratories were analyzed to find out the extent of accuracy achievable. Nd,w factors in Gray/Coulomb calibrated at IBA, GmBH, Germany showed a mean variation of about 0.2% increase per year in three Farmer chambers, in three subsequent calibrations. Another ion chamber calibrated in different accredited laboratory (PTW, Germany) showed consistent Nd,w for 9 years period. The Strontium-90 beta check source response indicated long-term stability of the ion chambers within 1% for three chambers. Results of IAEA postal TL “dose intercomparison” for three photon beams, 6 MV (two) and 15 MV (one), agreed well within our reported doses, with mean deviation of 0.03% (SD 0.87%) (n = 9). All the chamber/electrometer calibrated by a single SSDL realized absorbed doses in water within 0.13% standard deviations. However, about 1-2% differences in absorbed dose estimates observed when dosimeters calibrated from different calibration laboratories are compared in solid phantoms. Our data therefore imply that the dosimetry level maintained for clinical use of linear accelerator photon beams are within recommended levels of accuracy, and uncertainties are within reported values. PMID:24672156

Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP).

PubMed

Liu, Albert Y; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P; Greenblatt, Ruth M; Gandhi, Monica

2014-01-01

Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. ClinicalTrials.gov NCT00903084.

Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP)

PubMed Central

Liu, Albert Y.; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L.; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P.; Greenblatt, Ruth M.; Gandhi, Monica

2014-01-01

Background Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. Methods A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Results Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. Conclusions This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. Trial Registration ClinicalTrials.gov +NCT00903084. PMID:24421901

Variability in CT lung-nodule quantification: Effects of dose reduction and reconstruction methods on density and texture based features.

PubMed

Lo, P; Young, S; Kim, H J; Brown, M S; McNitt-Gray, M F

2016-08-01

To investigate the effects of dose level and reconstruction method on density and texture based features computed from CT lung nodules. This study had two major components. In the first component, a uniform water phantom was scanned at three dose levels and images were reconstructed using four conventional filtered backprojection (FBP) and four iterative reconstruction (IR) methods for a total of 24 different combinations of acquisition and reconstruction conditions. In the second component, raw projection (sinogram) data were obtained for 33 lung nodules from patients scanned as a part of their clinical practice, where low dose acquisitions were simulated by adding noise to sinograms acquired at clinical dose levels (a total of four dose levels) and reconstructed using one FBP kernel and two IR kernels for a total of 12 conditions. For the water phantom, spherical regions of interest (ROIs) were created at multiple locations within the water phantom on one reference image obtained at a reference condition. For the lung nodule cases, the ROI of each nodule was contoured semiautomatically (with manual editing) from images obtained at a reference condition. All ROIs were applied to their corresponding images reconstructed at different conditions. For 17 of the nodule cases, repeat contours were performed to assess repeatability. Histogram (eight features) and gray level co-occurrence matrix (GLCM) based texture features (34 features) were computed for all ROIs. For the lung nodule cases, the reference condition was selected to be 100% of clinical dose with FBP reconstruction using the B45f kernel; feature values calculated from other conditions were compared to this reference condition. A measure was introduced, which the authors refer to as Q, to assess the stability of features across different conditions, which is defined as the ratio of reproducibility (across conditions) to repeatability (across repeat contours) of each feature. The water phantom results demonstrated substantial variability among feature values calculated across conditions, with the exception of histogram mean. Features calculated from lung nodules demonstrated similar results with histogram mean as the most robust feature (Q ≤ 1), having a mean and standard deviation Q of 0.37 and 0.22, respectively. Surprisingly, histogram standard deviation and variance features were also quite robust. Some GLCM features were also quite robust across conditions, namely, diff. variance, sum variance, sum average, variance, and mean. Except for histogram mean, all features have a Q of larger than one in at least one of the 3% dose level conditions. As expected, the histogram mean is the most robust feature in their study. The effects of acquisition and reconstruction conditions on GLCM features vary widely, though trending toward features involving summation of product between intensities and probabilities being more robust, barring a few exceptions. Overall, care should be taken into account for variation in density and texture features if a variety of dose and reconstruction conditions are used for the quantification of lung nodules in CT, otherwise changes in quantification results may be more reflective of changes due to acquisition and reconstruction conditions than in the nodule itself.

TH-C-18A-08: A Management Tool for CT Dose Monitoring, Analysis, and Protocol Review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, J; Chan, F; Newman, B

2014-06-15

Purpose: To develop a customizable tool for enterprise-wide managing of CT protocols and analyzing radiation dose information of CT exams for a variety of quality control applications Methods: All clinical CT protocols implemented on the 11 CT scanners at our institution were extracted in digital format. The original protocols had been preset by our CT management team. A commercial CT dose tracking software (DoseWatch,GE healthcare,WI) was used to collect exam information (exam date, patient age etc.), scanning parameters, and radiation doses for all CT exams. We developed a Matlab-based program (MathWorks,MA) with graphic user interface which allows to analyze themore » scanning protocols with the actual dose estimates, and compare the data to national (ACR,AAPM) and internal reference values for CT quality control. Results: The CT protocol review portion of our tool allows the user to look up the scanning and image reconstruction parameters of any protocol on any of the installed CT systems among about 120 protocols per scanner. In the dose analysis tool, dose information of all CT exams (from 05/2013 to 02/2014) was stratified on a protocol level, and within a protocol down to series level, i.e. each individual exposure event. This allows numerical and graphical review of dose information of any combination of scanner models, protocols and series. The key functions of the tool include: statistics of CTDI, DLP and SSDE, dose monitoring using user-set CTDI/DLP/SSDE thresholds, look-up of any CT exam dose data, and CT protocol review. Conclusion: our inhouse CT management tool provides radiologists, technologists and administration a first-hand near real-time enterprise-wide knowledge on CT dose levels of different exam types. Medical physicists use this tool to manage CT protocols, compare and optimize dose levels across different scanner models. It provides technologists feedback on CT scanning operation, and knowledge on important dose baselines and thresholds.« less

Dedicated Linac for Radioneurosurgery at the National Institute of Neurology and Neurosurgery of Mexico

NASA Astrophysics Data System (ADS)

Celis-López, Miguel A.; Lárraga-Gutiérrez, José M.

2003-09-01

The objective is to present a description and the main clinical applications of this dedicated Linac for benign and malignant tumors in the central nervous system. The Novalis (BrainLab, Germany) is a 6 MV dedicated linac for a single high dose Radiosurgery (RS) and for fractionated doses in Stereotactic Radiotherapy with a high level of precision at the isocenter.

Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations

PubMed Central

Callebaut, Christian; Liu, Yang; Babusis, Darius; Ray, Adrian; Miller, Michael; Kitrinos, Kathryn

2017-01-01

Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100–400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations. PMID:28182625

Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations.

PubMed

Callebaut, Christian; Liu, Yang; Babusis, Darius; Ray, Adrian; Miller, Michael; Kitrinos, Kathryn

2017-01-01

Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100-400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations.

Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

PubMed

Bailie, George R; Larkina, Maria; Goodkin, David A; Li, Yun; Pisoni, Ronald L; Bieber, Brian; Mason, Nancy; Tong, Lin; Locatelli, Francesco; Marshall, Mark R; Inaba, Masaki; Robinson, Bruce M

2013-10-01

To examine patterns of intravenous (IV) iron use across 12 countries from 1999 to 2011. Trends in iron use are described among 32 192 hemodialysis (HD) patients in the Dialysis Outcomes and Practice Patterns Study. Adjusted associations of IV iron dose with serum ferritin and transferrin saturation (TSAT) values were also studied. IV iron was administered to 50% of patients over 4 months in 1999, increasing to 71% during 2009-11, with increasing use in most countries. Among patients receiving IV iron, the mean monthly dose increased from 232 ± 167 to 281 ± 211 mg. Most countries used 3 to 4 doses/month, but Canada used about 2 doses/month, Italy increased from 3 to almost 6 doses/month and Germany used 5 to 6 doses/month. The USA and most European countries predominantly used iron sucrose and sodium ferric gluconate. A significant use of iron dextran was limited to Canada and France; iron polymaltose was used in Australia and New Zealand; and Japan used ferric oxide saccharate, chondroitin polysulfate iron complex and cideferron. Ferritin values rose in most countries: 22% of patients had ≥ 800 ng/mL in the recent years of study. TSAT levels increased to a lesser degree over time. Japan had much lower IV iron dosing and ferritin levels, but similar TSAT levels. In adjusted analyses, serum ferritin and TSAT levels increased signifcantly by 14 ng/mL and 0.16%, respectively, for every 100 mg/month higher mean monthly iron dose. IV iron prescription patterns varied between countries and changed over time from 1999 to 2011. IV iron use and dose increased in most countries, with notable increases in ferritin but not TSAT levels. With rising cumulative IV iron doses, studies of the effects of changing IV iron dosing and other anemia management practices on clinical outcomes should be a high priority.

Dose-dependent establishment of Trichuris suis larvae in Göttingen minipigs.

PubMed

Vejzagić, Nermina; Roepstorff, Allan; Kringel, Helene; Thamsborg, Stig Milan; Nielsen, Mads Pårup; Kapel, Christian M O

2015-03-15

Embryonated eggs of the pig whipworm Trichuris suis (TSOee) constitute the active pharmaceutical ingredient (API) in a medicinal product explored in human clinical trials against several immune-mediated diseases. The measurement of TSO biological potency (hatchability and infectivity) is a requirement for the assessment of TSO's pharmacological potency in human clinical trials. The present study aims to validate the dose-dependent establishment of T. suis larvae in Göttingen minipigs and eventual clinical implication of a dose range (1000-10,000 TSO). Four groups of 5 minipigs were inoculated with doses of 1000, 2500, 7500, and 10,000 TSOee, respectively, to evaluate a range of concentrations of TSOee in a minipig infectivity model. Unembryonated eggs (TSOue) were added to keep the total egg number in the inoculum constant at 10,000 eggs. Two groups received 2500 and 7500 TSOee per pig without the addition of TSOue as controls. The intestinal larval establishment at 21 days post inoculation (dpi) demonstrated a clear positive linear dose-response relationship between numbers of inoculated TSOee and recovered larvae. There was a low level of variation in larval counts in all study groups. Thus, the infectivity model in minipigs within the tested dose range offers a reliable, sensitive and accurate assay for testing biological potency of TSO. Copyright © 2015 Elsevier B.V. All rights reserved.

Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity.

PubMed

Dayan, A D

2016-01-01

Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox(®) inhaler for short-term pain relief. It was formerly used in significantly higher doses to produce anaesthesia, when it caused a specific type of dose-related renal tubular damage. The pathogenesis of the renal damage and clinical use of methoxyflurane are discussed here with evidence that a low but effective analgesic dose is not associated with the risk of renal adverse effects. The maximum dose employed to produce analgesia is limited to methoxyflurane 6 mL/day and 15 mL/week, producing a minimum alveolar concentration (MAC) of 0.59 MAC-hours. Renal damage is due to the metabolism of methoxyflurane and release of fluoride ions. Exposure of humans to methoxyflurane ≤2.0 MAC-hours, resulting in serum fluoride ≤40 µmol/L, has not been associated with renal tubular toxicity. The safety margin of analgesic use of methoxyflurane in the Penthrox ((®)) inhaler is at least 2.7- to 8-fold, based on methoxyflurane MAC-hours or serum fluoride level, with clinical experience suggesting it is higher. It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity. © The Author(s) 2015.

TH-AB-201-01: A Feasibility Study of Independent Dose Verification for CyberKnife

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sato, A; Noda, T; Keduka, Y

2016-06-15

Purpose: CyberKnife irradiation is composed of tiny-size, multiple and intensity-modulated beams compared to conventional linacs. Few of the publications for Independent dose calculation verification for CyberKnife have been reported. In this study, we evaluated the feasibility of independent dose verification for CyberKnife treatment as Secondary check. Methods: The followings were measured: test plans using some static and single beams, clinical plans in a phantom and using patient’s CT. 75 patient plans were collected from several treatment sites of brain, lung, liver and bone. In the test plans and the phantom plans, a pinpoint ion-chamber measurement was performed to assess dosemore » deviation for a treatment planning system (TPS) and an independent verification program of Simple MU Analysis (SMU). In the clinical plans, dose deviation between the SMU and the TPS was performed. Results: In test plan, the dose deviations were 3.3±4.5%, and 4.1±4.4% for the TPS and the SMU, respectively. In the phantom measurements for the clinical plans, the dose deviations were −0.2±3.6% for the TPS and −2.3±4.8% for the SMU. In the clinical plans using the patient’s CT, the dose deviations were −3.0±2.1% (Mean±1SD). The systematic difference was partially derived from inverse square law and penumbra calculation. Conclusion: The independent dose calculation for CyberKnife shows −3.0±4.2% (Mean±2SD) and our study, the confidence limit was achieved within 5% of the tolerance level from AAPM task group 114 for non-IMRT treatment. Thus, it may be feasible to use independent dose calculation verification for CyberKnife treatment as the secondary check. This research is partially supported by Japan Agency for Medical Research and Development (AMED)« less

Different routes and doses influence protection in pigs immunised with the naturally attenuated African swine fever virus isolate OURT88/3.

PubMed

Sánchez-Cordón, Pedro J; Chapman, Dave; Jabbar, Tamara; Reis, Ana L; Goatley, Lynnette; Netherton, Christopher L; Taylor, Geraldine; Montoya, Maria; Dixon, Linda

2017-02-01

This study compares different combinations of doses and routes of immunisation of pigs with low virulent African swine fever virus (ASFV) genotype I isolate OURT88/3, including the intramuscular and intranasal route, the latter not previously tested. Intranasal immunisations with low and moderate doses (10 3 and 10 4 TCID 50 ) of OURT88/3 provided complete protection (100%) against challenge with virulent genotype I OURT88/1 isolate. Only mild and transient clinical reactions were observed in protected pigs. Transient moderate virus genome levels were detected in blood samples after challenge that decreased, but persisted until the end of the experiment in some animals. In contrast, pigs immunised intramuscularly with low and moderate doses (10 3 and 10 4 TCID 50 ) displayed lower percentages of protection (50-66%), and low or undetectable levels of virus genome were detected in blood samples throughout the study. In addition, clinical courses observed in protected pigs were asymptomatic. In pigs that were not protected and developed acute ASF, an exacerbated increase of IL-10 sometimes accompanied by an increase of IFNγ was observed before euthanasia. These results showed that factors including delivery route and dose determine the outcome of immunisation with the naturally attenuated isolate OURT88/3. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Radiation dose evaluation of dental cone beam computed tomography using an anthropomorphic adult head phantom

NASA Astrophysics Data System (ADS)

Wu, Jay; Shih, Cheng-Ting; Ho, Chang-hung; Liu, Yan-Lin; Chang, Yuan-Jen; Min Chao, Max; Hsu, Jui-Ting

2014-11-01

Dental cone beam computed tomography (CBCT) provides high-resolution tomographic images and has been gradually used in clinical practice. Thus, it is important to examine the amount of radiation dose resulting from dental CBCT examinations. In this study, we developed an in-house anthropomorphic adult head phantom to evaluate the level of effective dose. The anthropomorphic phantom was made of acrylic and filled with plaster to replace the bony tissue. The contour of the head was extracted from a set of adult computed tomography (CT) images. Different combinations of the scanning parameters of CBCT were applied. Thermoluminescent dosimeters (TLDs) were used to measure the absorbed doses at 19 locations in the head and neck regions. The effective doses measured using the proposed phantom at 65, 75, and 85 kVp in the D-mode were 72.23, 100.31, and 134.29 μSv, respectively. In the I-mode, the effective doses were 108.24, 190.99, and 246.48 μSv, respectively. The maximum percent error between the doses measured by the proposed phantom and the Rando phantom was l4.90%. Therefore, the proposed anthropomorphic adult head phantom is applicable for assessing the radiation dose resulting from clinical dental CBCT.

Radiation Exposure of Interventional Radiologists During Computed Tomography Fluoroscopy-Guided Renal Cryoablation and Lung Radiofrequency Ablation: Direct Measurement in a Clinical Setting.

PubMed

Matsui, Yusuke; Hiraki, Takao; Gobara, Hideo; Iguchi, Toshihiro; Fujiwara, Hiroyasu; Kawabata, Takahiro; Yamauchi, Takatsugu; Yamaguchi, Takuya; Kanazawa, Susumu

2016-06-01

Computed tomography (CT) fluoroscopy-guided renal cryoablation and lung radiofrequency ablation (RFA) have received increasing attention as promising cancer therapies. Although radiation exposure of interventional radiologists during these procedures is an important concern, data on operator exposure are lacking. Radiation dose to interventional radiologists during CT fluoroscopy-guided renal cryoablation (n = 20) and lung RFA (n = 20) was measured prospectively in a clinical setting. Effective dose to the operator was calculated from the 1-cm dose equivalent measured on the neck outside the lead apron, and on the left chest inside the lead apron, using electronic dosimeters. Equivalent dose to the operator's finger skin was measured using thermoluminescent dosimeter rings. The mean (median) effective dose to the operator per procedure was 6.05 (4.52) μSv during renal cryoablation and 0.74 (0.55) μSv during lung RFA. The mean (median) equivalent dose to the operator's finger skin per procedure was 2.1 (2.1) mSv during renal cryoablation, and 0.3 (0.3) mSv during lung RFA. Radiation dose to interventional radiologists during renal cryoablation and lung RFA were at an acceptable level, and in line with recommended dose limits for occupational radiation exposure.

Booster and higher antigen doses of inactivated influenza vaccine in HIV-infected patients.

PubMed

Johnston, Jessica A; Tincher, Lindsey B; Lowe, Denise K

2013-12-01

To review the literature regarding booster or higher doses of influenza antigen for increasing immunogenicity of inactivated influenza vaccine (IIV) in HIV-infected patients. MEDLINE (1966 to September 2013) was searched using the terms immunize, influenza, vaccine, and HIV or AIDS in combination with two-dose, booster-dose, increased antigen, or high-dose. One trial of booster dosing with standard doses (SDs) of IIV, trivalent (IIV3); 2 trials of booster dosing with intermediate doses (ID) of H1N1 IIV or IIV3; and 1 trial of high-dose (HD) IIV3 were identified. Trials administering 2-dose, booster-dose, or increased antigen of influenza vaccine to patients with HIV were reviewed. Because adjuvanted IIV is not available and IIV, quadrivalent was recently approved in the United States, studies evaluating these vaccines were excluded. HIV-infected individuals are at high risk for influenza-related complications; however, vaccination with SD IIV may not confer optimal protection. It has been postulated that booster or higher doses of influenza antigen may lead to increased immunogenicity. When ID and SD or ID with boosters were evaluated in HIV-infected patients, significant increases in surrogate markers for influenza protection were not achieved. However, HD IIV3 did result in significant increases in seroprotective antibody levels, though 'clinical' influenza was not evaluated. Currently, evidence is insufficient to reach conclusions about the efficacy of booster dosing, ID, or HD influenza vaccine in HIV-infected patients. Trials evaluating booster or higher-antigen doses of IIV for 'clinical' influenza are necessary before routinely recommending for HIV-infected patients.

How much image noise can be added in cardiac x-ray imaging without loss in perceived image quality?

NASA Astrophysics Data System (ADS)

Gislason-Lee, Amber J.; Kumcu, Asli; Kengyelics, Stephen M.; Rhodes, Laura A.; Davies, Andrew G.

2015-03-01

Dynamic X-ray imaging systems are used for interventional cardiac procedures to treat coronary heart disease. X-ray settings are controlled automatically by specially-designed X-ray dose control mechanisms whose role is to ensure an adequate level of image quality is maintained with an acceptable radiation dose to the patient. Current commonplace dose control designs quantify image quality by performing a simple technical measurement directly from the image. However, the utility of cardiac X-ray images is in their interpretation by a cardiologist during an interventional procedure, rather than in a technical measurement. With the long term goal of devising a clinically-relevant image quality metric for an intelligent dose control system, we aim to investigate the relationship of image noise with clinical professionals' perception of dynamic image sequences. Computer-generated noise was added, in incremental amounts, to angiograms of five different patients selected to represent the range of adult cardiac patient sizes. A two alternative forced choice staircase experiment was used to determine the amount of noise which can be added to a patient image sequences without changing image quality as perceived by clinical professionals. Twenty-five viewing sessions (five for each patient) were completed by thirteen observers. Results demonstrated scope to increase the noise of cardiac X-ray images by up to 21% +/- 8% before it is noticeable by clinical professionals. This indicates a potential for 21% radiation dose reduction since X-ray image noise and radiation dose are directly related; this would be beneficial to both patients and personnel.

Different Doses of Tripterygium Glycosides in the Treatment of Diabetic Nephropathy: Effects on Blood Lipids.

PubMed

Wang, Wei

2018-06-07

The aim of this study was to investigate the therapeutic effect of different doses of tripterygium glycosides (TG) in the treatment of diabetic nephropathy (DN). The effect of TG on blood lipids and safety were also evaluated. Sixty patients with type 2 DN were randomly divided into three groups (n=20 per group): low-dose (30 mg/day TG), double-dose (60 mg/day TG) and control (placebo) groups, all three times daily for 6 months. The levels of triglycerides, total cholesterol, urinary protein, plasma albumin and serum tumour necrosis factor (TNF)-α were compared between the three groups. After treatment, urinary protein and TNF-α level significantly decreased in patients in the treatment groups, compared with the control group. This decrease was significantly larger in the double-dose group than in the low-dose group. However, there was no significant decrease in triglycerides and total cholesterol in the two treatment groups. Furthermore, plasma albumin was lower in the treatment groups than in the control group. The double dose of TG has improved clinical efficacy, compared with the low dose, and the same safety profile. © 2018 The Author(s). Published by S. Karger AG, Basel.

Bortezomib for antibody mediated rejection treatment: experience at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City.

PubMed

Leyva, Sergio; Marino-Vázquez, Lluvia A; Reyes-Loaeza, Jorge A; Vega, Olynka; Uribe-Uribe, Norma; Alberú, Josefina; Morales-Buenrostro, Luis E

2009-01-01

The use of bortezomib as a treatment modality of AHR improved and stabilized graft function (clinical response) in the majority of patients. Its use in single dose, even combined with rituximab, does not seem to be useful to obtain a sustained clinical response neither to reduce HLAabs level. The use of 4 doses of bortezomib in days 1, 4, 7, and 10 (1.3 mg/m2 BSA each) plus plasmapheresis produced both a good clinical response and a reduction in DSA. Moving forward, it will necessary to define the long-term effectiveness of bortezomib and whether rituximab administration is indispensable to achieve this goal.

Optimization of contrast-enhanced spectral mammography depending on clinical indication

PubMed Central

Dromain, Clarisse; Canale, Sandra; Saab-Puong, Sylvie; Carton, Ann-Katherine; Muller, Serge; Fallenberg, Eva Maria

2014-01-01

Abstract. The objective is to optimize low-energy (LE) and high-energy (HE) exposure parameters of contrast-enhanced spectral mammography (CESM) examinations in four different clinical applications for which different levels of average glandular dose (AGD) and ratios between LE and total doses are required. The optimization was performed on a Senographe DS with a SenoBright® upgrade. Simulations were performed to find the optima by maximizing the contrast-to-noise ratio (CNR) on the recombined CESM image using different targeted doses and LE image quality. The linearity between iodine concentration and CNR as well as the minimal detectable iodine concentration was assessed. The image quality of the LE image was assessed on the CDMAM contrast-detail phantom. Experiments confirmed the optima found on simulation. The CNR was higher for each clinical indication than for SenoBright®, including the screening indication for which the total AGD was 22% lower. Minimal iodine concentrations detectable in the case of a 3-mm-diameter round tumor were 12.5% lower than those obtained for the same dose in the clinical routine. LE image quality satisfied EUREF acceptable limits for threshold contrast. This newly optimized set of acquisition parameters allows increased contrast detectability compared to parameters currently used without a significant loss in LE image quality. PMID:26158058

Optimization of contrast-enhanced spectral mammography depending on clinical indication.

PubMed

Dromain, Clarisse; Canale, Sandra; Saab-Puong, Sylvie; Carton, Ann-Katherine; Muller, Serge; Fallenberg, Eva Maria

2014-10-01

The objective is to optimize low-energy (LE) and high-energy (HE) exposure parameters of contrast-enhanced spectral mammography (CESM) examinations in four different clinical applications for which different levels of average glandular dose (AGD) and ratios between LE and total doses are required. The optimization was performed on a Senographe DS with a SenoBright® upgrade. Simulations were performed to find the optima by maximizing the contrast-to-noise ratio (CNR) on the recombined CESM image using different targeted doses and LE image quality. The linearity between iodine concentration and CNR as well as the minimal detectable iodine concentration was assessed. The image quality of the LE image was assessed on the CDMAM contrast-detail phantom. Experiments confirmed the optima found on simulation. The CNR was higher for each clinical indication than for SenoBright®, including the screening indication for which the total AGD was 22% lower. Minimal iodine concentrations detectable in the case of a 3-mm-diameter round tumor were 12.5% lower than those obtained for the same dose in the clinical routine. LE image quality satisfied EUREF acceptable limits for threshold contrast. This newly optimized set of acquisition parameters allows increased contrast detectability compared to parameters currently used without a significant loss in LE image quality.

Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen.

PubMed

Nakamura, Toshimichi; Toshimoto, Kota; Lee, Wooin; Imamura, Chiyo K; Tanigawara, Yusuke; Sugiyama, Yuichi

2018-06-19

The Tamoxifen Response by CYP2D6 Genotype-based Treatment-1 (TARGET-1) study (n = 180) was conducted from 2012-2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET-1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0.469 on average. As the population size of this virtual clinical study (VCS) increased, the expected probability was substantially increased (0.674 for n = 260). Our analyses also informed that the probability to achieve the end point in the TARGET-1 study was negatively impacted by a large variability in endoxifen levels. Our current efforts demonstrate the promising utility of the PBPK modeling and VCS approaches in prospectively designing effective clinical trials. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Refractory orthostatic hypotension in a patient with a spinal cord injury: Treatment with droxidopa.

PubMed

Canosa-Hermida, Eva; Mondelo-García, Cristina; Ferreiro-Velasco, María Elena; Salvador-de la Barrera, Sebastián; Montoto-Marqués, Antonio; Rodríguez-Sotillo, Antonio; Vizoso-Hermida, José Ramón

2018-01-01

Orthostatic hypotension (OH) is a common complication in patients with a spinal cord injury, mainly affecting complete injuries above neurological level T6. It is generally more severe during the acute phase but can remain symptomatic for several years. A 65-year-old male with a grade ASIA A post-traumatic cervical spinal cord injury, at neurological level C4, presenting with symptomatic refractory OH. Increased blood pressure (BP) levels and an overall clinical improvement was observed after administering an increasing dose of droxidopa. Treatment was started at a dose of 100 mg twice daily (bid), one to be taken upon rising in the morning and another one in the afternoon, at least three hours before bedtime. According to the patient's symptomatic response, each individual dose was increased by 100 mg at 48-hour intervals. Both increased mean BP levels and a subjective symptomatic improvement were evidenced at a dose of 300 mg bid. Treatment with droxidopa increases BP levels and improves symptoms related to refractory OH using all physical and pharmacological measures available. It could therefore constitute an effective alternative treatment for OH in patients with a spinal cord injury.

Low-dose CT in clinical diagnostics.

PubMed

Fuentes-Orrego, Jorge M; Sahani, Dushyant V

2013-09-01

Computed tomography (CT) has become key for patient management due to its outstanding capabilities for detecting disease processes and assessing treatment response, which has led to expansion in CT imaging for diagnostic and image-guided therapeutic interventions. Despite these benefits, the growing use of CT has raised concerns as radiation risks associated with radiation exposure. The purpose of this article is to familiarize the reader with fundamental concepts of dose metrics for assessing radiation exposure and weighting radiation-associated risks. The article also discusses general approaches for reducing radiation dose while preserving diagnostic quality. The authors provide additional insight for undertaking protocol optimization, customizing scanning techniques based on the patients' clinical scenario and demographics. Supplemental strategies are postulated using more advanced post-processing techniques for achieving further dose improvements. The technologic offerings of CT are integral to modern medicine and its role will continue to evolve. Although, the estimated risks from low levels of radiation of a single CT exam are uncertain, it is prudent to minimize the dose from CT by applying common sense solutions and using other simple strategies as well as exploiting technologic innovations. These efforts will enable us to take advantage of all the clinical benefits of CT while minimizing the likelihood of harm to patients.

Cortisol in schizophrenia: No association with tobacco smoking, clinical symptoms or antipsychotic medication.

PubMed

Nedic Erjavec, Gordana; Uzun, Suzana; Nikolac Perkovic, Matea; Kozumplik, Oliver; Svob Strac, Dubravka; Mimica, Ninoslav; Hirasawa-Fujita, Mika; Domino, Edward F; Pivac, Nela

2017-07-03

Cigarette smoking is associated with higher cortisol levels in healthy subjects. In schizophrenia this relationship is not clear. There are divergent results on the association between cortisol with smoking, clinical symptoms and medication in schizophrenia. This study evaluated this association in 196 Caucasian inpatients with schizophrenia (51.30±26.68years old), subdivided into 123 smokers and 73 non-smokers. Basal salivary cortisol levels were measured twice, at 08.00 and 09.00AM, 90-120min after awakening. The effect of smoking on cortisol was evaluated according to current smoking status, the number of cigarettes/day and the nicotine addiction intensity. The influence of clinical symptoms and/or antipsychotic medication on cortisol was determined using the Positive and Negative Syndrome Scale (PANSS), and chlorpromazine equivalent doses. Non-smokers were older, received lower doses of antipsychotics, had higher PANSS scores, and had longer duration of illness than smokers. Salivary cortisol was similar in schizophrenic patients subdivided according to the smoking status, the number of cigarettes/day and nicotine addiction intensity. No significant correlation was found between salivary cortisol and PANSS scores, chlorpromazine equivalent doses, age of onset or the duration of illness. The findings revealed no association between salivary cortisol and smoking, nicotine addiction intensity, or clinical symptoms. Our preliminary data showed no correlation between salivary cortisol and chlorpromazine equivalent doses and/or antipsychotic medication. Our findings suggest that smoking does not affect the cortisol response in schizophrenic patients as it has been shown in healthy individuals. Future studies should investigate a possible desensitization of the stress system to smoking. Copyright © 2017. Published by Elsevier Inc.

Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): A phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to severe atopic dermatitis (AD).

PubMed

Simpson, Eric L; Gadkari, Abhijit; Worm, Margitta; Soong, Weily; Blauvelt, Andrew; Eckert, Laurent; Wu, Richard; Ardeleanu, Marius; Graham, Neil M H; Pirozzi, Gianluca; Sutherland, E Rand; Mastey, Vera

2016-09-01

Moderate to severe atopic dermatitis (AD) is associated with substantial patient burden despite current therapies. We sought to evaluate dupilumab treatment on patient-reported outcomes in adults with moderate to severe AD. Adults (N = 380) with moderate to severe AD inadequately controlled by topical medications were randomized to 16 weeks of double-blind, subcutaneous treatment with dupilumab 100 mg every 4 weeks, 200 mg every 2 weeks, 300 mg every 2 weeks, 300 mg once weekly, or placebo. Patient-reported outcomes included pruritus numeric rating scale; patient-reported sleep item on Scoring AD scale; Patient-Oriented Eczema Measure; Hospital Anxiety and Depression Scale; Dermatology Life Quality Index; and 5-dimension 3-level EuroQol. Dupilumab reduced peak itch at 16 weeks relative to placebo by 1.1 to 3.2 points on numeric rating scale (P < .0001 all doses, except 100 mg every 4 weeks P < .05); improved sleep and health-related quality of life on Dermatology Life Quality Index and 5-dimension 3-level EuroQol (P < .05 all doses, except 100 mg every 4 weeks); and reduced anxiety and depression symptoms (P < .05 all doses). Dupilumab's effects appeared early and achieved clinically relevant improvements without significant safety concerns. There are potential cultural differences affecting patient-reported outcome responses. Outcomes were secondary or exploratory end points. Dupilumab produced early and sustained patient-reported and clinically relevant improvements in sleep, mental health, and health-related quality of life; the two 300-mg dose regimens resulted in greatest benefits. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Physiologically based pharmacokinetic model for 6-mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity

PubMed Central

Ogungbenro, Kayode; Aarons, Leon

2015-01-01

Aims To extend the physiologically based pharmacokinetic (PBPK) model developed for 6-mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6-mercaptopurine. Methods The developed PBPK model was extended for 6-mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6-mercaptopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data. Results The model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6-thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild-type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses. Conclusions The developed PBPK model has been extended for 6-mercaptopurine and can be used to predict plasma 6-mercaptopurine and tissue concentration of 6-mercaptopurine, 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6-mercaptopurine dosing, achieve better clinical outcome and reduce toxicity. PMID:25614061

Clinical Factors Associated with Dose of Loop Diuretics After Pediatric Cardiac Surgery: Post Hoc Analysis.

PubMed

Haiberger, Roberta; Favia, Isabella; Romagnoli, Stefano; Cogo, Paola; Ricci, Zaccaria

2016-06-01

A post hoc analysis of a randomized controlled trial comparing the clinical effects of furosemide and ethacrynic acid was conducted. Infants undergoing cardiac surgery with cardiopulmonary bypass were included in order to explore which clinical factors are associated with diuretic dose in infants with congenital heart disease. Overall, 67 patients with median (interquartile range) age of 48 (13-139) days were enrolled. Median diuretic dose was 0.34 (0.25-0.4) mg/kg/h at the end of postoperative day (POD) 0 and it significantly decreased (p = 0.04) over the following PODs; during this period, the ratio between urine output and diuretic dose increased significantly (p = 0.04). Age (r -0.26, p = 0.02), weight (r -0.28, p = 0.01), cross-clamp time (r 0.27, p = 0.03), administration of ethacrynic acid (OR 0.01, p = 0.03), and, at the end of POD0, creatinine levels (r 0.3, p = 0.009), renal near-infrared spectroscopy saturation (-0.44, p = 0.008), whole-blood neutrophil gelatinase-associated lipocalin levels (r 0.30, p = 0.01), pH (r -0.26, p = 0.02), urinary volume (r -0.2755, p = 0.03), and fluid balance (r 0.2577, p = 0.0266) showed a significant association with diuretic dose. At multivariable logistic regression cross-clamp time (OR 1.007, p = 0.04), use of ethacrynic acid (OR 0.2, p = 0.01) and blood pH at the end of POD0 (OR 0.0001, p = 0.03) was independently associated with diuretic dose. Early resistance to loop diuretics continuous infusion is evident in post-cardiac surgery infants: Higher doses are administered to patients with lower urinary output. Independently associated variables with diuretic dose in our population appeared to be cross-clamping time, the administration of ethacrynic acid, and blood pH.

Evaluation of Serum Lipid, Thyroid, and Hepatic Clinical Chemistries in Association With Serum Perfluorooctanesulfonate (PFOS) in Cynomolgus Monkeys After Oral Dosing With Potassium PFOS

PubMed Central

Allen, Bruce C.; Andres, Kara L.; Ehresman, David J.; Falvo, Ria; Provencher, Anne; Olsen, Geary W.; Butenhoff, John L.

2017-01-01

Abstract An oral dose study with perfluorooctanesulfonate (PFOS) was undertaken to identify potential associations between serum PFOS and changes in serum clinical chemistry parameters in purpose-bred young adult cynomolgus monkeys (Macaca fascicularis). In this study, control group (n = 6/sex) was sham-dosed with vehicle (0.5% Tween 20 and 5% ethanol in water), low-dose group (n = 6/sex) received 1 single K+PFOS dose (9 mg/kg), and high-dose group (n = 4–6/sex) received 3 separate K+ PFOS doses (11–17.2 mg/kg). Monkeys were given routine checkups and observed carefully for health problems on a daily basis. Scheduled blood samples were drawn from all monkeys prior to, during, and after K+PFOS administration for up to 1 year and they were analyzed for PFOS concentrations and clinical chemistry markers for coagulation, lipids, hepatic, renal, electrolytes, and thyroid-related hormones. No mortality occurred during the study. All the monkeys were healthy, gained weight, and were released back to the colony at the end of the study. The highest serum PFOS achieved was approximately 165 μg/ml. When compared with time-matched controls, administration of K+PFOS to monkeys did not result in any toxicologically meaningful or clinically relevant changes in serum clinical measurements for coagulation, lipids, hepatic, renal, electrolytes, and thyroid-related hormones. A slight reduction in serum cholesterol (primarily the high-density lipoprotein fraction), although not toxicologically significant, was observed. The corresponding lower-bound fifth percentile benchmark concentrations (BMCL1sd) were 74 and 76 μg/ml for male and female monkeys, respectively. Compared to the 2013–2014 geometric mean serum PFOS level of 4.99 ng/ml (0.00499 μg/ml) in US general population reported by CDC NHANES, this represents 4 orders of magnitude for margin of exposure. PMID:28115654

SU-F-T-195: Systematic Constraining of Contralateral Parotid Gland Led to Improved Dosimetric Outcomes for Multi-Field Optimization with Scanning Beam Proton Therapy: Promising Results From a Pilot Study in Patients with Base of Tongue Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, R; Liu, A; Poenisch, F

Purpose: Treatment planning for Intensity Modulated Proton Therapy (IMPT) for head and neck cancer is time-consuming due to the large number of organs-at-risk (OAR) to be considered. As there are many competing objectives and also wide range of acceptable OAR constraints, the final approved plan may not be most optimal for the given structures. We evaluated the dose reduction to the contralateral parotid by implementing standardized constraints during optimization for scanning beam proton therapy planning. Methods: Twenty-four (24) consecutive patients previously treated for base of tongue carcinoma were retrospectively selected. The doses were 70Gy, 63Gy and 57Gy (SIB in 33more » fractions) for high-, intermediate-, and standard-risk clinical target volumes (CTV), respectively; the treatment included bilateral neck. Scanning beams using MFO with standardized bilateral anterior oblique and PA fields were applied. New plans where then developed and optimized by employing additional contralateral parotid constraints at multiple defined dose levels. Using a step-wise iterative process, the volume-based constraints at each level were then further reduced until known target coverages were compromised. The newly developed plans were then compared to the original clinically approved plans using paired student t-testing. Results: All 24 newly optimized treatment plans maintained initial plan quality as compared to the approved plans, and the 98% prescription dose coverage to the CTV’s were not compromised. Representative DVH comparison is shown in FIGURE 1. The contralateral parotid doses were reduced at all levels of interest when systematic constraints were applied to V10, V20, V30 and V40Gy (All P<0.0001; TABLE 1). Overall, the mean contralateral parotid doses were reduced by 2.26 Gy on average, a ∼13% relative improvement. Conclusion: Applying systematic and volume-based contralateral parotid constraints for IMPT planning significantly reduced the dose at all dosimetric levels for patients with base of tongue cancer.« less

Using Quality of Life Measures in a Phase I Clinical Trial of Noni in Patients with Advanced Cancer to Select a Phase II Dose

PubMed Central

Issell, Brian F.; Gotay, Carolyn C.; Pagano, Ian; Franke, A. Adrian

2015-01-01

Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD).

PubMed

Press, Neil J; Taylor, Roger J; Fullerton, Joseph D; Tranter, Pamela; McCarthy, Clive; Keller, Thomas H; Arnold, Nicola; Beer, David; Brown, Lyndon; Cheung, Robert; Christie, Julie; Denholm, Alastair; Haberthuer, Sandra; Hatto, Julia D I; Keenan, Mark; Mercer, Mark K; Oakman, Helen; Sahri, Helene; Tuffnell, Andrew R; Tweed, Morris; Trifilieff, Alexandre

2015-09-10

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.

Kidney Injury Associated with Telavancin Dosing Regimen in an Animal Model

PubMed Central

Ledesma, Kimberly R.; Bowers, Dana R.; Zhou, Jian; Truong, Luan D.

2015-01-01

The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted. PMID:25712358

Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B: applying mechanistic modeling to enable preclinical to clinical translation and guide clinical trial design.

PubMed

Vugmeyster, Yulia; Rohde, Cynthia; Perreault, Mylene; Gimeno, Ruth E; Singh, Pratap

2013-01-01

TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B (TrkB), is currently being investigated as a potential body weight modulatory agent in humans. To support the selection of the dose range for the first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) obtained in lean cynomolgus and obese rhesus monkeys following single doses ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was used to describe the observed nonlinear PK and Emax approach was used to describe the observed dose-dependent PD effect. The TMDD model development was supported by the experimental determination of the binding affinity constant (9.4 nM) and internalization rate of the drug-target complex (2.08 h(-1)). These mechanistic analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological activity (e.g., PD) in monkeys, and indicated that ≥ 38% target coverage (time-average) was required to achieve significant body weight gain in monkeys. Based on the scaling of the TMDD model from monkeys to humans and assuming similar relationship between the target coverage and pharmacological activity between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans were projected to be the minimally and the fully pharmacologically active doses, respectively. Based on the minimal anticipated biological effect level (MABEL) approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg human) SC was recommended as the starting dose for FIH trials, because at this dose level<10% target coverage was projected at Cmax (and all other time points). This study illustrates a rational mechanistic approach for the selection of FIH dose range for a therapeutic protein with a complex model of action.

PROPOSALS FOR THE ESTABLISHMENT OF NATIONAL DIAGNOSTIC REFERENCE LEVELS FOR RADIOGRAPHY FOR ADULT PATIENTS BASED ON REGIONAL DOSE SURVEYS IN RUSSIAN FEDERATION.

PubMed

Vodovatov, A V; Balonov, M I; Golikov, V Yu; Shatsky, I G; Chipiga, L A; Bernhardsson, C

2017-04-01

In 2009-2014, dose surveys aimed to collect adult patient data and parameters of most common radiographic examinations were performed in six Russian regions. Typical patient doses were estimated for the selected examinations both in entrance surface dose and in effective dose. 75%-percentiles of typical patient effective dose distributions were proposed as preliminary regional diagnostic reference levels (DRLs) for radiography. Differences between the 75%-percentiles of regional typical patient dose distributions did not exceed 30-50% for the examinations with standardized clinical protocols (skull, chest and thoracic spine) and a factor of 1.5 for other examinations. Two different approaches for establishing national DRLs were evaluated: as a 75%-percentile of a pooled regional sample of patient typical doses (pooled method) and as a median of 75%-percentiles of regional typical patient dose distributions (median method). Differences between pooled and median methods for effective dose did not exceed 20%. It was proposed to establish Russian national DRLs in effective dose using a pooled method. In addition, the local authorities were granted an opportunity to establish regional DRLs if the local radiological practice and typical patient dose distributions are significantly different. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients.

PubMed

Ishmael, D Richard; Chen, Wei R; Hamilton, Steven A; Liu, Hong; Nordquist, Robert E

2003-01-01

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m2, gemcitabine 1500 mg/m2), three at dose level 2 (mitoguazone 500 mg/m2, gemcitabine 2000 mg/m2), and one at dose level 3 (mitoguazone 600 mg/m2, gemcitabine 2000 mg/m2). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.

A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lye, Jessica; Dunn, Leon, E-mail: leon.dunn@arpansa.gov.au; Alves, Andrew

Purpose: The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. Methods: The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantomsmore » are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference ≤3.3%, Pass (Action Level) is ≤5.0%, and Fail (Out of Tolerance) is >5.0%. Results: At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60° wedges which caused a delivered overdose of 5%–8%. Conclusions: The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, K; John R Marsh Cancer Center

Purpose: To evaluate the clinical rationale for Truebeam and Trilogy Linac machines from Varian Medical System as exchangeable treatment modalities in the same radiation oncology department. Methods: Intensity Modulated Radiotherapy (IMRT) plans for different diseases were selected for this study. These disease sites included brain, head and neck, breast, lung, and prostate. The parameters selected for this study were the energy amount, Monitor Unit (MU); dose coverage of target reflected by prescription isodose volume(PIV); dose spillage described by the volume of 50% isodoseline of the prescription; and dose homogeneities represented by the maximum dose (MaxD) and the minimum dose (MinD)more » of target volume (TV) and critical structure (CS). Each percentage difference between the values of these parameters formed an element of a matrix, which was called Similarity Comparison Matrix(SCM). The elements of the SCM were then simplified by dimensional conversion algorithm, which was used to determine clinical similarity between two machines through a single value. Results: For the selected clinical cases in this study, the average percentage differences between Trilogy and Truebeam in MU was 0.28% with standard deviation(SD) 0.66%, PIV was 0.23% with SD 0.20%, Volume at 50% prescription dose was 0.31% with SD at 0.78%, MaxD at TV is 0.26% with SD 0.35%, MinD at TV is −0.04% with SD 0.51%, MaxD in CS is −0.53% with SD 0.92%, and MinD in CS 3.31%, with SD at 2.89%. The sum, product, geometric and harmonic mean for the matrix elements were 19.0%, 0.00%, 0.19%, and 0.00%. Conclusion: A method to compare two machines in clinical level was developed and some reference values were calculated for decision-making in clinical practice, and this strategy could be expanded to different clinical applications.« less

Monitoring of isotretinoin therapy by measuring the plasma levels of isotretinoin and 4-oxo-isotretinoin. A useful tool for management of severe acne.

PubMed

Almond-Roesler, B; Blume-Peytavi, U; Bisson, S; Krahn, M; Rohloff, E; Orfanos, C E

1998-01-01

Isotretinoin for oral therapy in severe acne conglobata and acne nodulocystica represents a significant achievement; however, the drug exerts several mucocutaneous and systemic adverse effects, besides its teratogenic potency. The aim of this study was to investigate the plasma levels of isotretinoin and of 4-oxo-isotretinoin over long-term treatment of severe acne and to assess any correlation with the given dose, the clinical improvement and the occurrence of side effects. Forty-one patients with severe acne and acne-related disorders were studied under long-term oral intake of isotretinoin. Therapeutic effects and side effects were evaluated prior, during and at the end of therapy. The plasma levels of isotretinoin and of its major metabolite 4-oxo-isotretinoin were measured by reversed-phase HPLC and were correlated with the administered oral dose and the number and frequency of side effects. Dose-dependent plasma levels of isotretinoin and its metabolite were observed. At a mean dosage of 0.75-1.0 mg/kg/day, 404 +/- 142 ng/ml were measured, whereas the plasma levels of 4-oxo-isotretinoin were 1-2x higher. The plasma levels correlated well with the orally administered dose of isotretinoin and the observed mucocutaneous side effects. The study demonstrates that measuring of the plasma levels may be a helpful tool to monitor the individual therapeutic dose regimen in patients with severe acne in order to minimize undesired side effects and to control oral intake.

Preemptive carprofen for peri-operative analgesia in dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO): a prospective, randomized, blinded, placebo controlled clinical trial.

PubMed

Bufalari, A; Maggio, C; Cerasoli, I; Morath, U; Adami, C

2012-03-01

Eighteen client-owned dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO) were included in this blinded clinical study and randomly assigned to one of two treatment groups. Group C (carprofen) received intravenous (IV) carprofen, 4 mg/kg, prior to anesthesia, whereas group P (placebo) received IV saline. General anesthesia was maintained with isoflurane in oxygen and a constant rate infusion (CRI) of sufentanyl IV. Intra-operatively, assessment of nociception was based on changes in physiological parameters and on the analgesics requirement, whereas in the post-operative period evaluation of pain was performed by using a Hellyer and Gaynor pain score and by comparing the doses of rescue buprenorphine required by the two treatment groups. Although no statistically significant differences in intra-operative sufentanyl doses were found between treatment groups, group C had superior cardiovascular stability, and lower post-operative pain scores and rescue buprenorphine doses than group P. Our results indicate that administration of carprofen prior to surgery was effective in improving peri-operative analgesia in dogs undergoing TPLO.

Toxicity of dietary Heliotropium circinatum to rats.

PubMed

Eröksüz, H; Eröksüz, Y; Ozer, H; Ceribasi, A O; Tosun, F; Tamer, U; Kizilay, C Akyüz

2003-08-01

Pyrrolizidine alkaloid intoxication was produced in adult, male rats by feeding different levels (0, 1, 3, 5 or 10%) of Heliotropium circinatum for 20 w. Combined GC-MS revealed 0.15% total alkaloid content in the plant material of which 12% and 88% were basic and N-oxide forms, respectively. The specific alkaloids identified were europine (67.33%), heliotrine (16.34%), lasiocarpine (8.12%), heleurine (4.18%), echinatine (1.56%), 7-angeylheliotrine (1.19%), and an unknown alkaloid (1.28%). Neither mortality nor significant clinical changes occurred in test groups. Mild to moderate, dose-related hepatic megalocytosis was the most prominent histopathological finding. In addition to chronic hepatotoxicity, notable medial thickening occurred in the pulmonary arterioles and arteries of the high-dosed groups. This study indicated that H. circinatum plant has limited toxic potential in rats with mild to moderate histological changes and no mortality at the dosing levels, total doses, or time of exposure employed.

Effect of ketoconazole on cyclosporine dose in healthy dogs.

PubMed

Dahlinger, J; Gregory, C; Bea, J

1998-01-01

To determine the degree to which the dose of oral cyclosporine (CyA), in healthy dogs, can be decreased by concurrent oral administration of ketoconazole. Dogs in this study were observed for physical or biochemical side effects that might have been caused by the administration of CyA and ketoconazole. Prospective research study. Five healthy, intact female Beagle dogs. CyA was administered orally twice daily to achieve stable whole blood trough levels of 400 to 600 ng/mL. Ketoconazole was added at a low therapeutic dose (average dose: 13.6 mg/kg/d) then at a subtherapeutic dose (average dose: 4.7 mg/kg/d). CyA whole blood trough levels were monitored every 3 to 4 days and maintained at 400 to 600 ng/mL by adjusting CyA doses accordingly. Physical examination, CBC, biochemical profile, and urinalysis were performed at 2-week intervals throughout the study period. The initial mean dose of CyA required to achieve target blood levels was 14.5 mg/ kg/d. With concurrent ketoconazole (low therapeutic dose, average dose: 13.6 mg/kg/d) and CyA administration, the CyA dose declined to 3.4 mg/kg/day (range: 1.2 to 5.2 mg/kg/d), representing a 75% reduction in CyA dose and monetary savings of 57.8%. At a subtherapeutic dose of ketoconazole (average dose: 4.7 mg/kg/d), combination therapy resulted in a CyA dose of 10.1 mg/kg/day (4.9 to 10.6 mg/kg/d), representing a 38% reduction in CyA dose and monetary savings of 23.8%. Weight loss and transient hypoalbuminemia of unknown clinical significance were observed. Other physical and biochemical evaluations were unremarkable over the 12-week study period. The oral administration of ketoconazole can be used to reduce substantially the oral CyA dose needed to maintain selected blood levels in healthy dogs. The oral administration of ketoconazole can result in substantial cost savings to owners of dogs receiving CyA after renal allograft transplantation or for the treatment of autoimmune disease.

Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings.

PubMed

Keyserling, Constance H; Barbaras, Ronald; Benghozi, Renee; Dasseux, Jean-Louis

2017-05-01

CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day. Healthy volunteers, 18-55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25-45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements. Thirty-two subjects were enrolled. All CER-001 doses (0.25-45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg. CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport.

Plasma Methylphenidate Levels in Youths With Attention Deficit Hyperactivity Disorder Treated With OROS Formulation.

PubMed

Yorbik, Ozgur; Mutlu, Caner; Ozilhan, Selma; Eryilmaz, Gul; Isiten, Nuket; Alparslan, Serdar; Saglam, Esra

2015-06-01

There are limited studies investigating the relationship between oral release osmotic system-methylphenidate (OROS-MPH) doses and plasma methylphenidate (MPH) concentrations in children and adolescents. The aim of this study was to investigate the relationship between the doses of OROS-MPH and the plasma levels of the drug. We also examined the effects of the other drugs including aripiprazole, risperidone, fluoxetine, and sertraline on the levels of the MPH in the plasma. The files of 100 attention deficit hyperactivity disorder (ADHD) subjects (76 male, 24 female) who were diagnosed as ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria, were screened. The ages of subjects were between 6 and 18 years (mean = 11.5 ± 3.8 years). Plasma MPH levels were determined by high-performance liquid chromatography-tandem mass spectrometry assay. Daily mean OROS-MPH dose used in ADHD children was 0.7 ± 0.2 mg/kg (range: 0.3-1.3 mg/kg). The mean plasma OROS-MPH was 11.6 ± 7.3 ng/mL (range: 0.5-43.4 ng/mL). There was no group difference in the mean plasma MPH and dose-related MPH levels between the groups that used any additional drug including aripiprazole (n = 25), risperidone (n = 10), fluoxetine (n = 16), sertraline (n = 10), and did not use these drugs (P > 0.05). There was a positive correlation between the OROS-MPH doses (mg/kg) and the blood MPH levels (Pearson correlation = 0.40; P < 0.001). The plasma levels of MPH were found to be less than 13 ng/mL in 65% of the subjects. Our findings point to the fact that plasma levels of MPH show a wide range of changes at similar doses, correlate positively with the doses and, as expected, are not affected by using risperidone, sertraline, fluoxetine, and aripiprazole. Therapeutic drug monitoring may help to optimize MPH dose in patients not responding to treatment or in those experiencing serious side effects, but not in routine clinical practice. The presence of intermediate dose formulations such as 45-mg tablets for OROS-MPH may contribute to the optimization.

Low dose irradiation facilitates hepatocellular carcinoma genesis involving HULC.

PubMed

Li, Yuan; Ge, Chang; Feng, Guoxing; Xiao, Huiwen; Dong, Jiali; Zhu, Changchun; Jiang, Mian; Cui, Ming; Fan, Saijun

2018-03-24

Irradiation exposure positive correlates with tumor formation, such as breast cancer and lung cancer. However, whether low dose irradiation induces hepatocarcinogenesis and the underlying mechanism remain poorly defined. In the present study, we reported that low dose irradiation facilitated the proliferation of hepatocyte through up-regulating HULC in vitro and in vivo. Low dose irradiation exposure elevated HULC expression level in hepatocyte. Deletion of heightened HULC erased the cells growth accelerated following low dose irradiation exposure. CDKN1, the neighbor gene of HULC, was down-regulated by overexpression of HULC following low dose irradiation exposure via complementary base pairing, resulting in promoting cell cycle process. Thus, our findings provide new insights into the mechanism of low dose irradiation-induced hepatocarcinogenesis through HULC/CDKN1 signaling, and shed light on the potential risk of low dose irradiation for the development of hepatocellular carcinoma in pre-clinical settings. © 2018 Wiley Periodicals, Inc.

Evaluating the potential of gold, silver, and silica nanoparticles to saturate mononuclear phagocytic system tissues under repeat dosing conditions.

PubMed

Weaver, James L; Tobin, Grainne A; Ingle, Taylor; Bancos, Simona; Stevens, David; Rouse, Rodney; Howard, Kristina E; Goodwin, David; Knapton, Alan; Li, Xiaohong; Shea, Katherine; Stewart, Sharron; Xu, Lin; Goering, Peter L; Zhang, Qin; Howard, Paul C; Collins, Jessie; Khan, Saeed; Sung, Kidon; Tyner, Katherine M

2017-07-17

As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles.

LDL-C goal attainment in patients who remain on atorvastatin or switch to equivalent or non-equivalent doses of simvastatin: a retrospective matched cohort study in clinical practice.

PubMed

Rublee, Dale A; Burke, James P

2010-03-01

As clinical trials have shown the benefits of more intensive cholesterol control, treatment targets for low-density lipoprotein cholesterol (LDL-C) have decreased progressively. At the same time, physicians have been encouraged to contain costs by prescribing cheaper, generic statins for cholesterol management. To determine how these possibly conflicting goals are managed in clinical practice, we examined LDL-C control in patients switched from a potent, branded statin (atorvastatin) to a less potent, generic statin (simvastatin). Patients who switched from atorvastatin to simvastatin between July 2006 and January 2008 were retrospectively identified from a US medical and pharmacy claims database, and matched with controls remaining on atorvastatin. Outcomes measured were the number of switched patients receiving a simvastatin milligram dose>or=2 times their previous atorvastatin dose, changes in LDL-C levels, and percentage of patients achieving recommended LDL-C targets. All study variables were analyzed descriptively. After applying exclusion and inclusion criteria, 1048 patients who switched from atorvastatin to simvastatin and 1048 matched controls who remained on atorvastatin were included. Among the switchers, 379 (36%) received an inappropriately low dose of simvastatin (<2 times atorvastatin dose). In patients remaining on atorvastatin, mean LDL-C decreased from 105.7 mg/dL to 102.3 mg/dL after 44 weeks, whereas in switched patients, LDL-C remained similar, at 105.9 mg/dL on atorvastatin and 105.8 mg/dL on simvastatin. Before switching, when all patients were receiving atorvastatin, 67.4% of switchers and 69.9% of controls achieved recommended LDL-C targets. After switching, significantly fewer switchers than controls met LDL-C targets (69.1% vs 74.6%; P=0.005). However, among patients who switched to an equivalent dose of simvastatin (>or=2 times prior atorvastatin dose), similar proportions met LDL-C targets (72.8% vs 74.6% of controls; P=0.402), whereas among patients who switched to inappropriate non-equivalent dose of simvastatin, a significantly lower proportion met LDL-C targets (62.5% vs 74.6% of controls; P=0.001). Continuing atorvastatin was associated with lower LDL-C levels and better LDL-C target attainment compared with switching to simvastatin. Patients switched to an equivalent simvastatin dose had lower LDL-C levels and were more likely to achieve LDL-C targets than patients switched to a non-equivalent dose, suggesting physicians must consider dosage equivalence when switching statins, and should measure LDL-C and titrate statins as necessary to achieve LDL-C control.

High dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis

PubMed Central

Imam, Mohamad H.; Sinakos, Emmanouil; Gossard, Andrea A.; Kowdley, Kris V.; Luketic, Velimir A. C.; Harrison, M. Edwyn; McCashland, Timothy; Befeler, Alex S.; Harnois, Denise; Jorgensen, Roberta; Petz, Jan; Keach, Jill; DeCook, Alisha C.; Enders, Felicity; Lindor, Keith D.

2013-01-01

Background Ursodeoxycholic acid (UDCA) in a dose of 28–30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. Aim Our aim was to compare the risk of adverse clinical endpoints in patients with varying disease status. Methods We reviewed records from patients previously enrolled in a study evaluating the effects of high-dose (28–30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histologic stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, esophageal varices and cholangiocarcinoma was sought. Results One hundred fifty patients were included of which 49 patients developed endpoints. There was an increased development of endpoints amongst patients using UDCA vs. placebo (14 vs. 4, p = 0.0151) with early histologic disease (stage 1–2, n = 88) but not with late stage (stage 3–4, n = 62) disease (17 vs. 14, p = 0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, p = 0.0008) with normal bilirubin levels (total bilirubin ≤ 1.0 mg/dl) but not in patients with elevated bilirubin levels (15 vs. 16, p = 0.6018). Among patients not reaching endpoints 31.68% had normalization of their alkaline phosphatase levels as compared to 14.29% in patients who reached endpoints (p = 0.073). Conclusion The increased risk of adverse events with UDCA treatment as compared to placebo is only apparent in patients with early histologic stage disease or normal total bilirubin. PMID:21957881

High-Dose Estrogen and Clinical Selective Estrogen Receptor Modulators Induce Growth Arrest, p21, and p53 in Primate Ovarian Surface Epithelial Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wright, Jay W.; Stouffer, Richard L.; Rodland, Karin D.

2005-06-09

Ovarian cancer is the most lethal gynecological cancer affecting women. Hormone-based therapies are variably successful in treating ovarian cancer, but the reasoning behind these therapies is paradoxical. Clinical reagents such as tamoxifen are considered to inhibit or reverse tumor growth by competitive inhibition of the estrogen receptor (ER); however high dose estrogen is as clinically effective as tamoxifen, and it is unlikely that estrogen is acting by blocking ER activity; however, it may be activating a unique function of the ER that is nonmitogenic. For poorly defined reasons, 90% of varian cancers derive from the ovarian surface epithelium (OSE). Inmore » vivo the ER-positive OSE is exposed to high estrogen levels, reaching micromolar concentrations in dominant ovarian follicles. Using cultured OSE cells in vitro, we show that these levels of estradiol (1 ug/ml; {approx}3um) block the actions of serum growth factors, activate the G1 phase retinoblastoma AQ:A checkpoint, and induce p21, an inhibitor of kinases that normally inactivate the retinoblastoma checkpoint. We also show that estradiol increases p53 levels, which may contribute to p21 induction. Supporting the hypothesis that clinical selective ER modulators activate this novel ER function, we find that micromolar doses of tamoxifen and the ''pure antiestrogen'' ICI 182,780 elicit the same effects as estradiol. We propose that, in the context of proliferation, these data clarify some paradoxical aspects of hormone-based therapy and suggest that fuller understanding of normal ER function is necessary to improve therapeutic strategies that target the ER. (J Clin Endocrinol Metab 90: 0000-0000, 2005)« less

Clinical efficacy and pharmacokinetics of levothyroxine suppository in patients with hypothyroidism.

PubMed

Kashiwagura, Yasuharu; Uchida, Shinya; Tanaka, Shimako; Watanabe, Hiroshi; Masuzawa, Masahiro; Sasaki, Tadanori; Namiki, Noriyuki

2014-01-01

This study aimed to elucidate the clinical efficacy and pharmacokinetics of levothyroxine (LT4) suppository, thus, we examined the pharmacokinetics of thyroxine (T4) after the administration of the suppository in thyroidectomized rats and examined dose and the levels of free T4 (FT4) in patients with hypothyroidism receiving suppositories. Thyroidectomized rats were administered with LT4 solution and LT4 suppository (30 µg/kg), and plasma T4 concentrations were measured using LC/MS. The AUC0-168 of T4 after rectal administration of the LT4 suppository was 64% lower than these values after oral administration. To evaluate clinical effect of LT4 suppository, we enrolled 6 Japanese patients with hypothyroidism (2 men and 4 women; age, 68.2±13.5 years) who were administered LT4 suppository at Kameda Medical Center from 2007 to 2013 in this case series. The FT4 level during the administration of suppositories was significantly lower than that during the administration of tablets (0.657±0.183 ng/dL vs. 1.25±0.51 ng/dL, p=0.034). The FT4/dose ratio for the suppository was significantly 44% lower than that for the tablet (p=0.020). In conclusion, although the bioavailability of LT4 is lower after administration of the suppository than after the oral formulation, it was suggested that T4 levels can be maintained in patients with hypothyroidism by administering LT4 suppositories at a dose 1.8 times higher than that of the tablet. Thus, the administration of LT4 suppository can be an alternative for treatment with oral medication in clinical practice.

High dose androgen therapy in male pseudohermaphroditism due to 5 alpha-reductase deficiency and disorders of the androgen receptor.

PubMed

Price, P; Wass, J A; Griffin, J E; Leshin, M; Savage, M O; Large, D M; Bu'Lock, D E; Anderson, D C; Wilson, J D; Besser, G M

1984-10-01

We describe the clinical and biochemical features of six men with male pseudohermaphroditism due to androgen resistance. Each of the subjects had male-gender behavior but incomplete virilization. The underlying defects in androgen metabolism were defined by studies of the 5 alpha-reductase enzyme and the androgen receptor in fibroblasts cultured from biopsies of genital skin. Four of the six have 5 alpha-reductase deficiency, and two have defects of the androgen receptor (the Reifenstein syndrome). The responses of these men to androgen treatment were assessed by monitoring nitrogen balance, plasma luteinizing hormone (LH) values, and clinical parameters of virilization including penile growth, potency and ejaculatory volume, muscle bulk, and growth of body and facial hair. In all of the subjects with 5 alpha-reductase deficiency and one man with the Reifenstein syndrome significant response occurred, as evidence by nitrogen retention, lowered plasma LH levels, and improved virilization, with doses of parenteral testosterone esters that raised plasma testosterone levels above the normal male range and brought plasma dihydrotestosterone levels into the normal male range. The subject who did not respond with clinical virilization nevertheless showed nitrogen retention in response to acute testosterone administration. This patient had a profound deficiency of the androgen receptor, whereas the man with a receptor defect who did respond clinically to therapy had normal amounts of a qualitatively abnormal receptor. We conclude that high dose androgen therapy may be of benefit in improving virilization, self-image, and sexual performance in subjects with 5 alpha-reductase deficiency who have male-gender behavior and in some subjects with defects of the androgen receptor.

Anemia management trends in hospital-based dialysis centers (HBDCs), 2010 to 2013.

PubMed

Coritsidis, George N; Maglinte, Gregory A; Acharya, Anjali; Saxena, Anjali; Chang, Chun-Lan; Hill, Jerrold; Gitlin, Matthew; Lafayette, Richard A

2014-03-01

Few data have been reported on anemia management practices in hospital-based dialysis centers (HBDCs), which are uniquely different from other freestanding dialysis centers. Examining data from HBDCs would help determine if HBDCs and the general US dialysis population have similar trends related to how anemia is managed in dialysis patients. Given recent changes in the prescribing information of erythropoiesis-stimulating agents (ESAs) and in end-stage renal disease-related health policy and reimbursement, this study describes trends in anemia management practices in HBDCs from January 2010 through March 2013. Electronic medical records of 5404 adult hemodialysis patients in 50 US-based HBDCs were analyzed retrospectively. Patients included in the study cohort were aged ≥18 years and had at least 1 hemoglobin (Hb) measurement and 1 dose of an ESA between January 2010 and March 2013. End points included Hb concentration, darbepoetin alfa dosing, epoetin alfa dosing, and iron biomarkers (transferrin saturation and ferritin) and dosing. From 2010 to 2013, mean monthly Hb levels declined from 11.4 to 10.7 g/dL; the percentage of patients with mean monthly Hb levels <10 g/dL increased from 11.3% to 24.4%; and the percentage of patients with mean monthly Hb levels >12 g/dL declined from 30.1% to 11.2%. The median darbepoetin alfa cumulative 4-week dose also declined 38.8%, and the weekly epoetin alfa dose declined 24%. From January 2010 to March 2013, the percentage of patients with transferrin saturation >30% increased from 35.8% to 43.6%, the percentage of patients with ferritin levels >500 ng/mL increased from 62.0% to 77.9%, the percentage of patients with ferritin levels ≥800 ng/mL increased from 28.9% to 47.3%, and the median cumulative 4-week intravenous iron dose increased 50%. These study results support growing evidence that meaningful changes have occurred over the last 3 years in how anemia is clinically managed in US hemodialysis patients. Study limitations include that changes in patient clinical/demographic characteristics over time were not controlled for and that study findings may not be applicable to HBDCs that have different patient populations and/or do not use an electronic medical record system. Continuing to evaluate anemia management practices in HBDCs would provide additional information on the risks and benefits of anemia care. Consistent with national data, the findings from this study indicate that from 2010 to 2013, HBDCs modified anemia management practices for dialysis patients, as evidenced by reductions in mean monthly Hb levels and ESA dosing and by increases in iron biomarkers and dosing. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Diuretic Strategies in Acute Heart Failure and Renal Dysfunction: Conventional vs Carbohydrate Antigen 125-guided Strategy. Clinical Trial Design.

PubMed

García-Blas, Sergio; Bonanad, Clara; Llàcer, Pau; Ventura, Silvia; Núñez, José María; Sánchez, Ruth; Chamorro, Carlos; Fácila, Lorenzo; de la Espriella, Rafael; Vaquer, Juana María; Cordero, Alberto; Roqué, Mercè; Ortiz, Víctor; Racugno, Paolo; Bodí, Vicent; Valero, Ernesto; Santas, Enrique; Moreno, María Del Carmen; Miñana, Gema; Carratalá, Arturo; Bondanza, Lourdes; Payá, Ana; Cardells, Ingrid; Heredia, Raquel; Pellicer, Mauricio; Valls, Guillermo; Palau, Patricia; Bosch, María José; Raso, Rafael; Sánchez, Andrés; Bertomeu-González, Vicente; Bertomeu-Martínez, Vicente; Montagud-Balaguer, Vicente; Albiach-Montañana, Cristina; Pendás-Meneau, Jezabel; Marcaida, Goitzane; Cervantes-García, Sonia; San Antonio, Rodolfo; de Mingo, Elisabet; Chorro, Francisco J; Sanchis, Juan; Núñez, Julio

2017-12-01

The optimal treatment of patients with acute heart failure (AHF) and cardiorenal syndrome type 1 (CRS-1) is far from being well-defined. Arterial hypoperfusion in concert with venous congestion plays a crucial role in the pathophysiology of CRS-I. Plasma carbohydrate antigen 125 (CA125) has emerged as a surrogate of fluid overload in AHF. The aim of this study was to evaluate the clinical usefulness of CA125 for tailoring the intensity of diuretic therapy in patients with CRS-1. Multicenter, open-label, parallel clinical trial, in which patients with AHF and serum creatinine ≥ 1.4mg/dL on admission will be randomized to: a) standard diuretic strategy: titration-based on conventional clinical and biochemical evaluation, or b) diuretic strategy based on CA125: high dose if CA125 > 35 U/mL, and low doses otherwise. The main endpoint will be renal function changes at 24 and 72hours after therapy initiation. Secondary endpoints will include: a) clinical and biochemical changes at 24 and 72hours, and b) renal function changes and major clinical events at 30 days. The results of this study will add important knowledge on the usefulness of CA125 for guiding diuretic treatment in CRS-1. In addition, it will pave the way toward a better knowledge of the pathophysiology of this challenging situation. We hypothesize that higher levels of CA125 will identify a patient population with CRS-1 who could benefit from the use of a more intense diuretic strategy. Conversely, low levels of this glycoprotein could select those patients who would be harmed by high diuretic doses. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Efficacy and tolerability of high-dose phenobarbital in children with focal seizures.

PubMed

Okumura, Akihisa; Nakahara, Eri; Ikeno, Mitsuru; Abe, Shinpei; Igarashi, Ayuko; Nakazawa, Mika; Takasu, Michihiko; Shimizu, Toshiaki

2016-04-01

We retrospectively reviewed the outcomes of children with focal epilepsy treated with oral high-dose phenobarbital. We reviewed data on children (aged<15 years) with focal seizures treated with high-dose phenobarbital (>5 mg/kg/day to maintain a target serum level >40 μg/mL) for at least 6 months. Seizure frequency was evaluated after phenobarbital titration, and 1 and 2 years after high-dose phenobarbital treatment commenced. Treatment was judged effective when seizure frequencies fell by ⩾75%. Seven boys and eight girls were treated. The median age at commencement of high-dose phenobarbital therapy was 30 months. The maximal serum phenobarbital level ranged from 36.5 to 62.9 μg/mL. High-dose PB was effective in seven. In two patients, treatment was transiently effective, but seizure frequency later returned to the baseline. High-dose PB was ineffective in six. No significant association between effectiveness and any clinical variable was evident. Drowsiness was recorded in nine patients, but no patient developed a behavioral problem or hypersensitivity. Oral high-dose phenobarbital was effective in 7 of 15 patients with focal epilepsy and well tolerated. High-dose PB may be useful when surgical treatment is difficult. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors.

PubMed

Takahashi, Shunji; Nakano, Kenji; Yokota, Tomoya; Shitara, Kohei; Muro, Kei; Sunaga, Yoshinori; Ecstein-Fraisse, Evelyne; Ura, Takashi

2016-08-27

In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m 2 ombrabulin with 75 mg/m 2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors. This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m 2 combined with cisplatin 75 mg/m 2 . The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities. Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients. Ombrabulin 25 mg/m 2 with cisplatin 75 mg/m 2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Low dose Naltrexone for induction of remission in inflammatory bowel disease patients.

PubMed

Lie, Mitchell R K L; van der Giessen, Janine; Fuhler, Gwenny M; de Lima, Alison; Peppelenbosch, Maikel P; van der Ent, Cokkie; van der Woude, C Janneke

2018-03-09

Around 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function. Patients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples. Low dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected. Naltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients.

Inpatient management of sickle cell pain: a 'snapshot' of current practice.

PubMed

Miller, Scott T; Kim, Hae-Young; Weiner, Debra; Wager, Carrie G; Gallagher, Dianne; Styles, Lori; Dampier, Carlton D

2012-03-01

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. While PROACTIVE was not designed to assess pain management and was terminated early due to inadequate patient accrual, collection of clinical data allowed a "snapshot" of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain.

Inpatient Management of Sickle Cell Pain: a Snapshot of Current Practice

PubMed Central

Miller, Scott T.; Kim, Hae-Young; Weiner, Debra; Wager, Carrie G.; Gallagher, Dianne; Styles, Lori; Dampier, Carlton D.

2012-01-01

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. [1, 2] While PROACTIVE was not designed to assess pain management and terminated early due to inadequate patient accrual, collection of clinical data allowed a “snapshot” of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain. [3] PMID:22231150

SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF THE COMBINATION OF SORAFENIB AND TANESPIMYCIN

PubMed Central

Vaishampayan, Ulka N.; Burger, Angelika M.; Sausville, Edward A.; Heilbrun, Lance K.; Li, Jing; Horiba, Naomi; Egorin, Merrill J.; Ivy, Percy; Pacey, Simon; Lorusso, Patricia M.

2010-01-01

PURPOSE Heat shock protein 90 inhibition affects the Raf-kinase signaling pathway and could enhance anti-tumor effects of sorafenib, a Raf-kinase inhibitor. The combination of sorafenib and tanespimycin (17-AAG/17-allyl-amino-geldanamycin; NSC # 330507/KOS-953) was evaluated in a phase I trial with the primary objective of defining a phase II dose PATIENTS AND METHODS The dose cohorts consisted of fixed continuous oral dosing of sorafenib 400 mg twice daily, starting 14 days prior to tanespimycin which was administered intravenously, at escalating doses, (starting at 300 mg/m,2 with 50 mg/m2 increments), on days 1, 8 and 15, in a 28-day cycle. Toxicity was assessed weekly; response was evaluated every 2 cycles. RESULTS Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were: renal cancer (12), melanoma (6) and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in 1 patient each were observed at 450 mg/m2 of tanespimycin. 114 cycles were administered with a median of four cycles (range 1–17 cycles). Plasma concentrations of sorafenib and metabolites reached steady-state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients CONCLUSIONS Recommended phase II doses of this combination are sorafenib 400 mg twice daily and tanespimycin 400 mg/m2 on days 1, 8 and 15 every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma. PMID:20525756

Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA).

PubMed

Wagner, Michael J; Mitra, Rahul; McArthur, Mark J; Baze, Wallace; Barnhart, Kirstin; Wu, Sherry Y; Rodriguez-Aguayo, Cristian; Zhang, Xinna; Coleman, Robert L; Lopez-Berestein, Gabriel; Sood, Anil K

2017-06-01

To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice ( N = 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-adverse-effect level (NOAEL) for EPHARNA is considered >225 μg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human phase I clinical trial (NCT01591356). Mol Cancer Ther; 16(6); 1114-23. ©2017 AACR . ©2017 American Association for Cancer Research.

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

PubMed Central

Ricotti, Valeria; Spinty, Stefan; Roper, Helen; Hughes, Imelda; Tejura, Bina; Robinson, Neil; Layton, Gary; Davies, Kay

2016-01-01

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511 PMID:27055247

Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.

PubMed

Younger, Jarred; Noor, Noorulain; McCue, Rebecca; Mackey, Sean

2013-02-01

To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication. Copyright © 2013 by the American College of Rheumatology.

A hospital-based cost minimization study of the potential financial impact on the UK health care system of introduction of iron isomaltoside 1000.

PubMed

Bhandari, Sunil

2011-01-01

The clinical need to be able to administer high doses of intravenous iron conveniently in a single rapid infusion has been addressed by the recent introduction of ferric carboxymaltose and subsequently iron isomaltoside 1000. Neither requires a test dose. Ferric carboxymaltose can be administered at 15 mg/kg body weight to a maximum dose of 1000 mg, whereas iron isomaltoside 1000 can be administered at 20 mg/kg body weight. The ability to give high doses of iron is important in the context of managing iron deficiency anemia in a number of clinical conditions where demands for iron are high (including chronic blood loss associated with inflammatory bowel disease, menorrhagia, and chronic kidney disease). It is also an important component in the strategy as an alternative to a blood transfusion. Affordability is a key issue for health services. This study was a comparative analysis of the costs of administering the newly available intravenous iron formulations against standard practice (blood transfusion, intravenous iron sucrose) by considering the cost of this treatment option plus nursing costs associated with administration, equipment for administration, and patient transportation in the secondary care (hospital) setting across three dosage levels (600 mg, 1000 mg, and 1600 mg). The analysis indicates that the use of iron isomaltoside 1000 results in a net saving when compared with iron sucrose, blood, and ferric carboxymaltose. At 600 mg and 1000 mg doses, it is cheaper than low-molecular-weight iron dextran but more expensive at a dose of 1600 mg. However, it takes six hours to administer low-molecular-weight iron dextran at this dose level, which is inconvenient and reduces patient throughput (productivity).

A randomised clinical trial on the efficacy of oxytetracycline dose through water medication of nursery pigs on diarrhoea, faecal shedding of Lawsonia intracellularis and average daily weight gain.

PubMed

Larsen, Inge; Hjulsager, Charlotte Kristiane; Holm, Anders; Olsen, John Elmerdahl; Nielsen, Søren Saxmose; Nielsen, Jens Peter

2016-01-01

Oral treatment with antimicrobials is widely used in pig production for the control of gastrointestinal infections. Lawsonia intracellularis (LI) causes enteritis in pigs older than six weeks of age and is commonly treated with antimicrobials. The objective of this study was to evaluate the efficacy of three oral dosage regimens (5, 10 and 20mg/kg body weight) of oxytetracycline (OTC) in drinking water over a five-day period on diarrhoea, faecal shedding of LI and average daily weight gain (ADG). A randomised clinical trial was carried out in four Danish pig herds. In total, 539 animals from 37 batches of nursery pigs were included in the study. The dosage regimens were randomly allocated to each batch and initiated at presence of assumed LI-related diarrhoea. In general, all OTC doses used for the treatment of LI infection resulted in reduced diarrhoea and LI shedding after treatment. Treatment with a low dose of 5mg/kg OTC per kg body weight, however, tended to cause more watery faeces and resulted in higher odds of pigs shedding LI above detection level when compared to medium and high doses (with odds ratios of 5.5 and 8.4, respectively). No association was found between the dose of OTC and the ADG. In conclusion, a dose of 5mg OTC per kg body weight was adequate for reducing the high-level LI shedding associated with enteropathy, but a dose of 10mg OTC per kg body weight was necessary to obtain a maximum reduction in LI shedding. Copyright © 2015 Elsevier B.V. All rights reserved.

Mesalamine Dose Escalation Reduces Fecal Calprotectin In Patients With Quiescent Ulcerative Colitis

PubMed Central

Osterman, Mark T.; Aberra, Faten N; Cross, Raymond; Liakos, Steven; McCabe, Robert; Shafran, Ira; Wolf, Douglas; Hardi, Robert; Nessel, Lisa; Brensinger, Colleen; Gilroy, Erin; Lewis, James D.

2014-01-01

Background & Aims Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized, controlled trial to investigate whether increasing doses mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. Methods We screened 119 patients with UC in remission, based on Simple Clinical Colitis Activity Index scores, FC >50 mcg/g, and intake of no more than 3g/day of mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n=26) or a group that increased its dose by 2.4 g/day for 6 weeks (n=26). The primary outcome was continued remission with FC<50 mcg/g. Secondary outcomes were continued remission with FC<100 mcg/g or <200 mcg/g (among patients with pre-randomization values above these levels). Results The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P=.0496). More patients in the dose escalation group reduced FC to below 100 mcg/g (P=.04) and 200 mcg/g (P=.005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 mcg/g compared to those with FC <200 mcg/g (P=.01). Conclusion Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov: NCT00652145 PMID:24793028

Gentamicin ototoxicity: a 23-year selected case series of 103 patients.

PubMed

Ahmed, Rebekah M; Hannigan, Imelda P; MacDougall, Hamish G; Chan, Raymond C; Halmagyi, G Michael

2012-06-18

To review patients with severe bilateral vestibular loss associated with gentamicin treatment in hospital. A retrospective case series of presentations to a balance disorders clinic between 1988 and 2010. Relationship between vestibulotoxicity and gentamicin dose or dosing profile; indications for prescribing gentamicin. 103 patients (age, 18-84 years; mean, 64 years) presented with imbalance, oscillopsia or both, but none had vertigo. Only three noted some hearing impairment after having gentamicin, but audiometric thresholds for all patients were consistent with their age. In all patients, the following tests gave positive results: a bilateral clinical head-impulse test, a vertical head-shaking test for vertical oscillopsia, and a foam Romberg test. In 21 patients, imbalance occurred during gentamicin treatment (ignored or dismissed by prescribers in 20) and in 66 after treatment; the remaining 16 could not recall when symptoms were first noticed, except that it was after gentamicin treatment in hospital. Total gentamicin dose range was 2-318 mg/kg (mean, 52 mg/kg), daily dose range was 1.5-5.6 mg/kg (mean, 3.5mg/kg), and duration was 1-80 days (mean, 17 days). Six patients had only a single dose; 26 had five or fewer doses. Serum gentamicin levels, measured in 82 patients, were in the recommended range in 59. Time to diagnosis ranged from 4 days to 15 years. Nephrotoxicity developed in 43 patients. Gentamicin dosage complied with contemporary or current Australian antibiotic guidelines in under half the patients. Gentamicin ototoxicity is vestibular, not cochlear, producing permanent loss of balance, but not of hearing. Gentamicin can be vestibulotoxic in any dose, in any regimen, at any serum level.

How modeling and simulation have enhanced decision making in new drug development.

PubMed

Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

2005-04-01

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.

Clinical study of double dose of valsartan combined with tacrolimus in treatment of diabetic nephropathy.

PubMed

Jin, H; Zhang, H-N; Hou, X-L; Zhang, B; Wu, J; Zhang, H-B

2016-01-01

To investigate the clinical effect of double dose of valsartan combined with tacrolimus in the treatment of diabetic nephropathy (DN). HA total of 86 cases diagnosed with DN were selected from October 2013 to October 2014 in Zaozhuang Municipal Hospital, China. The study was approved by our hospital Ethics Committee and written consent was obtained from patients and their family members. Patients were randomly divided into three groups according to the sequence of admission, group A (conventional dose of valsartan group, n = 28 cases), group B (double dose of valsartan group, n = 29 cases) and group C (double dose of valsartan combined with tacrolimus group, n = 29). Clinical effects were compared by analyzing the renal function tests after 8 weeks. 24h urine protein, serum creatinine level of patients in group B and group C were significantly lower than that of group A. Those in group C was much lower. The glomerular filtration rates were significantly higher for group B and C than that of group A, and those in group C were much higher. The difference is statistically significant (p < 0.05). High-sensitivity C-reactive protein (hs CRP) and adiponectin levels of patients in group B and C of were significantly lower than that of group A and those in group C were much lower. The difference is statistically significant (p < 0.05). The high mobility group protein 1 (HMGB1) and renal tubular and interstitial damage index (TDI) of patients in B and C groups were significantly lower than those in the A group, and those in C group were significantly lower. The difference was statistically significant p < 0.05). The clinical effective rates of patients in group B and C were significantly higher than that in group A, and those of group C were much higher. The difference is statistically significant (p < 0.05). The recurrence rates of patients in group B and group C were significantly lower than those of group A and those in group C were much lower. The difference is statistically significant (p < 0.05). Patients in three groups showed no obvious drug complications. Double dose of valsartan combined with tacrolimus treatment of DN patients can improve clinical symptoms, reducing inflammation, inhibiting or even reversing the interstitial fibrosis, which will improve the curative effect and reduce the recurrence, as to provide a new theoretical basis for the clinical treatment of the disease.

Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial.

PubMed

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W

2012-10-17

Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. INTERVENTION The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. The composite of HIV disease progression or death from any cause. The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87) vs standard-dose supplementation. CONCLUSION In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Clinicaltrials.gov Identifier: NCT00383669.

[Pharmacokinetics and clinical studies of flomoxef in the pediatric field].

PubMed

Motohiro, T; Oda, K; Aramaki, M; Kawakami, A; Tanaka, K; Koga, T; Shimada, Y; Tomita, S; Sakata, Y; Fujimoto, T

1987-08-01

Flomoxef (FMOX, 6315-S), a new intravenous cephem antibiotics, was administered to a total of 11 cases with their ages ranging from 7 years and 4 months to 10 years and 10 months. Among them, two were administered with (FMOX at) a dose level of 10 mg/kg, three each with 20 mg/kg and 40 mg/kg using one shot intravenous injection, and the remaining 3 with 40 mg/kg by intravenous drip infusion over 30 minutes. Plasma concentrations, urine concentrations and urinary recovery rates were determined. The clinical efficacy of FMOX was evaluated in 2 cases with tonsillitis, 45 with acute pneumonia, 10 with urinary tract infections, 2 with purulent lymphadenitis, and 2 with abscess, a total of 61 cases. Of these cases, one case of pneumonia in which a side effect occurred was excluded from the evaluation because the treatment was interrupted short of the required period. In the remaining 60 cases, the mean daily dose was 79.3 mg/kg in 3 or 4 divided doses and, except one case treated by 30-minute intravenous drip infusion, all cases were treated by one shot intravenous injection for a mean period of 6 days. Bacteriological effects of FMOX, its side effects and influences on laboratory test values were also investigated. 1. Maximum plasma concentrations after one shot intravenous injections of FMOX occurred at 5 minutes after administration regardless of dose levels (10 mg/kg in 2 cases, 20 mg/kg in 3 and 40 mg/kg in 3). Mean peak values obtained upon the 3 different dose levels were 62.5, 103.1 and 244.7 micrograms/ml, respectively. Mean plasma half-lives were 0.670, 0.915 and 0.595 hour, and mean AUCs were 33.0, 65.2 and 133.1 micrograms.hr/ml, respectively. Thus, a positive dose-response relationship was found among the 3 doses. 2. Plasma concentrations after 30-minute intravenous drip infusions of FMOX at 40 mg/kg always reached a peak at 30 minutes after the initiation of infusion, i.e. at the completion of infusion, and the mean value for 3 administrations was 151.0 micrograms/ml. The mean half-life was 0.973 hour and the mean AUC was 149.1 micrograms.hr/ml. 3. Maximum concentrations in urine after one shot intravenous injections of FMOX were always obtained in 0 approximately 2 hours after administration regardless of dose levels (10 mg/kg, 2 cases, 20 mg/kg, 3 cases and at 40 mg/kg, 3 cases) and mean values for the 3 dose levels were 2,570, 4,410 and 6,290 micrograms/ml, respectively. Thus, urine concentrations were also dose-dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

The Effect of High Dose Folic Acid throughout Pregnancy on Homocysteine (Hcy) Concentration and Pre-Eclampsia: A Randomized Clinical Trial

PubMed Central

Sayyah-Melli, Manizheh; Ghorbanihaghjo, Amir; Alizadeh, Mahasti; Kazemi-Shishvan, Maryamalsadat; Ghojazadeh, Morteza; Bidadi, Sanam

2016-01-01

Pre-eclampsia is a pregnancy-related multi-systemic hypertensive disorder and affects at least 5% of pregnancies. This randomized clinical trial aimed at assessing the effect of low doses and high doses of folic acid on homocysteine (Hcy) levels, blood pressure, urea, creatinine and neonatal outcome. A randomized clinical trial was done at Alzahra Teaching Hospital, Tabriz University of Medical Sciences from April 2008 to March 2013. Four-hundred and sixty nulliparous pregnant women were randomly assigned into two groups. Group 1 (n = 230) received 0.5 mg of folic acid and group 2 (n = 230) received 5 mg of folic acid per daily. They were followed until delivery. Blood pressure and laboratory changes, including plasma Hcy levels, were measured and compared between the groups. Homocysteine concentrations were significantly higher at the time of delivery in group 1 (13.17±3.89 μmol/l) than in group 2 (10.31±3.54, μmol/l) (p<0.001). No statistically significant differences were observed in systolic and diastolic blood pressure (p = 0.84 and 0.15, respectively). Birth weight was significantly higher in group 2 (p = 0.031) and early abortion was significantly higher in group 1 than group 2 (p = 0.001). This study has provided evidence that a high dosage of folic acid supplements throughout pregnancy reduces Hcy concentrations at the time of delivery. Trial Registration: Iranian Registry of Clinical Trials IRCT201402175283N9 PMID:27166794

Pharmacokinetic and Tolerability Assessment of a Pediatric Oral Formulation of Pentoxifylline in Kawasaki Disease☆

PubMed Central

Best, Brookie M.; Burns, Jane C.; DeVincenzo, John; Phelps, Stephanie J.; Blumer, Jeffrey L.; Wilson, John T.; Capparelli, Edmund V.; Connor, James D.

2003-01-01

Background: In infants and children, treatment of Kawasaki disease (KD) with high-dose intravenous immunoglobulin (IVIG) and acetylsalicylic acid ([ASA] aspirin) diminishes inflammatory response and reduces the risk for coronary artery abnormalities. However, patients with high serum concentrations of tumor necrosis factor (TNF)-alpha, which is associated with vascular damage, may develop coronary artery lesions even with treatment. The hemorheologic agent pentoxifylline blocks the production of TNF-alpha and may be an appropriate adjunctive therapy to IVIG and ASA. Objective: The objective of this study was to assess the pharmacokinetic characteristics and tolerability of a new oral syrup formulation of pentoxifylline as an adjunct to IVIG and ASA in the treatment of KD in children. Methods: Hospitalized boys and girls aged 6 months to 5 years and who were diagnosed with KD within the first 10 days of illness were eligible. Patients were assigned to 1 of 4 pentoxifylline treatment groups, by dose level (dose levels 1, 2, 3, and 4: 10, 15, 20, and 25 mg/kg daily, respectively, divided into 3 doses). Six plasma samples collected at the time the first dose was administered, and 4 samples collected after administration of the last dose on study day 6, were assessed by high-performance liquid chromatography using noncompartmental and 1-compartment pharmacokinetic analyses for pentoxifylline and its active metabolite (M-1). TNF-alpha levels on days 1 and 6 were assessed using electroimmunoassay. Results: Fourteen boys and 10 girls were enrolled. The mean age, body weight, and illness day at study entry were 34.5 months, 13.8 kg, and 6, respectively. Pentoxifylline exhibited nonlinear kinetic characteristics, with median area under the plasma concentration–time curve from time 0 to infinity(AUC0–∞) values of 622, 3428, 8416, and 10,347 ng/mL · h for dose levels 1 to 4, respectively, on study day 1. Pentoxifylline noncompartmental oral clearance and volume of distribution were significantly lower, and dose-normalized AUC0–∞ was significantly higher, for dose level 3 than dose level 1. M-1 parameters were not significantly different between dose levels. No accumulation of pentoxifylline or M-1 was noted. Fifteen of 24 patients (63%) reported mild to moderate adverse events that may or may not have been treatment related. Frequency and severity did not differ significantly between dose levels. Conclusions: In the children in this study, pentoxifylline was well tolerated at the doses studied. No notable differences in clinical outcomes were observed between dose levels, and dose levels 3 and 4 (20 and 25 mg/kg daily, respectively) resulted in similar exposure to both pentoxifylline and M-1. Future efficacy and tolerability studies should use a daily dose of 20 mg/kg of pentoxifylline in acute KD. PMID:24944359

Evaluation of genotoxicity and subclinical toxicity of Agaricus blazei Murrill in the Ames test and in histopathological and biochemical analysis.

PubMed

Chang, Jin-Biou; Lu, Hsu-Feng; Liao, Nien-Chieh; Lee, Ching-Sung; Yeh, Ming-Yang; Liu, Chi-Ming; Chung, Ming-Teng; Man-Kuan, Au; Lin, Jen-Jyh; Wu, Ming-Fang; Chung, Jing-Gung

2012-01-01

This study was conducted in order to assess the safety and tolerability of Agaricus blazei Murrill (ABM) in general toxicological studies by Ames tests in vitro and in 28-day feeding toxicity experiments. There were no dose-dependent increases or decreases in the number of revertant colonies both with and without metabolic activation in Ames tests. Doses of 10, 5 and 0.1 mg/per mouse of ABM daily were administered by oral gavage to mice (n=10) for 28 days. The effects on clinical observations, clinical pathology, and histopathology were evaluated. There were no significant changes in the brain, heart, kidney, liver, spleen, adrenal gland, testes or ovaries visually. With increasing doses, male and female treated mice did not show any gradual elevation of serum concentration in any of the nine items we examined, except for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in females. The AST levels of the treatment by medium or high dose and the ALT levels of the treatment by high dose in females were abnormal in comparison to those of the baseline control group, with significant differences. On studying the histological changes in mice, tissue sections of negative control and experimental groups exhibited no apparent pathological alterations. In summary, the Ames test, pathology determinations, biochemical analysis and routine blood parameters were all normal, except for AST and ALT in females. Results showed that the statistical differences observed in one sex were not observed in the other and were not dose dependent.

Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response.

PubMed

Tavira, Beatriz; Cheramy, Mikael; Axelsson, Stina; Åkerman, Linda; Ludvigsson, Johnny; Casas, Rosaura

2017-07-01

A European Phase III trial of GAD formulated with aluminium hydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response. In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD 65 -induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD-alum. GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was ≥210 days (p < 0.05). In the group that received two doses of GAD-alum, levels of several GAD 65 -induced cytokines were higher in participants who received the H1N1 vaccination and the first GAD-alum injection at least 150 days apart, and the change in fasting and stimulated C-peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum. In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. <150 days, seemed to affect both GAD 65 -induced immune response and C-peptide preservation. ClinicalTrials.gov NCT00723411.

Controlled-release systemic delivery - a new concept in cancer chemoprevention

PubMed Central

2012-01-01

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo. PMID:22696595

Bulgarian experience in the establishment of reference dose levels and implementation of a quality control system in diagnostic radiology.

PubMed

Vassileva, J; Dimov, A; Slavchev, A; Karadjov, A

2005-01-01

Results from a Bulgarian patient dose survey in diagnostic radiology are presented. Reference levels for entrance surface dose (ESD) were 0.9 mGy for chest radiography (PA), 30 mGy for lumbar spine (Lat), 10 mGy for pelvis, 5 mGy for skull (AP), 3 mGy for skull (Lat) and 13 mGy for mammography. Quality control (QC) programmes were proposed for various areas of diagnostic radiology. Film processing QC warranted special attention. Proposed QC programmes included parameters to be tested, level of expertise needed and two action levels: remedial and suspension. Programmes were tested under clinical conditions to assess initial results and draw conclusions for further QC system development. On the basis of international experience, measurement protocols were developed for all parameters tested. QC equipment was provided as part of the PHARE project. A future problem for QC programme implementation may be the small number of medical physics experts in diagnostic radiology.

Dosimetric verification and clinical evaluation of a new commercially available Monte Carlo-based dose algorithm for application in stereotactic body radiation therapy (SBRT) treatment planning

NASA Astrophysics Data System (ADS)

Fragoso, Margarida; Wen, Ning; Kumar, Sanath; Liu, Dezhi; Ryu, Samuel; Movsas, Benjamin; Munther, Ajlouni; Chetty, Indrin J.

2010-08-01

Modern cancer treatment techniques, such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), have greatly increased the demand for more accurate treatment planning (structure definition, dose calculation, etc) and dose delivery. The ability to use fast and accurate Monte Carlo (MC)-based dose calculations within a commercial treatment planning system (TPS) in the clinical setting is now becoming more of a reality. This study describes the dosimetric verification and initial clinical evaluation of a new commercial MC-based photon beam dose calculation algorithm, within the iPlan v.4.1 TPS (BrainLAB AG, Feldkirchen, Germany). Experimental verification of the MC photon beam model was performed with film and ionization chambers in water phantoms and in heterogeneous solid-water slabs containing bone and lung-equivalent materials for a 6 MV photon beam from a Novalis (BrainLAB) linear accelerator (linac) with a micro-multileaf collimator (m3 MLC). The agreement between calculated and measured dose distributions in the water phantom verification tests was, on average, within 2%/1 mm (high dose/high gradient) and was within ±4%/2 mm in the heterogeneous slab geometries. Example treatment plans in the lung show significant differences between the MC and one-dimensional pencil beam (PB) algorithms within iPlan, especially for small lesions in the lung, where electronic disequilibrium effects are emphasized. Other user-specific features in the iPlan system, such as options to select dose to water or dose to medium, and the mean variance level, have been investigated. Timing results for typical lung treatment plans show the total computation time (including that for processing and I/O) to be less than 10 min for 1-2% mean variance (running on a single PC with 8 Intel Xeon X5355 CPUs, 2.66 GHz). Overall, the iPlan MC algorithm is demonstrated to be an accurate and efficient dose algorithm, incorporating robust tools for MC-based SBRT treatment planning in the routine clinical setting.

SU-F-R-11: Designing Quality and Safety Informatics Through Implementation of a CT Radiation Dose Monitoring Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilson, JM; Samei, E; Departments of Physics, Electrical and Computer Engineering, and Biomedical Engineering, and Medical Physics Graduate Program, Duke University, Durham, NC

2016-06-15

Purpose: Recent legislative and accreditation requirements have driven rapid development and implementation of CT radiation dose monitoring solutions. Institutions must determine how to improve quality, safety, and consistency of their clinical performance. The purpose of this work was to design a strategy and meaningful characterization of results from an in-house, clinically-deployed dose monitoring solution. Methods: A dose monitoring platform was designed by our imaging physics group that focused on extracting protocol parameters, dose metrics, and patient demographics and size. Compared to most commercial solutions, which focus on individual exam alerts and global thresholds, the program sought to characterize overall consistencymore » and targeted thresholds based on eight analytic interrogations. Those were based on explicit questions related to protocol application, national benchmarks, protocol and size-specific dose targets, operational consistency, outliers, temporal trends, intra-system variability, and consistent use of electronic protocols. Using historical data since the start of 2013, 95% and 99% intervals were used to establish yellow and amber parameterized dose alert thresholds, respectively, as a function of protocol, scanner, and size. Results: Quarterly reports have been generated for three hospitals for 3 quarters of 2015 totaling 27880, 28502, 30631 exams, respectively. Four adult and two pediatric protocols were higher than external institutional benchmarks. Four protocol dose levels were being inconsistently applied as a function of patient size. For the three hospitals, the minimum and maximum amber outlier percentages were [1.53%,2.28%], [0.76%,1.8%], [0.94%,1.17%], respectively. Compared with the electronic protocols, 10 protocols were found to be used with some inconsistency. Conclusion: Dose monitoring can satisfy requirements with global alert thresholds and patient dose records, but the real value is in optimizing patient-specific protocols, balancing image quality trade-offs that dose-reduction strategies promise, and improving the performance and consistency of a clinical operation. Data plots that capture patient demographics and scanner performance demonstrate that value.« less

Adjunctive aripiprazole in the treatment of risperidone-induced hyperprolactinemia: A randomized, double-blind, placebo-controlled, dose-response study.

PubMed

Chen, Jing-Xu; Su, Yun-Ai; Bian, Qing-Tao; Wei, Li-He; Zhang, Rong-Zhen; Liu, Yan-Hong; Correll, Christoph; Soares, Jair C; Yang, Fu-De; Wang, Shao-Li; Zhang, Xiang-Yang

2015-08-01

Hyperprolactinemia is an unwanted adverse effect associated with several antipsychotics. The addition of partial dopamine receptor agonist aripiprazole may attenuate antipsychotic-induced hyperprolactinemia effectively. However, the ideal dosing regimen for this purpose is unknown. We aimed to evaluate the dose effects of adjunctive treatment with aripiprazole on prolactin levels and hyperprolactinemia in schizophrenia patients. Stable subjects 18-45 years old with schizophrenia and hyperprolactinemia (i.e., >24 ng/ml for females and >20 ng/ml for males) were randomly assigned to receive 8 weeks of placebo (n=30) or oral aripiprazole 5mg/day (n=30), 10mg/day (n=29), or 20mg/day (n=30) added on to fixed dose risperidone treatment. Serum prolactin levels were measured at baseline and after 2, 4 and 8 weeks; clinical symptoms and side effects were assessed at baseline and week 8 using the Positive and Negative Syndrome Scale, Clinical Global Impressions Severity scale, Barnes Akathisia Scale, Simpson-Angus Scale and UKU Side Effects Rating Scale. Of 119 randomized patients, 107 (89.9%) completed the 8-week study. At study end, all three aripiprazole doses resulted in significantly lower prolactin levels (beginning at week 2), higher response rates (≥30% prolactin reduction) and higher prolactin normalization rates than placebo. Effects were significantly greater in the 10 and 20mg/day groups than the 5mg/day group. No significant changes were observed in any treatment groups regarding psychopathology and adverse effect ratings. Adjunctive aripiprazole treatment was effective and safe for resolving risperidone-induced hyperprolactinemia, producing significant and almost maximal improvements by week 2 without significant effects on psychopathology and side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

On the prescribing of oral doxycycline or minocycline by UK optometrists as part of management of chronic Meibomian Gland Dysfunction (MGD).

PubMed

Doughty, Michael J

2016-02-01

To review the special pharmacology of tetracycline antibiotics as anti-inflammatory drugs for treatment of obstructive Meibomian gland disease (MGD) METHODS: PubMed was used as principal resource for articles, regardless of language, on doxycycline and minocycline with key interests being on their serum and tissue pharmacokinetics and their use in clinical studies as part of management of MGD. With oral dosing of between 50 and 200mg, peak blood levels of these antibiotics have been reported to be predictably dose-dependent at between 1 and 5 microgram/mL, with human tear film levels not being detectable with 100mg dosing of doxycycline but levels of 0.2 microgram/mL with 200mg minocycline. That these two tetracycline antibiotics reach the conjunctiva is indicated by conjunctival pigmentary changes due to photosensitization after very long term use. Based the reported use in a range of clinical studies on MGD, dosing with these two antibiotics for MGD is likely to be useful at relatively low doses (e.g. 100mg for doxycycline or 50mg for minocycline, either at once or twice daily depending on severity at presentation and previous history) continued for 2 to 3 months, with the expected outcome being small-to-substantial decreases in abnormal appearance of the glands (from -4 to -89%) and increases in tear film stability (from 21 to 273%). Oral doxycycline and minocycline have predictable pharmacokinetics and have been reported to improve Meibomian gland dysfunction over a few months of use. Copyright © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

GMP-grade α-TEA lysine salt: a 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs.

PubMed

Guerrouahen, Bella S; Hahn, Tobias; Alderman, Zefora; Curti, Brendan; Urba, Walter; Akporiaye, Emmanuel T

2016-03-08

Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic derivative of naturally occurring vitamin E (alpha-tocopherol) that can be delivered via an oral route. Preclinical in vitro and in vivo data demonstrated that α-TEA is a potent anti-tumor agent with a safe toxicity profile in mice. We report a comprehensive study to evaluate the toxokinetics of good manufacturing practice (GMP)-grade α-TEA in dogs after daily oral administration for 28 days, followed by a 28-day recovery period. Male and female beagle dogs received capsules of α-TEA Lysine Salt at doses of 100, 300, 1500 mg/kg/day. α-TEA plasma levels were determined by high-performance liquid chromatography (HPLC) with mass spectrometric detection. During the treatment, animals were observe for clinical signs, food consumption, body weight, and subjected to ophthalmoscopic, and electrocardiographic assessments. At the end of the dosing period, blood was taken and toxicokinetic analyses and histopathology assessments were performed when animals were necropsied. Our findings showed that there was no α-TEA-related mortality or moribundity. At the highest dose, increases in white blood cells and fibrinogen levels were observed. These levels returned to normal at the end of the recovery period. Histopathological evaluation of major organs revealed no significant lesions related to α-TEA-treatment. We demonstrate that for designing clinical trials in patients, the highest non-severely toxic dose (HNSTD) of α-TEA is 1500 mg/kg/day in Beagle dogs and this data informed the design of dose-escalation studies of α-TEA in patients with advanced cancer.

A noise power spectrum study of a new model-based iterative reconstruction system: Veo 3.0.

PubMed

Li, Guang; Liu, Xinming; Dodge, Cristina T; Jensen, Corey T; Rong, X John

2016-09-08

The purpose of this study was to evaluate performance of the third generation of model-based iterative reconstruction (MBIR) system, Veo 3.0, based on noise power spectrum (NPS) analysis with various clinical presets over a wide range of clinically applicable dose levels. A CatPhan 600 surrounded by an oval, fat-equivalent ring to mimic patient size/shape was scanned 10 times at each of six dose levels on a GE HD 750 scanner. NPS analysis was performed on images reconstructed with various Veo 3.0 preset combinations for comparisons of those images reconstructed using Veo 2.0, filtered back projection (FBP) and adaptive statistical iterative reconstruc-tion (ASiR). The new Target Thickness setting resulted in higher noise in thicker axial images. The new Texture Enhancement function achieved a more isotropic noise behavior with less image artifacts. Veo 3.0 provides additional reconstruction options designed to allow the user choice of balance between spatial resolution and image noise, relative to Veo 2.0. Veo 3.0 provides more user selectable options and in general improved isotropic noise behavior in comparison to Veo 2.0. The overall noise reduction performance of both versions of MBIR was improved in comparison to FBP and ASiR, especially at low-dose levels. © 2016 The Authors.

Concurrent ganirelix and follitropin beta therapy is an effective and safe regimen for ovulation induction in women with polycystic ovary syndrome.

PubMed

Elkind-Hirsch, Karen E; Webster, Bobby W; Brown, Crystal P; Vernon, Michael W

2003-03-01

To evaluate controlled ovarian stimulation cycles using the GnRH antagonist ganirelix in combination with the recombinant FSH, follitropin-beta, in women with polycystic ovary syndrome (PCOS). Prospective, nonrandomized clinical study. Hospital-based infertility practice. Twenty women with PCOS planning to undergo ovarian stimulation. Fasting glucose and insulin levels were used to calculate insulin resistance ratios (FG/I). After pretreatment with oral contraceptives, serum LH levels were determined, and 250 microg ganirelix was administered on cycle day 2. Upon suppression of LH, concurrent ganirelix and follitropin-beta therapy (morning ganirelix and evening follitropin-beta) was started and continued until the day of hCG. Days of stimulation, dose of follitropin-beta, pregnancy, and ongoing pregnancy were compared based on FG/I ratios. One dose of ganirelix effectively suppressed LH levels in all patients. All patients ovulated as documented by a rise in progesterone. Significant differences were observed between the insulin-resistant and non-insulin-resistant groups for both days of stimulation and dose of follitropin-beta. The overall clinical pregnancy rate was 44.4%, with an ongoing pregnancy rate of 27.8%. In this preliminary study, we demonstrate the effectiveness of a concurrent ganirelix and follitropin-beta therapy for ovarian stimulation in women with PCOS.

Benign course after acute high dose levothyroxine intoxication in a 3-year-old boy.

PubMed

Hartman, Stan; Noordam, Kees; Maseland, Machiel; van Setten, Petra

2017-01-01

Acute ingestion of thyroid hormone preparations is a common intoxication, with 181 cases in children <12 yr in 2009 in the Netherlands, but generally has a mild course. However, some reports show that even low dosages may cause serious events such as seizures, thyroid storm and coma. We report a 3 yr old boy case with an acute intoxication with high dose levothyroxine (0.5 mg/kg). We describe the proper management of levothyroxine intoxication in children. A 3-year-old boy with no notable medical history ingested sixty tablets of levothyroxine 150 µg. His vital-signs were normal and the only symptom during admission was a tachycardia the following day. Laboratory data showed elevated T3, fT3 and fT4 levels; and decrease TSH levels. He was treated prophylactically and therapeutically with activated charcoal and propranolol. Despite very high levels, his clinical symptoms were relatively mild. After clinical follow-up for 3 d he was discharged. We propose that children with thyroid hormone intoxication with either a levothyroxine dose >0.1 g/kg, a short interval since ingestion, symptomatic presentation, and/or a fT4 >100 pmol/l should be monitored in the hospital during at least 48-72 h post-ingestion and on an outpatient basis for 14 d.

Ocular allergy modulation to hi-dose antigen sensitization is a Treg-dependent process.

PubMed

Lee, Hyun Soo; Schlereth, Simona; Khandelwal, Payal; Saban, Daniel R

2013-01-01

A reproducible method to inhibit allergic immune responses is accomplished with hi-dose Ag sensitization, via intraperitoneal (IP) injection. However, the role of CD4+ CD25+ FoxP3+ T regulatory cells (Treg) in this process is unknown, as is whether such modulation extends to ocular allergy. We therefore determined herein whether hi-dose sensitization modulates ocular allergy, and whether CD4+ CD25+ FoxP3+ Treg are involved. C57BL/6 mice were IP sensitized via low-dose (100 µg) versus hi-dose (1000 µg) ovalbumin (OVA), in aluminum hydroxide (1 mg) and pertussis-toxin (300 ng). Other mice received anti-CD25 Ab (PC61) to ablate Treg during sensitization. In another experiment, Treg from hi-dose sensitized mice were adoptively transferred into low-dose sensitized mice. Once daily OVA challenges were administered. Clinical signs, IgE, T cell cytokines, and eosinophils were assessed. Data revealed that hi-dose, but not low-dose, sensitization led to allergy modulation, indicated by decreased clinical signs, serum IgE levels, Th2 recall responses, and eosinophil recruitment. T cells from hi-dose sensitized mice showed a robust increase in TGF-b production, and Treg from these mice were able to efficiently suppress effector T cell proliferation in vitro. In addition, in vivo Treg ablation in hi-dose sensitized mice revoked allergy modulation. Lastly, Treg from hi-dose sensitized mice were able to adoptively transfer allergy modulation to their low-dose sensitized counterparts. Collectively, these findings indicate that modulation to hi-dose sensitization, which is extended to ocular allergy, occurs in a Treg-dependent manner. In addition, our data suggest that hi-dose sensitization may henceforth facilitate the further examination of CD4+ CD25+ FoxP3+ Treg in allergic disease.

WE-AB-209-07: Explicit and Convex Optimization of Plan Quality Metrics in Intensity-Modulated Radiation Therapy Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Engberg, L; KTH Royal Institute of Technology, Stockholm; Eriksson, K

Purpose: To formulate objective functions of a multicriteria fluence map optimization model that correlate well with plan quality metrics, and to solve this multicriteria model by convex approximation. Methods: In this study, objectives of a multicriteria model are formulated to explicitly either minimize or maximize a dose-at-volume measure. Given the widespread agreement that dose-at-volume levels play important roles in plan quality assessment, these objectives correlate well with plan quality metrics. This is in contrast to the conventional objectives, which are to maximize clinical goal achievement by relating to deviations from given dose-at-volume thresholds: while balancing the new objectives means explicitlymore » balancing dose-at-volume levels, balancing the conventional objectives effectively means balancing deviations. Constituted by the inherently non-convex dose-at-volume measure, the new objectives are approximated by the convex mean-tail-dose measure (CVaR measure), yielding a convex approximation of the multicriteria model. Results: Advantages of using the convex approximation are investigated through juxtaposition with the conventional objectives in a computational study of two patient cases. Clinical goals of each case respectively point out three ROI dose-at-volume measures to be considered for plan quality assessment. This is translated in the convex approximation into minimizing three mean-tail-dose measures. Evaluations of the three ROI dose-at-volume measures on Pareto optimal plans are used to represent plan quality of the Pareto sets. Besides providing increased accuracy in terms of feasibility of solutions, the convex approximation generates Pareto sets with overall improved plan quality. In one case, the Pareto set generated by the convex approximation entirely dominates that generated with the conventional objectives. Conclusion: The initial computational study indicates that the convex approximation outperforms the conventional objectives in aspects of accuracy and plan quality.« less

SU-E-T-50: A Multi-Institutional Study of Independent Dose Verification Software Program for Lung SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawai, D; Takahashi, R; Kamima, T

2015-06-15

Purpose: The accuracy of dose distribution depends on treatment planning system especially in heterogeneity-region. The tolerance level (TL) of the secondary check using the independent dose verification may be variable in lung SBRT plans. We conducted a multi-institutional study to evaluate the tolerance level of lung SBRT plans shown in the AAPM TG114. Methods: Five institutes in Japan participated in this study. All of the institutes used a same independent dose verification software program (Simple MU Analysis: SMU, Triangle Product, Ishikawa, JP), which is Clarkson-based and CT images were used to compute radiological path length. Analytical Anisotropic Algorithm (AAA), Pencilmore » Beam Convolution with modified Batho-method (PBC-B) and Adaptive Convolve (AC) were used for lung SBRT planning. A measurement using an ion-chamber was performed in a heterogeneous phantom to compare doses from the three different algorithms and the SMU to the measured dose. In addition to it, a retrospective analysis using clinical lung SBRT plans (547 beams from 77 patients) was conducted to evaluate the confidence limit (CL, Average±2SD) in dose between the three algorithms and the SMU. Results: Compared to the measurement, the AAA showed the larger systematic dose error of 2.9±3.2% than PBC-B and AC. The Clarkson-based SMU showed larger error of 5.8±3.8%. The CLs for clinical plans were 7.7±6.0 % (AAA), 5.3±3.3 % (AC), 5.7±3.4 % (PBC -B), respectively. Conclusion: The TLs from the CLs were evaluated. A Clarkson-based system shows a large systematic variation because of inhomogeneous correction. The AAA showed a significant variation. Thus, we must consider the difference of inhomogeneous correction as well as the dependence of dose calculation engine.« less

Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials.

PubMed

Figueroa, Xavier A; Wright, James K

2016-09-27

First, to demonstrate that B-level evidence exists for the use of hyperbaric oxygen therapy (HBOT) as an effective treatment in mild to moderate traumatic brain injury/persistent postconcussion syndrome (mTBI/PPCS). Second, to alert readers and researchers that currently used pressurized air controls (≥21% O2, >1.0 ATA) are therapeutically active and cannot be utilized as sham controls without further validation. Review of published, peer-reviewed articles of HBOT prospective and controlled clinical trials of mTBI/PPCS symptoms. Published results demonstrate that HBOT is effective in the treatment of mTBI/PPCS symptoms. Doses of oxygen that are applied at ≥21% O2 and at pressures of >1.0 ATA produce improvements from baseline measures. Some of the recently published clinical trials are mischaracterized as sham-controlled clinical trials (i.e., sham = 21% O2/1.2-1.3 ATA), but are best characterized as dose-varying (variation in oxygen concentration, pressure applied, or both) clinical trials. Hyperbaric oxygen and hyperbaric air have demonstrated therapeutic effects on mTBI/PPCS symptoms and can alleviate posttraumatic stress disorder symptoms secondary to a brain injury in 5 out of 5 peer-reviewed clinical trials. The current use of pressurized air (1.2-1.3 ATA) as a placebo or sham in clinical trials biases the results due to biological activity that favors healing. © 2016 American Academy of Neurology.

Multiple anatomy optimization of accumulated dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watkins, W. Tyler, E-mail: watkinswt@virginia.edu; Siebers, Jeffrey V.; Moore, Joseph A.

Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dosemore » variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.« less

Concentrations in plasma clozapine levels in schizophrenic and schizoaffective patients.

PubMed

Iglesias García, Celso; Iglesias Alonso, Ana; Bobes, Julio

There is great variability in plasma levels of clozapine. The objective of this study is to know the characteristics of patients treated with clozapine and the relationship between them and the variability of plasma levels. Descriptive, cross-sectional study of all patients currently treated with clozapine in a Psychiatric Service with a diagnosis of schizophrenic psychosis or schizoaffective disorder. The present study assessed physical situation, psychopathology and functionality of the patients and explored the associations and correlations between clinical variables and plasma levels. We studied 39 patients, predominantly men, with negative and depressive symptoms and cardiovascular risk factors (metabolic syndrome and smoking). Significant variability in dose and even greater in clozapine levels were observed. The levels of clozapine at equal doses/kg of body weight were higher in non-smokers, they had positive correlation with BMI and negative correlation with systolic BP, disruptive behaviors and number of cigarettes consumed. Plasma level monitoring clozapine is an important tool to avoid clozapine plasma levels monitoring and minimize undesirable clinical situations (metabolic syndrome, sedation, negative symptoms and functional impairment). It is also important to control the effects of a smoking habit for optimum drug bioavailability. Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.

Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.

PubMed

Howley, Eimear; Bestwick, Michael; Fradley, Rosa; Harrison, Helen; Leveridge, Mathew; Okada, Kengo; Fieldhouse, Charlotte; Farnaby, Will; Canning, Hannah; Sykes, Andy P; Merchant, Kevin; Hazel, Katherine; Kerr, Catrina; Kinsella, Natasha; Walsh, Louise; Livermore, David G; Hoffman, Isaac; Ellery, Jonathan; Mitchell, Phillip; Patel, Toshal; Carlton, Mark; Barnes, Matt; Miller, David J

2017-11-01

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.

Low level laser therapy on injured rat muscle

NASA Astrophysics Data System (ADS)

Mantineo, M.; Pinheiro, J. P.; Morgado, A. M.

2013-06-01

Although studies show the clinical effectiveness of low level laser therapy (LLLT) in facilitating the muscle healing process, scientific evidence is still required to prove the effectiveness of LLLT and to clarify the cellular and molecular mechanisms triggered by irradiation. Here we evaluate the effect of different LLLT doses, using continuous illumination (830 nm), in the treatment of inflammation induced in the gastrocnemius muscle of Wistar rats, through the quantification of cytokines in systemic blood and histological analysis of muscle tissue. We verified that all applied doses produce an effect on reducing the number of inflammatory cells and the concentration of pro-inflammatory TNF-α and IL-1β cytokines. The best results were obtained for 40 mW. The results may suggest a biphasic dose response curve.

Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder.

PubMed

Qi, Wei; Gevonden, Martin; Shalev, Arieh

2017-02-01

Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 ± 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram.

Comprehensive clinical commissioning and validation of the RayStation treatment planning system for proton therapy with active scanning and passive treatment techniques.

PubMed

Bäumer, C; Geismar, D; Koska, B; Kramer, P H; Lambert, J; Lemke, M; Plaude, S; Pschichholz, L; Qamhiyeh, S; Schiemann, A; Timmermann, B; Vermeren, X

2017-11-01

To commission the treatment planning system (TPS) RayStation for proton therapy including beam models for spot scanning and for uniform scanning. Tests consist of procedures from ESTRO booklet number 7, the German DIN for constancy checks of TPSs, and extra tests checking the dose perturbation function. The dose distributions within patients were verified in silico by a comparison of 65 clinical treatment plans with the TPS XiO. Dose-volume parameters, dose differences, and three-dimensional gamma-indices serve as measures of similarity. The monthly constancy checks of Raystation have been automatized with a script. The basic functionality of the software complies with ESTRO booklet number 7. For a few features minor enhancements are suggested. The dose distribution in RayStation agrees with the calculation in XiO. This is supported by a gamma-index (3mm/3%) pass rate of >98.9% (median over 59 plans) for the volume within the 20% isodose line and a difference of <0.3% of V 95 of the PTV (median over 59 plans). If spot scanning is used together with a range shifter, the dose level calculated by RayStation can be off by a few percent. RayStation can be used for the creation of clinical proton treatment plans. Compared to XiO RayStation has an improved modelling of the lateral dose fall-off in passively delivered fields. For spot scanning fields with range shifter blocks an empirical adjustment of monitor units is required. The computation of perturbed doses also allows the evaluation of the robustness of a treatment plan. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Evaluation of computerized decision support for oral anticoagulation management based in primary care.

PubMed

Fitzmaurice, D A; Hobbs, F D; Murray, E T; Bradley, C P; Holder, R

1996-09-01

Increasing indications for oral anticoagulation has led to pressure on general practices to undertake therapeutic monitoring. Computerized decision support (DSS) has been shown to be effective in hospitals for improving clinical management. Its usefulness in primary care has previously not been investigated. To test the effectiveness of using DSS for oral anticoagulation monitoring in primary care by measuring the proportions of patients adequately controlled, defined as within the appropriate therapeutic range of International Normalised Ratio (INR). All patients receiving warfarin from two Birmingham inner city general practices were invited to attend a practice-based anticoagulation clinic. In practice A all patients were managed using DSS. In practice B patients were randomized to receive dosing advice either through DSS or through the local hospital laboratory. Clinical outcomes, adverse events and patient acceptability were recorded. Forty-nine patients were seen in total. There were significant improvements in INR control from 23% to 86% (P > 0.001) in the practice where all patients received dosing through DSS. In the practice where patients were randomized to either DSS or hospital dosing, logistic regression showed a significant trend for improvement in intervention patients which was not apparent in the hospital-dosed patients (P < 0.001). Mean recall times were significantly extended in patients who were dosed by the practice DSS through the full 12 months (24 days to 36 days) (P = 0.033). Adverse events were comparable between hospital and practice-dosed patients, although a number of esoteric events occurred. Patient satisfaction with the practice clinics was high. Computerized DSS enables the safe and effective transfer of anticoagulation management from hospital to primary care and may result in improved patient outcome in terms of the level of control, frequency of review and general acceptability.

Sci-Sat AM: Radiation Dosimetry and Practical Therapy Solutions - 03: Energy dependence of a clinical probe-format calorimeter and its pertinence to absolute photon and electron beam dosimetry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renaud, James; Seuntjens, Jan; Sarfehnia, Arman

Purpose: To evaluate the intrinsic and absorbed-dose energy dependence of a small-scale graphite calorimeter probe (GPC) developed for use as a routine clinical dosimeter. The influence of charge deposition on the response of the GPC was also assessed by performing absolute dosimetry in clinical linac-based electron beams. Methods: Intrinsic energy dependence was determined by performing constant-temperature calorimetry dose measurements in a water-equivalent solid phantom, under otherwise reference conditions, in five high-energy photon (63.5 < %dd(10){sub X} < 76.3), and five electron (2.3 cm < R{sub 50} < 8.3 cm) beams. Reference dosimetry was performed for all beams in question usingmore » an Exradin A19 ion chamber with a calibration traceable to national standards. The absorbed-dose component of the overall energy dependence was calculated using the EGSnrc egs-chamber user code. Results: A total of 72 measurements were performed with the GPC, resulting in a standard error on the mean absorbed dose of better than 0.3 % for all ten beams. For both the photon and electron beams, no statistically-significant energy dependence was observed experimentally. Peak-to-peak, variations in the relative response of the GPC across all beam qualities of a given radiation type were on the order of 1 %. No effects, either transient or permanent, were attributable to the charge deposited by the electron beams. Conclusions: The GPC’s apparent energy-independence, combined with its well-established linearity and dose rate independence, make it a potentially useful dosimetry system capable measuring photon and electron doses in absolute terms at the clinical level.« less

Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.

PubMed

Everett, Brendan M; Pradhan, Aruna D; Solomon, Daniel H; Paynter, Nina; Macfadyen, Jean; Zaharris, Elaine; Gupta, Milan; Clearfield, Michael; Libby, Peter; Hasan, Ahmed A K; Glynn, Robert J; Ridker, Paul M

2013-08-01

Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death. Copyright © 2013 Mosby, Inc. All rights reserved.

Plasma fluoxetine concentrations and clinical improvement in an adolescent sample diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder.

PubMed

Blázquez, Ana; Mas, Sergi; Plana, Maria Teresa; Gassó, Patricia; Méndez, Iria; Torra, Mercè; Arnaiz, Joan Albert; Lafuente, Amàlia; Lázaro, Luisa

2014-06-01

Fluoxetine (FLX) has been one of the most widely studied selective serotonin reuptake inhibitors in adolescents. Despite its efficacy, however, 30% to 40% of patients do not respond to treatment. The aim of this study was to evaluate whether clinical improvement or adverse events are related to the corrected dose of FLX at 8 and 12 weeks after starting treatment in a sample of adolescents diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder. Seventy-four subjects aged between 10 and 17 years participated in the study. Clinical improvement was measured with the Clinical Global Impression-Improvement Scale, whereas the UKU (Udvalg for Klinske Undersogelser) scale was administered to assess adverse effects of treatment. Fluoxetine per kilograms of body weight was related to serum concentration of FLX, NORFLX (norfluoxetine), FLX + NORFLX, and FLX/NORFLX. No relationship was found between dose-corrected FLX levels and therapeutic or adverse effects. No differences in serum concentrations were found between responders and nonresponders to treatment. Sex differences were observed in relation to dose and FLX serum concentration. The analysis by diagnosis revealed differences in FLX dose between obsessive-compulsive disorder patients and both generalized anxiety disorder and major depressive disorder patients. Fluoxetine response seems to be influenced by factors such as sex, diagnosis, or certain genes that might be involved in the drug's pharmacokinetics and pharmacodynamics. Clinical and pharmacogenetic studies are needed to elucidate further the differences between treatment responders and nonresponders.

Prospective estimation of organ dose in CT under tube current modulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian, Xiaoyu, E-mail: xt3@duke.edu; Li, Xiang; Segars, W. Paul

Purpose: Computed tomography (CT) has been widely used worldwide as a tool for medical diagnosis and imaging. However, despite its significant clinical benefits, CT radiation dose at the population level has become a subject of public attention and concern. In this light, optimizing radiation dose has become a core responsibility for the CT community. As a fundamental step to manage and optimize dose, it may be beneficial to have accurate and prospective knowledge about the radiation dose for an individual patient. In this study, the authors developed a framework to prospectively estimate organ dose for chest and abdominopelvic CT examsmore » under tube current modulation (TCM). Methods: The organ dose is mainly dependent on two key factors: patient anatomy and irradiation field. A prediction process was developed to accurately model both factors. To model the anatomical diversity and complexity in the patient population, the authors used a previously developed library of computational phantoms with broad distributions of sizes, ages, and genders. A selected clinical patient, represented by a computational phantom in the study, was optimally matched with another computational phantom in the library to obtain a representation of the patient’s anatomy. To model the irradiation field, a previously validated Monte Carlo program was used to model CT scanner systems. The tube current profiles were modeled using a ray-tracing program as previously reported that theoretically emulated the variability of modulation profiles from major CT machine manufacturers Li et al., [Phys. Med. Biol. 59, 4525–4548 (2014)]. The prediction of organ dose was achieved using the following process: (1) CTDI{sub vol}-normalized-organ dose coefficients (h{sub organ}) for fixed tube current were first estimated as the prediction basis for the computational phantoms; (2) each computation phantom, regarded as a clinical patient, was optimally matched with one computational phantom in the library; (3) to account for the effect of the TCM scheme, a weighted organ-specific CTDI{sub vol} [denoted as (CTDI{sub vol}){sub organ,weighted}] was computed for each organ based on the TCM profile and the anatomy of the “matched” phantom; (4) the organ dose was predicted by multiplying the weighted organ-specific CTDI{sub vol} with the organ dose coefficients (h{sub organ}). To quantify the prediction accuracy, each predicted organ dose was compared with the corresponding organ dose simulated from the Monte Carlo program with the TCM profile explicitly modeled. Results: The predicted organ dose showed good agreements with the simulated organ dose across all organs and modulation profiles. The average percentage error in organ dose estimation was generally within 20% across all organs and modulation profiles, except for organs located in the pelvic and shoulder regions. For an average CTDI{sub vol} of a CT exam of 10 mGy, the average error at full modulation strength (α = 1) across all organs was 0.91 mGy for chest exams, and 0.82 mGy for abdominopelvic exams. Conclusions: This study developed a quantitative model to predict organ dose for clinical chest and abdominopelvic scans. Such information may aid in the design of optimized CT protocols in relation to a targeted level of image quality.« less

Change in plasma lactate concentration during arctigenin administration in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer

PubMed Central

Fujioka, Rumi; Mochizuki, Nobuo; Ikeda, Masafumi; Sato, Akihiro; Nomura, Shogo; Owada, Satoshi; Yomoda, Satoshi; Tsuchihara, Katsuya; Kishino, Satoshi

2018-01-01

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle. PMID:29856804

Change in plasma lactate concentration during arctigenin administration in a phase I clinical trial in patients with gemcitabine-refractory pancreatic cancer.

PubMed

Fujioka, Rumi; Mochizuki, Nobuo; Ikeda, Masafumi; Sato, Akihiro; Nomura, Shogo; Owada, Satoshi; Yomoda, Satoshi; Tsuchihara, Katsuya; Kishino, Satoshi; Esumi, Hiroyasu

2018-01-01

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.

Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial.

PubMed

Mayer, Kenneth H; Seaton, Kelly E; Huang, Yunda; Grunenberg, Nicole; Isaacs, Abby; Allen, Mary; Ledgerwood, Julie E; Frank, Ian; Sobieszczyk, Magdalena E; Baden, Lindsey R; Rodriguez, Benigno; Van Tieu, Hong; Tomaras, Georgia D; Deal, Aaron; Goodman, Derrick; Bailer, Robert T; Ferrari, Guido; Jensen, Ryan; Hural, John; Graham, Barney S; Mascola, John R; Corey, Lawrence; Montefiori, David C

2017-11-01

VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 μg/ml (95% CI: 1,033, 1,340) and 420 μg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 μg/ml (95% CI: 10, 27) and 6 μg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits. VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials. Clinical Trials Registration: NCT02165267.

[Effect of low-dose or standard-dose conjugated equine estrogen combined with different progesterone on bone density in menopause syndrome women].

PubMed

Zuo, H L; Deng, Y; Wang, Y F; Gao, L L; Xue, W; Zhu, S Y; Ma, X; Sun, A J

2018-04-25

Objective: To explore the effect of low-dose or standard-dose conjugated equine estrogen (CEE) combined with natural progesterone or dydrogesterone on bone density in menopause syndrome women. Methods: Totally 123 patients with menopause syndrome were recruited and randomly assigned to 3 treatment groups: group A (low-dose CEE+progesterone) , group B (standard-dose CEE+progesterone) , group C (standard-dose CEE+dydrogesterone) . Using continuous sequential regimen, the duration of intervention was 12 cycles. The bone mineral density of lumbar 2-4 and neck of femur, the bone metabolic markers, the level of FSH and estradiol were examined just before the drug administration and 12 months after the beginning of experiment. Results: There were 107 cases completed the one year trial. (1) Bone density: after 12 cycles of treatment, there was no significant change in bone density in group A ( P> 0.05) ; lumbar vertebrae of group B and C increased significantly, at 3.0% and 2.1%respectively (all P< 0.05) . The bone density of left femoral neck of group C significantly increased by 2.9% ( P= 0.029) . There was no significant difference among the treatment groups at the beginning of experiment ( P> 0.05) . (2) Bone metabolic markers: after 12 cycles of treatment, the levels of calcium, phosphorus, alkaline phosphatase, Ca/Cr decreased significantly, the difference were statistically significant (all P< 0.05) . There was no significant difference among the treatment groups at the beginning of experiment ( P> 0.05) . (3) Levels of FSH and estradiol: after 12 cycles of treatment, the levels of FSH in three groups were decreased significantly (all P< 0.01) . The levels of estradiol in three groups were increased significantly (all P< 0.01) . There was no significant difference among the treatment groups at the beginning of experiment ( P> 0.05) . Conclusions: Both low-dose and standard-dose menopause hormone therapy (MHT) could elevate the level of estradiol, reduce bone turnover, prevent bone loss of postmenopausal women effectively. The standard dose of MHT could also increase the density of vertebrae and femoral neck, and generate more clinical benefits.

Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice

PubMed Central

De Cock, R. F. W.; Allegaert, K.; Vanhaesebrouck, S.; Danhof, M.; Knibbe, C. A. J.

2015-01-01

Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization. PMID:26248375

[Interferons--its method of administration and adverse effect related to pharmacokinetics ].

PubMed

Furue, H

1984-02-01

The potential role of interferons in the treatment of malignant diseases is currently being evaluated. This paper reviews experimental and clinical findings regarding pharmacokinetics, method of administration, and side reactions of interferons. Interferon in the blood is rapidly cleared from the circulation. Intramuscular injection of alpha-interferon causes low but stable interferon levels in the blood. However, in the case of beta-interferon, interferon is never detected consistently in the blood after intramuscular or subcutaneous administration. The studies with animal models suggest that doses higher than those given in current clinical trials will be necessary to obtain clearly beneficial effects in human. The maximum safely tolerated daily dose is appreciably higher than that used in most previous studies, although even at this level, considerable toxicity may be encountered. Adequate method of administration, route, dose and interval are not yet established at all. Exact mechanism of anticancer activity is not yet well defined. The most frequent side reaction is fever. However, the exact mechanism to cause these side reactions is also not yet clarified. Dose limiting central nervous system toxicities, hypotension, hypocalcaemia etc. are occasionally encountered in some instances. Antibody to interferon is demonstrated in some cases. Purification of interferon does not always causes reduction of side reactions. The treatment of cancer cases with interferon has just started and there are many problems to be solved. However, therapeutic beneficial may be achieved in the treatment of malignant tumors by appropriate combinations of interferon with conventional treatment. More laboratory studies as well as carefully controlled clinical observations are warranted.

The observed correlation between in vivo clinical pharmacokinetic parameters and in vitro potency of VEGFR-2 inhibitors. Can this be used as a prospective guide for the development of novel compounds?

PubMed

Benjamin, B; Sahu, M; Bhatnagar, U; Abhyankar, D; Srinivas, N R

2012-04-01

Literature data on the clinical pharmacokinetics of various VEGFR-2 inhibitors along with in vitro potency data were correlated and a linear relationship was established in spite of limited data set. In this work, a model set comprised of axitinib, recentin, sunitinib, pazopanib, and sorafenib were used. The in vitro potencies of the model set compounds were correlated with the published unbound plasma concentrations (Cmax, Cavg, Ctrough). The established linear regression (r2>0.90) equation was used to predict Cmax, Cavg, Ctrough of the 'prediction set' (motesanib, telatinib, CP547632, vatalanib, vandetanib) using in vitro potency and unbound protein free fraction. Cavg and Ctrough of prediction set were closely matched (0.2-1.8 fold of reported), demonstrating the usefulness of such predictions for tracking the target related modulation and/or efficacy signals within the clinically optimized population average. In case of Cmax where correlation was least anticipated, the predicted values were within 0.1-1.1 fold of those reported. Such predictions of appropriate parameters would provide rough estimates of whether or not therapeutically relevant dose(s) have been administered when clinical investigations of novel agents of this class are being performed. Therefore, it may aid in increasing clinical doses to a desired level if safety of the compound does not compromise such dose increases. In conclusion, the proposed model may prospectively guide the dosing strategies and would greatly aid the development of novel compounds in this class. © Georg Thieme Verlag KG Stuttgart · New York.

Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis.

PubMed

Xu, Hongmei; Zhou, Wangda; Zhou, Diansong; Li, Jianguo; Al-Huniti, Nidal

2017-03-01

Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment. © 2016, The American College of Clinical Pharmacology.

Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentration in Routine Clinical Care

PubMed Central

DeGorter, Marianne K.; Tirona, Rommel G.; Schwarz, Ute I.; Choi, Yun-Hee; Dresser, George K.; Suskin, Neville; Myers, Kathryn; Zou, GuangYong; Iwuchukwu, Otito; Wei, Wei-Qi; Wilke, Russell A.; Hegele, Robert A.; Kim, Richard B.

2014-01-01

Background A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. Methods and Results In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for gender, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (p < 0.001) and ABCG2 c.421C>A (p < 0.01) were important to rosuvastatin concentration (adjusted R2 = 0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (p < 0.01) and c.521T>C (p < 0.05), and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2 = 0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Conclusions Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine if this approach reduces incidence of statin-myopathy. PMID:23876492

RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chinnaiyan, Prakash, E-mail: prakash.chinnaiyan@moffitt.org; Won, Minhee; Wen, Patrick Y.

Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established dailymore » dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.« less

Method for simulating dose reduction in digital mammography using the Anscombe transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borges, Lucas R., E-mail: lucas.rodrigues.borges@usp.br; Oliveira, Helder C. R. de; Nunes, Polyana F.

2016-06-15

Purpose: This work proposes an accurate method for simulating dose reduction in digital mammography starting from a clinical image acquired with a standard dose. Methods: The method developed in this work consists of scaling a mammogram acquired at the standard radiation dose and adding signal-dependent noise. The algorithm accounts for specific issues relevant in digital mammography images, such as anisotropic noise, spatial variations in pixel gain, and the effect of dose reduction on the detective quantum efficiency. The scaling process takes into account the linearity of the system and the offset of the detector elements. The inserted noise is obtainedmore » by acquiring images of a flat-field phantom at the standard radiation dose and at the simulated dose. Using the Anscombe transformation, a relationship is created between the calculated noise mask and the scaled image, resulting in a clinical mammogram with the same noise and gray level characteristics as an image acquired at the lower-radiation dose. Results: The performance of the proposed algorithm was validated using real images acquired with an anthropomorphic breast phantom at four different doses, with five exposures for each dose and 256 nonoverlapping ROIs extracted from each image and with uniform images. The authors simulated lower-dose images and compared these with the real images. The authors evaluated the similarity between the normalized noise power spectrum (NNPS) and power spectrum (PS) of simulated images and real images acquired with the same dose. The maximum relative error was less than 2.5% for every ROI. The added noise was also evaluated by measuring the local variance in the real and simulated images. The relative average error for the local variance was smaller than 1%. Conclusions: A new method is proposed for simulating dose reduction in clinical mammograms. In this method, the dependency between image noise and image signal is addressed using a novel application of the Anscombe transformation. NNPS, PS, and local noise metrics confirm that this method is capable of precisely simulating various dose reductions.« less

Method for simulating dose reduction in digital mammography using the Anscombe transformation

PubMed Central

Borges, Lucas R.; de Oliveira, Helder C. R.; Nunes, Polyana F.; Bakic, Predrag R.; Maidment, Andrew D. A.; Vieira, Marcelo A. C.

2016-01-01

Purpose: This work proposes an accurate method for simulating dose reduction in digital mammography starting from a clinical image acquired with a standard dose. Methods: The method developed in this work consists of scaling a mammogram acquired at the standard radiation dose and adding signal-dependent noise. The algorithm accounts for specific issues relevant in digital mammography images, such as anisotropic noise, spatial variations in pixel gain, and the effect of dose reduction on the detective quantum efficiency. The scaling process takes into account the linearity of the system and the offset of the detector elements. The inserted noise is obtained by acquiring images of a flat-field phantom at the standard radiation dose and at the simulated dose. Using the Anscombe transformation, a relationship is created between the calculated noise mask and the scaled image, resulting in a clinical mammogram with the same noise and gray level characteristics as an image acquired at the lower-radiation dose. Results: The performance of the proposed algorithm was validated using real images acquired with an anthropomorphic breast phantom at four different doses, with five exposures for each dose and 256 nonoverlapping ROIs extracted from each image and with uniform images. The authors simulated lower-dose images and compared these with the real images. The authors evaluated the similarity between the normalized noise power spectrum (NNPS) and power spectrum (PS) of simulated images and real images acquired with the same dose. The maximum relative error was less than 2.5% for every ROI. The added noise was also evaluated by measuring the local variance in the real and simulated images. The relative average error for the local variance was smaller than 1%. Conclusions: A new method is proposed for simulating dose reduction in clinical mammograms. In this method, the dependency between image noise and image signal is addressed using a novel application of the Anscombe transformation. NNPS, PS, and local noise metrics confirm that this method is capable of precisely simulating various dose reductions. PMID:27277017

Evaluation of lens dose from anterior electron beams: comparison of Pinnacle and Gafchromic EBT3 film

PubMed Central

Wronski, Matt; Yeboah, Collins

2015-01-01

Lens dose is a concern during the treatment of facial lesions with anterior electron beams. Lead shielding is routinely employed to reduce lens dose and minimize late complications. The purpose of this work is twofold: 1) to measure dose profiles under large‐area lead shielding at the lens depth for clinical electron energies via film dosimetry; and 2) to assess the accuracy of the Pinnacle treatment planning system in calculating doses under lead shields. First, to simulate the clinical geometry, EBT3 film and 4 cm wide lead shields were incorporated into a Solid Water phantom. With the lead shield inside the phantom, the film was positioned at a depth of 0.7 cm below the lead, while a variable thickness of solid water, simulating bolus, was placed on top. This geometry was reproduced in Pinnacle to calculate dose profiles using the pencil beam electron algorithm. The measured and calculated dose profiles were normalized to the central‐axis dose maximum in a homogeneous phantom with no lead shielding. The resulting measured profiles, functions of bolus thickness and incident electron energy, can be used to estimate the lens dose under various clinical scenarios. These profiles showed a minimum lead margin of 0.5 cm beyond the lens boundary is required to shield the lens to ≤10% of the dose maximum. Comparisons with Pinnacle showed a consistent overestimation of dose under the lead shield with discrepancies of ∼25% occurring near the shield edge. This discrepancy was found to increase with electron energy and bolus thickness and decrease with distance from the lead edge. Thus, the Pinnacle electron algorithm is not recommended for estimating lens dose in this situation. The film measurements, however, allow for a reasonable estimate of lens dose from electron beams and for clinicians to assess the lead margin required to reduce the lens dose to an acceptable level. PACS number(s): 87.53.Bn, 87.53.Kn, 87.55.‐x, 87.55.D‐ PMID:27074448

Influence of Age and Dose of African Swine Fever Virus Infections on Clinical Outcome and Blood Parameters in Pigs.

PubMed

Post, Jacob; Weesendorp, Eefke; Montoya, Maria; Loeffen, Willie L

African swine fever (ASF) is a fatal disease for domestic pigs, leading to serious economic losses in countries where ASF is endemic. Despite extensive research, efficient vaccines against ASF are lacking. Since peripheral blood cells are important mediators for vaccines, we study the impact of ASF on blood parameters in pigs with different ages and infected with different doses of ASF virus. Four different groups were studied: (1) 12 weeks of age/low virus dose; (2) 12 weeks of age/high virus dose; (3) 18 weeks of age/low virus dose; and (4) 18 weeks of age/high virus dose. By varying in age and/or ASFV inoculation dose, we monitor blood parameters during different degrees of disease. Thirty percent of the pigs survived the infection with a moderately virulent strain of African swine fever virus (ASFV). Animals that did survive infection were generally older, independent from the inoculation dose used. A firm reduction in many different cell types at 3-5 days postinfection (DPI) was accompanied by an increase in body temperature, followed by clinical signs and mortality from day 6 PI. While blood parameters generally normalized in survivors, γδ T cells and IL-10 levels could be related to mortality. These conclusions should be considered in new approaches for protection against ASF.

Development, validation, and implementation of a patient-specific Monte Carlo 3D internal dosimetry platform

NASA Astrophysics Data System (ADS)

Besemer, Abigail E.

Targeted radionuclide therapy is emerging as an attractive treatment option for a broad spectrum of tumor types because it has the potential to simultaneously eradicate both the primary tumor site as well as the metastatic disease throughout the body. Patient-specific absorbed dose calculations for radionuclide therapies are important for reducing the risk of normal tissue complications and optimizing tumor response. However, the only FDA approved software for internal dosimetry calculates doses based on the MIRD methodology which estimates mean organ doses using activity-to-dose scaling factors tabulated from standard phantom geometries. Despite the improved dosimetric accuracy afforded by direct Monte Carlo dosimetry methods these methods are not widely used in routine clinical practice because of the complexity of implementation, lack of relevant standard protocols, and longer dose calculation times. The main goal of this work was to develop a Monte Carlo internal dosimetry platform in order to (1) calculate patient-specific voxelized dose distributions in a clinically feasible time frame, (2) examine and quantify the dosimetric impact of various parameters and methodologies used in 3D internal dosimetry methods, and (3) develop a multi-criteria treatment planning optimization framework for multi-radiopharmaceutical combination therapies. This platform utilizes serial PET/CT or SPECT/CT images to calculate voxelized 3D internal dose distributions with the Monte Carlo code Geant4. Dosimetry can be computed for any diagnostic or therapeutic radiopharmaceutical and for both pre-clinical and clinical applications. In this work, the platform's dosimetry calculations were successfully validated against previously published reference doses values calculated in standard phantoms for a variety of radionuclides, over a wide range of photon and electron energies, and for many different organs and tumor sizes. Retrospective dosimetry was also calculated for various pre-clinical and clinical patients and large dosimetric differences resulted when using conventional organ-level methods and the patient-specific voxelized methods described in this work. The dosimetric impact of various steps in the 3D voxelized dosimetry process were evaluated including quantitative imaging acquisition, image coregistration, voxel resampling, ROI contouring, CT-based material segmentation, and pharmacokinetic fitting. Finally, a multi-objective treatment planning optimization framework was developed for multi-radiopharmaceutical combination therapies.

Vitamin D and muscle function.

PubMed

Dawson-Hughes, Bess

2017-10-01

Muscle weakness is a hallmark of severe vitamin D deficiency, but the effect of milder vitamin D deficiency or insufficiency on muscle mass and performance and risk of falling is uncertain. In this presentation, I review the evidence that vitamin D influences muscle mass and performance, balance, and risk of falling in older adults. Special consideration is given to the impact of both the starting 25-hydroxyvitamin D [25(OH)D] level and the dose administered on the clinical response to supplemental vitamin D in older men and women. Based on available evidence, older adults with serum 25(OH)D levels <40nmol/L appear most likely to improve their muscle performance with supplementation. The vitamin D dose range of 800-1000 IU per day has been effective in many studies; lower doses have generally been ineffective and several doses above this range have increased the risk of falls. In conclusion, older adults with serum 25(OH)D levels <40nmol/L are likely to have fewer falls if supplemented with 800-1000 IU per day of vitamin D. Copyright © 2017 Elsevier Ltd. All rights reserved.

A review of the use of clozapine levels to guide treatment and determine cause of death.

PubMed

Stark, Anne; Scott, James

2012-09-01

To review the literature to examine the use of clozapine levels to (i) guide therapy and prevent toxicity in clinical care and (ii) determine cause of death in post-mortem examination of patients who were treated with clozapine. MEDLINE was searched in December 2010 using the following keywords: 'clozapine levels', 'clozapine and toxicity', 'clozapine and death', 'clozapine and mortality' and 'post-mortem redistribution'. Data was also collected from the 2010 MIMS Annual. The literature reported significant variation in clozapine levels attained with any given dose, and considerable variability in the clinical response achieved at any given clozapine level. The lowest effective clozapine levels ranged from 250 to 550 µg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 µg/L. There was minimal correlation between clozapine levels and side effects, with the exception of sedation, hypotension and seizure activity. The risk of seizures increased with plasma clozapine levels greater than 600 µg/L or rapid upward titration. In addition to prescribed dose, there are many factors that influence plasma clozapine levels. After death, the process of post-mortem drug redistribution resulted in 3.00 to 4.89 times increases in clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels. The exact range of clozapine levels that corresponds to toxicity remains unclear. However, levels between 350 µg/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity. Ongoing clozapine level monitoring is indicated, especially when (i) prescribing higher doses (> 600 mg/day) of clozapine, (ii) there has been a change in a patient's concomitant pharmacotherapy or cigarette use and (iii) there has been a suboptimal response to treatment. The use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable.

A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients.

PubMed Central

Milligan, N M; Dhillon, S; Griffiths, A; Oxley, J; Richens, A

1984-01-01

The clinical anticonvulsant efficacy of single dose rectal and oral administration of diazepam 20 mg was examined in two double-blind placebo-controlled trials in adult epileptic patients. All subjects suffered from drug resistant epilepsy and frequently experienced serial seizures. Diazepam was administered rectally as a new experimental suppository formulation immediately after a seizure and was highly effective in preventing recurrent fits within a 24 h observation period (p less than 0.001). Pharmacokinetic studies revealed a wide range of serum diazepam concentrations 60 min after administration of the suppository (mean serum diazepam level 190 +/- 73 (SD ng/ml). In a similar study oral administration of diazepam 20 mg significantly reduced the incidence of serial seizures compared with a placebo (p less than 0.01) and the mean 60 min serum diazepam level was 273 +/- 190 (SD) ng/ml. PMID:6368753

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.

PubMed

Ray, Kausik K; Landmesser, Ulf; Leiter, Lawrence A; Kallend, David; Dufour, Robert; Karakas, Mahir; Hall, Tim; Troquay, Roland P T; Turner, Traci; Visseren, Frank L J; Wijngaard, Peter; Wright, R Scott; Kastelein, John J P

2017-04-13

In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).

A randomized controlled clinical trial investigating the effect of calcium supplement plus low-dose aspirin on hs-CRP, oxidative stress and insulin resistance in pregnant women at risk for pre-eclampsia.

PubMed

Asemi, Z; Samimi, M; Heidarzadeh, Z; Khorrammian, H; Tabassi, Z

2012-05-15

Increased levels of pro-inflammatory factors, markers of oxidative stress and insulin resistance during pregnancy have been associated with the development of pre-eclampsia. There is some evidence to suggest that calcium supplement and aspirin can reduce the risk of the disorder. To our knowledge, no reports are available indicating the effects of consumed calcium supplement plus aspirin on high sensitivity C-reactive protein (hs-CRP), oxidative stress parameters and insulin resistance in pregnant women at risk for pre-eclampsia. This study was designed to investigate the effects of consumed calcium supplement plus low-dose aspirin on hs-CRP, oxidative stress parameters and insulin resistance among Iranian pregnant women at risk for pre-eclampsia. This randomized single-blind controlled clinical trial was carried out among 42 pregnant women at risk for pre-eclampsia, primigravida, aged 18-40 year old who were carrying singleton pregnancy at their third trimester. Subjects were randomly assigned to received either the placebo (n = 22) or calcium supplement plus low-dose aspirin (n = 20) for 9 weeks. Calcium supplement plus low-dose aspirin were containing 500 mg carbonate calcium plus 80 mg aspirin. Fasting blood samples were taken at baseline and after 9 weeks intervention to measure serum hs-CRP, oxidative stress parameters including plasma Total Antioxidant Capacity (TAC) and Total Glutathione (GSH), Fasting Plasma Glucose (FPG), serum insulin and HOMA-IR score. Consumption of calcium supplement plus low-dose aspirin resulted in a significant difference serum hs-CRP levels as compared to the placebo (102.87 vs. 3227.75 ng mL(-1), p = 0.01). Also, mean changes for plasma TAC (68.96 vs. -74.46 mmol L(-1), p = 0.04) and total GSH levels (304.33 vs. -39.33 micromol L(-1), p = 0.03) were significantly different between the two groups. No significant differences were found comparing calcium supplement plus low-dose aspirin and placebo in terms of their effects on FPG, serum insulin levels and HOMA-IR. Within-group differences in the placebo group revealed a significant increase in serum hs-CRP levels (3227.75 ng mL(-1), p = 0.008) and marginally significant increase in plasma total GSH levels (304.33 micromol L(-1), p = 0.07). In conclusion, consumption calcium supplement plus low-dose aspirin during pregnancy for 9 weeks in pregnant women at risk for pre-eclampsia resulted in a significant difference serum hs-CRP and increased levels of plasma TAC and total GSH as compared to the placebo group, but could not affect serum insulin levels and HOMA-IR score.

Beneficial Effects of Pentoxifylline Plus Losartan Dual Therapy in Type 2 Diabetes with Nephropathy.

PubMed

Rabizadeh, Soghra; Dehghani Firouzabadi, Fatemeh; Noshad, Sina; Esteghamati, Sadaf; Afarideh, Mohsen; Ghajar, Alireza; Ganji, Morsaleh; Saadat, Mohammad; Heidari, Behnam; Najafi, Mohammad Taghi; Nakhjavani, Manouchehr; Esteghamati, Alireza

2018-05-01

This study was designed to comparatively assess the effects of add-on pentoxifylline to losartan versus increasing the dose of losartan on serum N-terminal pro-brain natriuretic peptide (NT-proBNP), serum highly sensitive C-reactive protein (hsCRP) and the urinary albumin excretion (UAE) rate in patients with type 2 diabetes and nephropathy. In an open-label, single-center, parallel-group, randomized clinical trial (NCT03006952), 30 patients received b.i.d. dose of pentoxifylline 400mg plus daily dose of losartan 50mg (pentoxifylline arm) and 29 patients received b.i.d. dose of losartan 50mg (losartan arm) during a 12-week follow-up period. Serum NT-proBNP, serum hsCRP and UAE levels all significantly decreased from baseline in both trial arms. The pentoxifylline and losartan trial arms were equally effective in reducing serum NT-proBNP levels during the course of trial (multivariable adjusted model P value = 0.864, effect size = 0.2%). There was a greater decrease in UAE and serum hsCRP levels in the pentoxifylline arm (P = 0.034, effect size = 7.8%; P = 0.009, effect size = 11.7%, respectively). Conversely, patients in the losartan arm achieved better systolic and diastolic blood pressure control (P < 0.001, effect size = 25.4%; P = 0.010, effect size = 11.3%, respectively). Circulating NT-proBNP levels equally and significantly reduced from baseline in the pentoxifylline and losartan treatment arms, in parallel with comparatively superior decreases of UAE and serum hsCRP in the pentoxifylline arm, and larger decreases of systolic and diastolic blood pressures in the losartan arm. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

PubMed Central

Rini, Brian I.; Garcia, Jorge A.; Cooney, Matthew M.; Elson, Paul; Tyler, Allison; Beatty, Kristi; Bokar, Joseph; Mekhail, Tarek; Bukowski, R.M.; Budd, G. Thomas; Triozzi, Pierre; Borden, Ernest; Ivy, Percy; Chen, Helen X.; Dolwati, Afshin; Dreicer, Robert

2009-01-01

Purpose Bevacizumab is an antibody against vascular endothelial growth factor (VEGF); sunitinib is an inhibitor of VEGF and related receptors. The safety and maximum tolerated dose (MTD) of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level 5 mg/kg) on days 1, 15 and 29 of a 42-day cycle. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. Results Thirty-eight patients were enrolled. Pts received a median of 3 cycles of treatment (range, 1–17+). There was one DLT (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed RECIST-defined PR (18%; 95% confidence interval: 8–34%). Nineteen of the 32 patients with a post-baseline scan (59%) had at least some reduction in overall tumor burden (median 32%, range 3–73%). Conclusions The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Anti-tumor activity was observed across multiple solid tumors. PMID:19773375

A new treatment regimen with high-dose and fractioned immunoglobulin in a special subgroup of severe and dependent CIDP patients.

PubMed

Debs, Rabab; Reach, Pauline; Cret, Corina; Demeret, Sophie; Saheb, Samir; Maisonobe, Thierry; Viala, Karine

2017-10-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is treated with intravenous immunoglobulins (IVIg), corticosteroids or plasma exchange (PE). IVIg dosage is not universal and markers for treatment management are needed. We report the response to high-dose and fractioned IVIg in a subgroup of definite CIDP patients, resistant to corticosteroids and PE, responders to IVIg but with an efficacy window <15 d. Four patients were included with similar predominantly clinical motor form and conduction abnormalities. Treatment management consisted of fractioning IVIg and increasing the monthly cumulated dose (mean: 3 g/kg/month). Serum IgG concentration was measured and correlated to the clinical state. Monitoring of serum IgG helped to guide IVIg administration dosage and frequency. A mean of 10 months was required to improve symptoms; therapy was then switched to subcutaneous (SC) route (maintenance dose: 3.5 g/kg/month). The mean Overall Neuropathy Limitations Scale was improved from 11 to 3.2 and the mean Medical Research Council scale from 26 to 90. It is important to distinguish patients with short IVIg efficacy window from those with classical resistance since the former may benefit from fractioning and increasing the IVIg dose. The monitoring of serum IgG level and its correlation to the clinical response could be of help in monitoring each individual's dosage.

Efficient production of therapeutic doses of [131I]-metaiodobenzylguanidine for clinical use.

PubMed

Prabhakar, G; Mathur, Anupam; Shunmugam, G; Teje, Y D; Sachdev, S S; Sivaprasad, N

2011-01-01

[(131)I]-metaiodobenzylguanidine (mIBG) is a known radiopharmaceutical used for the treatment of neuroendocrine tumors. The development of therapeutic [(131)I]-mIBG doses at production level is highly challenging due to rapid product degradation and high radiation exposures to the production plant personnel. In the present work, a working module for the production of 10 doses (100 mCi each) in a single operation was developed following copper (I) assisted isotope exchange. The labeled product complies with the pharmaceutical specifications suitable for in-vivo patient use. Copyright © 2010 Elsevier Ltd. All rights reserved.

Effects of fenfluramine on plasma homovanillic acid in healthy subjects.

PubMed

Hollander, E; Stein, D J; Saoud, J B; DeCaria, C M; Cooper, T B; Islam, M N; Liebowitz, M R; Stanley, M

1992-01-01

The specificity of fenfluramine as a pharmacological probe of the serotonin system has been questioned, since animal studies with high dose l-fenfluramine show increases in striatal levels of the dopamine metabolite homovanillic acid. To test the specificity of fenfluramine in humans with clinical doses, we compared plasma homovanillic acid (pHVA) concentration in healthy volunteers after administration of fenfluramine (60 mg) and placebo. There were no significant effects on pHVA, which supports previous findings that at doses used in pharmacological challenge paradigms, the effect of fenfluramine on the dopamine system is insufficient to alter measures of its change.

Elevated Prostaglandin E Metabolites and Abnormal Plasma Fatty Acids at Baseline in Pediatric Cystic Fibrosis Patients: A Pilot Study

PubMed Central

O’Connor, Michael Glenn; Thomsen, Kelly; Brown, Rebekah F.; Laposata, Michael; Seegmiller, Adam

2016-01-01

Background Airway inflammation is a significant contributor to the morbidity of cystic fibrosis (CF) disease. One feature of this inflammation is the production of oxygenated metabolites, such as prostaglandins. Individuals with CF are known to have abnormal metabolism of fatty acids, typically resulting in reduced levels of linoleic acid (LA) and docosahexaenoic acid (DHA). Methods This is a randomized, double-blind, cross-over clinical trial of DHA supplementation with endpoints of plasma fatty acid levels and prostaglandin E metabolite (PGE-M) levels. Patients with CF age 6 to 18 years with pancreatic insufficiency were recruited. Each participant completed 3 four-week study periods: DHA at two different doses (high dose and low dose) and placebo with a minimum 4 week wash-out between each period. Blood, urine, and exhaled breath condensate (EBC) were collected at baseline and after each study period for measurement of plasma fatty acids as well as prostaglandin E metabolites. Results Seventeen participants were enrolled, and 12 participants completed all 3 study periods. Overall, DHA supplementation was well tolerated without significant adverse events. There was a significant increase in plasma DHA levels with supplementation, but no significant change in arachidonic acid (AA) or LA levels. However, at baseline, AA levels were lower and LA levels were higher than previously reported for individuals with CF. Urine PGE-M levels were elevated in the majority of participants at baseline, and while levels decreased with DHA supplementation, they also decreased with placebo. Conclusions Urine PGE-M levels are elevated at baseline in this cohort of pediatric CF patients, but there was no significant change in these levels with DHA supplementation compared to placebo. In addition, baseline plasma fatty acid levels for this cohort showed some difference to prior reports, including higher levels of LA and lower levels of AA, which may reflect changes in clinical care, and consequently warrants further investigation. PMID:27720040

Elevated prostaglandin E metabolites and abnormal plasma fatty acids at baseline in pediatric cystic fibrosis patients: a pilot study.

PubMed

O'Connor, Michael Glenn; Thomsen, Kelly; Brown, Rebekah F; Laposata, Michael; Seegmiller, Adam

2016-10-01

Airway inflammation is a significant contributor to the morbidity of cystic fibrosis (CF) disease. One feature of this inflammation is the production of oxygenated metabolites, such as prostaglandins. Individuals with CF are known to have abnormal metabolism of fatty acids, typically resulting in reduced levels of linoleic acid (LA) and docosahexaenoic acid (DHA). This is a randomized, double-blind, cross-over clinical trial of DHA supplementation with endpoints of plasma fatty acid levels and prostaglandin E metabolite (PGE-M) levels. Patients with CF age 6-18 years with pancreatic insufficiency were recruited. Each participant completed 3 four-week study periods: DHA at two different doses (high dose and low dose) and placebo with a minimum 4 week wash-out between each period. Blood, urine, and exhaled breath condensate (EBC) were collected at baseline and after each study period for measurement of plasma fatty acids as well as prostaglandin E metabolites. Seventeen participants were enrolled, and 12 participants completed all 3 study periods. Overall, DHA supplementation was well tolerated without significant adverse events. There was a significant increase in plasma DHA levels with supplementation, but no significant change in arachidonic acid (AA) or LA levels. However, at baseline, AA levels were lower and LA levels were higher than previously reported for individuals with CF. Urine PGE-M levels were elevated in the majority of participants at baseline, and while levels decreased with DHA supplementation, they also decreased with placebo. Urine PGE-M levels are elevated at baseline in this cohort of pediatric CF patients, but there was no significant change in these levels with DHA supplementation compared to placebo. In addition, baseline plasma fatty acid levels for this cohort showed some difference to prior reports, including higher levels of LA and lower levels of AA, which may reflect changes in clinical care, and consequently warrants further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity.

PubMed

Marzo, Antonio; Dal Bo, Lorenzo; Monti, Nunzia Ceppi; Crivelli, Fabrizio; Ismaili, Shevqet; Caccia, Carla; Cattaneo, Carlo; Fariello, Ruggero G

2004-07-01

This paper describes the pharmacokinetics and the pharmacodynamics, in terms of monoamino oxidase type B (MAO-B) inhibition, in male healthy volunteers of orally administered safinamide, a new neuroprotectant that in experimental models has demonstrated strong anticonvulsant and antiparkinson activities. Four clinical trials covering the dose range of 25-10,000 microg/kg were carried out to describe pharmacokinetics, pharmacodynamics and tolerability of safinamide, administered in single or repeated dose regimen to steady state, including a food interaction trial. All the above trials were carried out after the Ethics Committee's approval and signature of the consent form by the volunteers. In single dose trials blood sampling covered a 24 h-period in pharmacodynamic trials, 48 h-period in pharmacokinetic trials. In the case of repeated dose regimen to steady state a pre-dose sample was drawn on the first six study days, whereas the curve was explored on the 7th study day, prolonging blood sampling over a 48 h-period after the last dosing. Safinamide level was determined in plasma by a very sensitive and specific LC-MS-MS method, with a low limit of quantification of 0.5 ng/ml of plasma. Pharmacokinetic analysis was carried out with non-compartmental method and, in one case, also with the two-compartmental method. Monoamine oxidase activity of both types A and B (MAO-A and MAO-B) was determined in plasma at different times (MAO-B) and correlated to safinamide levels, or in urine (MAO-A). Pharmacokinetics of safinamide proved to be linearly and proportionally related to the administered doses. The absorption of safinamide was rapid with peak plasma concentrations ranging from 2 to 4 h. Food prolonged the rate and did not affect the extent of absorption of safinamide. In repeat dose regimen once daily, the steady state was reached on the 5th study day with a marginal accumulation factor of 1.5-1.7. The drug was cleared with a t(1/2) of about 22 h. Safinamide reversibly inhibited MAO-B enzyme. Full inhibition was observed with single doses >/= 600 microg/kg, and a relevant, dose dependent, progressive inhibition was encountered with doses starting from 25 microg/kg. Even at the highest single dose of 10 mg/kg no evidence of MAO-A inhibition was observed. Enteral absorption of the drug is linear and proportional to the doses administered. The drug is cleared from the body with a t(1/2) of approximately equal to 22 h, without producing any clinically relevant accumulation at steady state. The MAO-B inhibitory activity, without affecting MAO-A, is useful to prevent a dopamine bioinactivation in patients suffering from Parkinson's disease. Safinamide tolerability in the four clinical trials proved to be good.

Investigation of dose characteristics in three-dimensional MAGAT-type polymer gel dosimetry with MSE MR imaging

NASA Astrophysics Data System (ADS)

Lee, Jason J. S.; Tsai, Chia-Jung; Lo, Man-Kuok; Huang, Yung-Hui; Chen, Chien-Chuan; Wu, Jay; Tyan, Yeu-Sheng; Wu, Tung-Hsin

2008-05-01

A new type of normoxic polymer gel dosimeter, named MAGAT responses well to absorbed dose even when manufacturing in the presence of normal levels of oxygen. The aim of this study was to evaluate dose response, diffusion effect and cumulated dose response under multiple fractional irradiations of the MAGAT gel dosimeter using Multiple Spin-Echo (MSE) Magnetic Resonance (MR) sequence. Dose response was performed by irradiating MAGAT-gel-filled testing vials with a 6 MV linear accelerator and a linear relationship was present with doses from 0 to 6 Gy, but gradually, a bi-exponential function result was obtained with given doses up to 20 Gy. No significant difference in dose response was present between single and cumulated doses (p > 0.05). For study of diffusion effect, edge sharpness of the R2 map imaging between two split doses was smaller than 1 cm of dose profile penumbra between 20% and 80%. In conclusion, the MAGAT polymer gel dosimeter with MSE MR imaging is a promising method for dose verification in clinical radiation therapy practice.

Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ryan, Patricia C., E-mail: ryanp@medimmune.com; Sleeman, Matthew A.; Rebelatto, Marlon

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters othermore » than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus monkeys. • Lung changes observed reflect role of GM-CSF in alveolar macrophage function. • High safety margins support continued clinical development of mavrilimumab.« less

An information and communication technology-based centralized clinical trial to determine the efficacy and safety of insulin dose adjustment education based on a smartphone personal health record application: a randomized controlled trial.

PubMed

Kim, Gyuri; Bae, Ji Cheol; Yi, Byoung Kee; Hur, Kyu Yeon; Chang, Dong Kyung; Lee, Moon-Kyu; Kim, Jae Hyeon; Jin, Sang-Man

2017-07-18

A Personal Health Record (PHR) is an online application that allows patients to access, manage, and share their health data. PHRs not only enhance shared decision making with healthcare providers, but also enable remote monitoring and at-home-collection of detailed data. The benefits of PHRs can be maximized in insulin dose adjustment for patients starting or intensifying insulin regimens, as frequent self-monitoring of glucose, self-adjustment of insulin dose, and precise at-home data collection during the visit-to-visit period are important for glycemic control. The aim of this study is to examine the efficacy and safety of insulin dose adjustment based on a smartphone PHR application in patients with diabetes mellitus (DM) and to confirm the validity and stability of an information and communication technology (ICT)-based centralized clinical trial monitoring system. This is a 24-week, open-label, randomized, multi-center trial. There are three follow-up measures: baseline, post-intervention at week 12, and at week 24. Subjects diagnosed with type 1 DM, type 2 DM, and/or post-transplant DM who initiate basal insulin or intensify their insulin regimen to a basal-bolus regimen are included. After education on insulin dose titration and prevention for hypoglycemia and a 1-week acclimation period, subjects are randomized in a 1:1 ratio to either an ICT-based intervention group or a conventional intervention group. Subjects in the conventional intervention group will save and send their health information to the server via a PHR application, whereas those in ICT-based intervention group will receive additional algorithm-based feedback messages. The health information includes level of blood glucose, insulin dose, details on hypoglycemia, food diary, and step count. The primary outcome will be the proportion of patients who reach an optimal insulin dose within 12 weeks of study enrollment, without severe hypoglycemia or unscheduled clinic visits. This clinical trial will reveal whether insulin dose adjustment based on a smartphone PHR application can facilitate the optimization of insulin doses in patients with DM. In addition, the process evaluation will provide information about the validity and stability of the ICT-based centralized clinical trial monitoring system in this research field. Clinicaltrials.gov NCT 03112343 . Registered on 12 April 2017.

Effect of low-dose ketamine on post-operative serum IL-6 production among elective surgical patients: a randomized clinical trial.

PubMed

Luggya, Tonny Stone; Roche, Tony; Ssemogerere, Lameck; Kintu, Andrew; Kasumba, John Mark; Kwizera, Arthur; Tindimwebwa, Jose Vb

2017-06-01

Surgery and Anesthesia cause an excessive pro-inflammatory response. Mulago Hospital is faced with staff shortage making post-operative pain management difficult.Interleukin-6 (IL-6) drives inflammatory pain, endothelial cell dysfunction and fibrogenesis. Ketamine is cheap and, readily available. We hypothesized that its attenuation of serum IL-6 was a surrogate for clinical benefit. Institutional Review Board's approval was sought and RCT was registered at clinical trials.gov (identifier number: NCT01339065). Consenting patients were randomized to receive pre-incision intravenous ketamine - 0.5mg/kg or 0.9% saline placebo in weighted dosing. Blood samples were collected and laboratory analyzed at baseline, post-operatively in PACU, 24 and 48 hours respectively. We recruited 39 patients of whom 18 were randomized to the ketamine arm and 21 in the placebo arm with follow up at 24 and 48 hours. Serum IL-6 and IL-1β levels were analyzed using ELIZA assay of pre-coated micro wells. Ketamine suppressed serum IL-6 at PACU with reduced increase at 24 hours. There was no reaction in 98% of IL-1β assayed. Low-dose ketamine attenuated early serum IL-6 levels due to surgical response with reduced 24 hour increase, but the difference was not statistically significant and we recommend more studies.

Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

PubMed

Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

2009-01-01

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

TH-A-19A-06: Site-Specific Comparison of Analytical and Monte Carlo Based Dose Calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schuemann, J; Grassberger, C; Paganetti, H

2014-06-15

Purpose: To investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict dose distributions and to verify currently used uncertainty margins in proton therapy. Methods: Dose distributions predicted by an analytical pencilbeam algorithm were compared with Monte Carlo simulations (MCS) using TOPAS. 79 complete patient treatment plans were investigated for 7 disease sites (liver, prostate, breast, medulloblastoma spine and whole brain, lung and head and neck). A total of 508 individual passively scattered treatment fields were analyzed for field specific properties. Comparisons based on target coverage indices (EUD, D95, D90 and D50)more » were performed. Range differences were estimated for the distal position of the 90% dose level (R90) and the 50% dose level (R50). Two-dimensional distal dose surfaces were calculated and the root mean square differences (RMSD), average range difference (ARD) and average distal dose degradation (ADD), the distance between the distal position of the 80% and 20% dose levels (R80- R20), were analyzed. Results: We found target coverage indices calculated by TOPAS to generally be around 1–2% lower than predicted by the analytical algorithm. Differences in R90 predicted by TOPAS and the planning system can be larger than currently applied range margins in proton therapy for small regions distal to the target volume. We estimate new site-specific range margins (R90) for analytical dose calculations considering total range uncertainties and uncertainties from dose calculation alone based on the RMSD. Our results demonstrate that a reduction of currently used uncertainty margins is feasible for liver, prostate and whole brain fields even without introducing MC dose calculations. Conclusion: Analytical dose calculation algorithms predict dose distributions within clinical limits for more homogeneous patients sites (liver, prostate, whole brain). However, we recommend treatment plan verification using Monte Carlo simulations for patients with complex geometries.« less

Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients.

PubMed

Reichel, Felix F; Peters, Tobias; Wilhelm, Barbara; Biel, Martin; Ueffing, Marius; Wissinger, Bernd; Bartz-Schmidt, Karl U; Klein, Reinhild; Michalakis, Stylianos; Fischer, M Dominik

2018-04-01

To study longitudinal changes of anti-drug antibody (ADA) titers to recombinant adeno-associated virus serotype 8 (rAAV8) capsid epitopes in nonhuman primates (NHP) and patients. Three groups of six NHP each received subretinal injections (high dose: 1 × 1012 vector genomes [vg], low dose: 1 × 1011 vg, or vehicle only). Four additional animals received intravitreal injections of the high dose (1 × 1012 vg). Three patients received 1 × 1010 vg as subretinal injections. ELISA quantified ADA levels at baseline and 1, 2, 3, 7, 28, and 90 days after surgery in NHP and at baseline and 1, 3, and 6 months after surgery in patients. Two out of 22 animals lacked ADA titers at baseline and developed low ADA titers toward the end of the study. Titers in the low-dose group stayed constant, while two of six animals from the high-dose group developed titers that rose beyond the range of the assay. All animals from the intravitreal control group showed a rise in ADA titer by day 7 that peaked at day 28. Preliminary data from the clinical trial (NCT02610582) show no humoral immune response in patients following subretinal delivery of 1 × 1010 vg. No significant induction of ADA occurred in NHP when mimicking the clinical scenario of subretinal delivery with a clinical-grade rAAV8 and concomitant immunosuppression. Likewise, clinical data showed no humoral immune response in patients. In contrast, intravitreal delivery was associated with a substantial humoral immune response. Subretinal delivery might be superior to an intravitreal application regarding immunologic aspects.

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.

PubMed

Roberts, Andrew W; Davids, Matthew S; Pagel, John M; Kahl, Brad S; Puvvada, Soham D; Gerecitano, John F; Kipps, Thomas J; Anderson, Mary Ann; Brown, Jennifer R; Gressick, Lori; Wong, Shekman; Dunbar, Martin; Zhu, Ming; Desai, Monali B; Cerri, Elisa; Heitner Enschede, Sari; Humerickhouse, Rod A; Wierda, William G; Seymour, John F

2016-01-28

New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Optimization of radiotherapy. Some notes on the principles and practice of optimization in cancer treatment and implications for clinical research.

PubMed

Andrews, J R

1981-01-01

Two methods dominate cancer treatment--one, the traditional best practice, individualized treatment method and two, the a priori determined decision method of the interinstitutional, cooperative, clinical trial. In the first, choices are infinite and can be made at the time of treatment; in the second, choices are finite and are made in advance of treatment on a random basis. Neither method systematically selects, identifies, or formalizes the optimum level of effect in the treatment chosen. Of the two, it can be argued that the first, other things being equal, is more likely to select the optimum treatment. The determination of level of effect for the optimization of cancer treatment requires the generation of dose-response relationships for both benefit and risk and the introduction of benefit and risk considerations and judgements. The clinical trial, as presently constituted, doses not yield this kind of information, it being, generally, of the binary yes or no, better or worse type. The best practice, individualized treatment method can yield, when adequately documented, both a range of dose-response relationships and a variety of benefit and risk considerations. The presentation will be limited to a consideration of a single modality of cancer treatment, radiation therapy, but an analogy with other modalities of cancer treatment will be inferred. Criteria for optimization will be developed and graphic means for its identification and formalization will be demonstrated with examples taken from the radiotherapy literature. The general problem of optimization theory and practice will be discussed; the necessity for its exploration in relation to the increasing complexity of cancer treatment will be developed; and recommendations for clinical research will be made including a proposal for the support of clinics as an alternative to the support of programs.

National dosimetric audit network finds discrepancies in AAA lung inhomogeneity corrections.

PubMed

Dunn, Leon; Lehmann, Joerg; Lye, Jessica; Kenny, John; Kron, Tomas; Alves, Andrew; Cole, Andrew; Zifodya, Jackson; Williams, Ivan

2015-07-01

This work presents the Australian Clinical Dosimetry Service's (ACDS) findings of an investigation of systematic discrepancies between treatment planning system (TPS) calculated and measured audit doses. Specifically, a comparison between the Anisotropic Analytic Algorithm (AAA) and other common dose-calculation algorithms in regions downstream (≥2cm) from low-density material in anthropomorphic and slab phantom geometries is presented. Two measurement setups involving rectilinear slab-phantoms (ACDS Level II audit) and anthropomorphic geometries (ACDS Level III audit) were used in conjunction with ion chamber (planar 2D array and Farmer-type) measurements. Measured doses were compared to calculated doses for a variety of cases, with and without the presence of inhomogeneities and beam-modifiers in 71 audits. Results demonstrate a systematic AAA underdose with an average discrepancy of 2.9 ± 1.2% when the AAA algorithm is implemented in regions distal from lung-tissue interfaces, when lateral beams are used with anthropomorphic phantoms. This systemic discrepancy was found for all Level III audits of facilities using the AAA algorithm. This discrepancy is not seen when identical measurements are compared for other common dose-calculation algorithms (average discrepancy -0.4 ± 1.7%), including the Acuros XB algorithm also available with the Eclipse TPS. For slab phantom geometries (Level II audits), with similar measurement points downstream from inhomogeneities this discrepancy is also not seen. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shaib, Walid L.; Hawk, Natalyn; Cassidy, Richard J.

Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV,more » and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.« less

Acute small bowel toxicity and preoperative chemoradiotherapy for rectal cancer: Investigating dose-volume relationships and role for inverse planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tho, Lye Mun; Glegg, Martin; Paterson, Jennifer

2006-10-01

Purpose: The relationship between volume of irradiated small bowel (VSB) and acute toxicity in rectal cancer radiotherapy is poorly quantified, particularly in patients receiving concurrent preoperative chemoradiotherapy. Using treatment planning data, we studied a series of such patients. Methods and Materials: Details of 41 patients with locally advanced rectal cancer were reviewed. All received 45 Gy in 25 fractions over 5 weeks, 3-4 fields three-dimensional conformal radiotherapy with daily 5-fluorouracil and folinic acid during Weeks 1 and 5. Toxicity was assessed prospectively in a weekly clinic. Using computed tomography planning software, the VSB was determined at 5 Gy dose intervalsmore » (V{sub 5}, V{sub 1}, etc.). Eight patients with maximal VSB had dosimetry and radiobiological modeling outcomes compared between inverse and conformal three-dimensional planning. Results: VSB correlated strongly with diarrheal severity at every dose level (p < 0.03), with strongest correlation at lowest doses. Median VSB differed significantly between patients experiencing Grade 0-1 and Grade 2-4 diarrhea (p {<=} 0.05). No correlation was found with anorexia, nausea, vomiting, abdominal cramps, age, body mass index, sex, tumor position, or number of fields. Analysis of 8 patients showed that inverse planning reduced median dose to small bowel by 5.1 Gy (p = 0.008) and calculated late normal tissue complication probability (NTCP) by 67% (p = 0.016). We constructed a model using mathematical analysis to predict for acute diarrhea occurring at V{sub 5} and V{sub 15}. Conclusions: A strong dose-volume relationship exists between VSB and acute diarrhea at all dose levels during preoperative chemoradiotherapy. Our constructed model may be useful in predicting toxicity, and this has been derived without the confounding influence of surgical excision on bowel function. Inverse planning can reduce calculated dose to small bowel and late NTCP, and its clinical role warrants further investigation.« less

Adaptive statistical iterative reconstruction and bismuth shielding for evaluation of dose reduction to the eye and image quality during head CT

NASA Astrophysics Data System (ADS)

Kim, Myeong Seong; Choi, Jiwon; Kim, Sun Young; Kweon, Dae Cheol

2014-03-01

There is a concern regarding the adverse effects of increasing radiation doses due to repeated computed tomography (CT) scans, especially in radiosensitive organs and portions thereof, such as the lenses of the eyes. Bismuth shielding with an adaptive statistical iterative reconstruction (ASIR) algorithm was recently introduced in our clinic as a method to reduce the absorbed radiation dose. This technique was applied to the lens of the eye during CT scans. The purpose of this study was to evaluate the reduction in the absorbed radiation dose and to determine the noise level when using bismuth shielding and the ASIR algorithm with the GE DC 750 HD 64-channel CT scanner for CT of the head of a humanoid phantom. With the use of bismuth shielding, the noise level was higher in the beam-hardening artifact areas than in the revealed artifact areas. However, with the use of ASIR, the noise level was lower than that with the use of bismuth alone; it was also lower in the artifact areas. The reduction in the radiation dose with the use of bismuth was greatest at the surface of the phantom to a limited depth. In conclusion, it is possible to reduce the radiation level and slightly decrease the bismuth-induced noise level by using a combination of ASIR as an algorithm process and bismuth as an in-plane hardware-type shielding method.

Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin.

PubMed

O'Donnell, Martin J; Kearon, Clive; Johnson, Judy; Robinson, Marlene; Zondag, Michelle; Turpie, Irene; Turpie, Alexander G

2007-02-06

Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. Prospective cohort study. Single university hospital. Consecutive patients who had warfarin therapy interrupted before an invasive procedure. Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. Blood anti-factor Xa heparin levels measured shortly before surgery. Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.

Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats

PubMed Central

Han, Chung-Tack; Kim, Myoung-Jun; Moon, Seol-Hee; Jeon, Yu-Rim; Hwang, Jae-Sik; Nam, Chunja; Park, Chong-Woo; Lee, Sun-Ho; Na, Jae-Bum; Park, Chan-Sung; Park, Hee-Won; Lee, Jung-Min; Jang, Ho-Song; Park, Sun-Hee; Han, Kyoung-Goo; Choi, Young Whan

2015-01-01

Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes. PMID:26877842

Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats.

PubMed

Han, Chung-Tack; Kim, Myoung-Jun; Moon, Seol-Hee; Jeon, Yu-Rim; Hwang, Jae-Sik; Nam, Chunja; Park, Chong-Woo; Lee, Sun-Ho; Na, Jae-Bum; Park, Chan-Sung; Park, Hee-Won; Lee, Jung-Min; Jang, Ho-Song; Park, Sun-Hee; Han, Kyoung-Goo; Choi, Young Whan; Lee, Hye-Yeong; Kang, Jong-Koo

2015-12-01

Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes.

Implications of the 2013 ACC/AHA cholesterol guidelines on contemporary clinical practice for patients with atherosclerotic coronary and peripheral arterial disease.

PubMed

Gunasekaran, Prasad; Jeevanantham, Vinodh; Sharma, Suresh; Thapa, Rashmi; Gupta, Kamal

Cholesterol management guidelines from the American College of Cardiology/American Heart Association (ACC/AHA-2013) recommend fixed statin dosing (dose depends on age ≤ or >75years) compared to the earlier adult treatment panel III (ATPIII) guidelines which recommended specific low-density lipoprotein-cholesterol (LDL-C) targets. Clinical implications of this recommendation are not known. We retrospectively compared cholesterol levels and statin utilization across cohorts with coronary artery disease (CAD) (n=9563), peripheral arterial disease (PAD) (n=596) and CAD+PAD (n=975) by applying both guidelines. The percentage of patients who achieved guideline-specific targets using 2013 ACC/AHA (use of moderate/high intensity statins) or ATPIII guidelines (LDL-C<100mg/dl) was compared between all groups. Using both guidelines, the PAD only group demonstrated lower utilization and lower statin doses than the CAD or CAD+PAD groups. When applying the ACC/AHA guidelines, more patients in the CAD only group (age ≤75 years) were considered at goal as compared to the ATPIII guidelines (92.2% vs. 75%), primarily driven by the group placed on moderate/high intensity statins but had an LDL-C level >100mg/dl. Application of the ACC/AHA guidelines results in a higher percentage of patients considered to be 'at goal' when compared to the ATP III guidelines without changes in clinical practice. This is due to patients ≤75 years old on adequate statin doses but still have LDL-C levels >100mg/dl, thereby raising concerns that physicians may not pursue alternate LDL reduction strategies since they are now considered at goal despite LDL-C >100mg/dl. Lipid management of PAD patients remains sub-optimal as compared to CAD and CAD+PAD. Copyright © 2017. Published by Elsevier B.V.

Human radiation tolerance

NASA Technical Reports Server (NTRS)

Lushbaugh, C. C.

1974-01-01

The acute radiation syndrome in man is clinically bounded by death at high dose levels and by the prodromal syndrome of untoward physiological effects at minimal levels of clinically effective exposure. As in lower animals, man experiences principally three acute modes of death from radiation exposure (Bond et al., 1965). These are known collectively as the lethal radiation syndromes: central nervous system death, gastrointestinal death, and hematopoietic death. The effect of multiple exposure on lethality, the effect of multiple exposure on hematopoietic recovery, and quantitative aspects of cell and tissue repair are discussed.

Predicted levels of human radiation tolerance extrapolated from clinical studies of radiation effects

NASA Technical Reports Server (NTRS)

Lushbaugh, C. C.

1972-01-01

Results of clinical studies of radiation effects on man are used to evaluate space radiation hazards encountered during manned space travel. Considered are effects of photons as well as of mixed fission neutrons and gamma irradiations in establishing body radiosensitivity and tolerance levels. Upper and lower dose-response-time relations for acute radiation syndromes in patients indicate that man is more than sufficiently radioresistant to make the risks of an early radiation effect during one short space mission intangibly small in relation to the other nonradiation risks involved.

Quantitative imaging for clinical dosimetry

NASA Astrophysics Data System (ADS)

Bardiès, Manuel; Flux, Glenn; Lassmann, Michael; Monsieurs, Myriam; Savolainen, Sauli; Strand, Sven-Erik

2006-12-01

Patient-specific dosimetry in nuclear medicine is now a legal requirement in many countries throughout the EU for targeted radionuclide therapy (TRT) applications. In order to achieve that goal, an increased level of accuracy in dosimetry procedures is needed. Current research in nuclear medicine dosimetry should not only aim at developing new methods to assess the delivered radiation absorbed dose at the patient level, but also to ensure that the proposed methods can be put into practice in a sufficient number of institutions. A unified dosimetry methodology is required for making clinical outcome comparisons possible.

Boosting effect of a second dose of measles vaccine given to 12-year-old children.

PubMed

Böttiger, M

1993-01-01

In Sweden, a two-dose programme of vaccination against measles, mumps and rubella (MMR) was introduced in 1982 and the target groups were children aged 18 months and 12 years. In 1993 the first age group of 12-year-olds that were vaccinated with MMR at 18 months will appear. The majority of the 12-year-old vaccines for many years, however, had already been vaccinated against measles and the MMR measles component was thus a booster dose. As the benefit of a booster dose against measles has been questioned, this was studied in a group of 163 12-year-old children, 122 of whom had been vaccinated against measles as young children. Of the 41 unvaccinated children, 23 had a history of clinical measles. The mean neutralizing titre level of the earlier vaccinated children, prior to the booster, was lower than that of the naturally immune children (reciprocal titre level 8 versus 20). After the booster the corresponding titre levels were 13 and 23. Among the seronegative children receiving their first dose, this figure amounted to 14. A moderate rise in titre was seen in those with low prevaccination titres. As the antibody protection afforded by vaccination was slightly lower than that of natural infection, even after a booster, follow-up studies must be recommended to evaluate the long-term protection of both a single and a two-dose programme.

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

PubMed Central

Novalic, Zlata; van der Wal, Annemieke M.; Leonhard, Wouter N.; Koehl, Gudrun; Breuning, Martijn H.; Geissler, Edward K.; de Heer, Emile

2012-01-01

Inhibition of the mammalian target of rapamycin (mTOR) shows beneficial effects in animal models of polycystic kidney disease (PKD); however, two clinical trials in patients with autosomal dominant PKD failed to demonstrate a short-term benefit in either the early or progressive stages of disease. The stage of disease during treatment and the dose of mTOR inhibitors may account for these differing results. Here, we studied the effects of a conventional low dose and a higher dose of sirolimus (blood levels of 3 ng/ml and 30–60 ng/ml, respectively) on mTOR activity and renal cystic disease in two Pkd1-mutant mouse models at different stages of the disease. When initiated at early but not late stages of disease, high-dose treatment strongly reduced mTOR signaling in renal tissues, inhibited cystogenesis, accelerated cyst regression, and abrogated fibrosis and the infiltration of immune cells. In contrast, low-dose treatment did not significantly reduce renal cystic disease. Levels of p-S6RpSer240/244, which marks mTOR activity, varied between kidneys; severity of the renal cystic phenotype correlated with the level of mTOR activity. Taken together, these data suggest that long-term treatment with conventional doses of sirolimus is insufficient to inhibit mTOR activity in renal cystic tissue. Mechanisms to increase bioavailability or to target mTOR inhibitors more specifically to kidneys, alone or in combination with other compounds, may improve the potential for these therapies in PKD. PMID:22343118

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects.

PubMed

Krishna, Rajesh; Gheyas, Ferdous; Liu, Yang; Cote, Josee; Laterza, Omar; Ruckle, Jon L; Wagner, John A; Denker, Andrew E

2018-02-01

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects. © 2017, The American College of Clinical Pharmacology.

The Effect of Low Monotonic Doses of Zearalenone on Selected Reproductive Tissues in Pre-Pubertal Female Dogs--A Review.

PubMed

Gajęcka, Magdalena; Zielonka, Łukasz; Gajęcki, Maciej

2015-11-19

The growing interest in toxic substances combined with advancements in biological sciences has shed a new light on the problem of mycotoxins contaminating feeds and foods. An interdisciplinary approach was developed by identifying dose-response relationships in key research concepts, including the low dose theory of estrogen-like compounds, hormesis, NOAEL dose, compensatory response and/or food tolerance, and effects of exposure to undesirable substances. The above considerations increased the researchers' interest in risk evaluation, namely: (i) clinical symptoms associated with long-term, daily exposure to low doses of a toxic compound; and (ii) dysfunctions at cellular or tissue level that do not produce clinical symptoms. Research advancements facilitate the extrapolation of results and promote the use of novel tools for evaluating the risk of exposure, for example exposure to zearalenone in pre-pubertal female dogs. The arguments presented in this paper suggest that low doses of zearalenone in commercial feeds stimulate metabolic processes and increase weight gains. Those processes are accompanied by lower proliferation rates in the ovaries, neoangiogenesis and vasodilation in the ovaries and the uterus, changes in the steroid hormone profile, and changes in the activity of hydroxysteroid dehydrogenases. All of the above changes result from exogenous hyperestrogenizm.

Clinical knowledge-based inverse treatment planning

NASA Astrophysics Data System (ADS)

Yang, Yong; Xing, Lei

2004-11-01

Clinical IMRT treatment plans are currently made using dose-based optimization algorithms, which do not consider the nonlinear dose-volume effects for tumours and normal structures. The choice of structure specific importance factors represents an additional degree of freedom of the system and makes rigorous optimization intractable. The purpose of this work is to circumvent the two problems by developing a biologically more sensible yet clinically practical inverse planning framework. To implement this, the dose-volume status of a structure was characterized by using the effective volume in the voxel domain. A new objective function was constructed with the incorporation of the volumetric information of the system so that the figure of merit of a given IMRT plan depends not only on the dose deviation from the desired distribution but also the dose-volume status of the involved organs. The conventional importance factor of an organ was written into a product of two components: (i) a generic importance that parametrizes the relative importance of the organs in the ideal situation when the goals for all the organs are met; (ii) a dose-dependent factor that quantifies our level of clinical/dosimetric satisfaction for a given plan. The generic importance can be determined a priori, and in most circumstances, does not need adjustment, whereas the second one, which is responsible for the intractable behaviour of the trade-off seen in conventional inverse planning, was determined automatically. An inverse planning module based on the proposed formalism was implemented and applied to a prostate case and a head-neck case. A comparison with the conventional inverse planning technique indicated that, for the same target dose coverage, the critical structure sparing was substantially improved for both cases. The incorporation of clinical knowledge allows us to obtain better IMRT plans and makes it possible to auto-select the importance factors, greatly facilitating the inverse planning process. The new formalism proposed also reveals the relationship between different inverse planning schemes and gives important insight into the problem of therapeutic plan optimization. In particular, we show that the EUD-based optimization is a special case of the general inverse planning formalism described in this paper.

Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013.

PubMed

Suh, Hoon Young; Peck, Carl C; Yu, Kyung-Sang; Lee, Howard

2016-01-01

A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011-2013 than in 1990-2007 (31.6% vs 6.3%, P =0.036), reflecting a slow, but steady acceptance of the European Medicines Agency's guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2-53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster.

Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.

PubMed

Sessa, Cristiana; Lorusso, Patricia; Tolcher, Anthony; Farace, Françoise; Lassau, Nathalie; Delmonte, Angelo; Braghetti, Antonio; Bahleda, Rastislav; Cohen, Patrick; Hospitel, Marie; Veyrat-Follet, Christine; Soria, Jean-Charles

2013-09-01

The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. ©2013 AACR.

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer

PubMed Central

Rampurwala, Murtuza; Wisinski, Kari B; Burkard, Mark E; Ehsani, Sima; O’Regan, Ruth M; Carmichael, Lakeesha; Kim, KyungMann; Kolesar, Jill; Tevaarwerk, Amye J

2017-01-01

Intro Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3+3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47–73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1–2 nausea (n=4) and bone pain (n=3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n=2). The only grade 3 AE was hypertension (n=2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer. PMID:27826831

Urinary Phenylacetylglutamine as Dosing Biomarker for Patients with Urea Cycle Disorders

PubMed Central

Mokhtarani, M; Diaz, GA; Rhead, W; Lichter-Konecki, U; Bartley, J; Feigenbaum, A; Longo, N; Berquist, W; Berry, SA; Gallagher, R; Bartholomew, D; Harding, CO; Korson, MS; McCandless, SE; Smith, W; Vockley, J; Bart, S; Kronn, D; Zori, R; Cederbaum, S; Dorrani, N; Merritt, JL; Sreenath-Nagamani, Sandesh; Summar, M; LeMons, C; Dickinson, K; Coakley, DF; Moors, TL; Lee, B; Scharschmidt, BF

2013-01-01

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). Study Design These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6–17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. Results Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5–31.8 g/day and of sodium phenylbutyrate ranging from 1.3–31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% –5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% -to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r=0.730, p<0.001) or as total 24-hour excretion (r=0.791 p<0.001), followed by plasma phenylacetylglutamine AUC24-hour, plasma phenylacetic acid AUC24-hour and phenylbutyric acid AUC24-hour. Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. Conclusion The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring. PMID:22958974

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heijst, T C F van; Hoekstra, N; Philippens, M E P

Purpose: The Utrecht MRI-linac (MRL) design enables new MR-guided radiotherapy (RT) approaches. This is a feasibility study for a single-fraction high dose (boost) to individual lymph nodes (LNs) in breast-cancer patients, after breast-conserving surgery (BCS) and hypofractionated whole-breast irradiation (WBI) with conventional axillary RT (AxRT). Methods: After written informed consent, 5 breast-cancer patients (cT1-3N0) were enrolled (NL500460.041.14 trial) and underwent 1.5T MRI in supine RT position, after BCS. Axillary levels, based on ESTRO guidelines, and organs-at-risk (OARs) – including lungs, chest wall, plexus and neurovascular bundle (NVB) – were delineated. Pseudo-CT scans (pCTs) were generated by HU bulk-assignment of water,more » lung, and air. With Monaco treatment-planning software (TPS Elekta), VMAT plans were generated for simultaneous WBI and AxRT, prescribing 16×2.66=42.56Gy (V95%>99% V107%<2cc). Two scenarios were considered: AxRT of levels I–II; AxRT of levels I–IV, depending on boost location. Per patient, 4 LNs with varying axillary locations were selected, delineated, and expanded to PTV with 2-mm margin. Using dedicated MRL TPS, accounting for magnetic-field effects, an IMRT 1×8.5Gy boost was simulated for each LN, to achieve a total target dose of 66Gy EQD2 (α/β=3.5Gy). WBI/ART doses and boost doses were added, and evaluated in EQD2. Results: For all scenarios, 1×8.5Gy boosts could be simulated within clinical constraints for a 66Gy total dose, in addition to WBI/AxRT. LN target coverage was excellent (V95%>95%, mean >8.5Gy). Additional dose to OARs was limited. Conclusion: Our study explored the concept of LN boosting using on-line MRI guidance. It is feasible to boost individual axillary LNs – with 2-mm margin – with an additional 1×8.5Gy, in all axillary levels, within clinical constraints. This may lead to more personalized RT approaches for patients with involved LNs and may reduce RT-induced toxicity, or the need for axillary surgery. Other LN boost strategies, including dose escalation, are under investigation.« less

Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.

PubMed

Mokhtarani, M; Diaz, G A; Rhead, W; Lichter-Konecki, U; Bartley, J; Feigenbaum, A; Longo, N; Berquist, W; Berry, S A; Gallagher, R; Bartholomew, D; Harding, C O; Korson, M S; McCandless, S E; Smith, W; Vockley, J; Bart, S; Kronn, D; Zori, R; Cederbaum, S; Dorrani, N; Merritt, J L; Sreenath-Nagamani, Sandesh; Summar, M; Lemons, C; Dickinson, K; Coakley, D F; Moors, T L; Lee, B; Scharschmidt, B F

2012-11-01

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring. Copyright © 2012 Elsevier Inc. All rights reserved.

Poster - 47: A parametrized prediction model of rectal toxicity in focal SBRT of low risk prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stevens, Todd; Bauman, Glenn

There has been a recent trend towards watchful waiting in place of intervention for early stage prostate cancer (CaP). However, this approach can allow for disease progression, and subsequent whole-gland therapies such as prostatectomy and whole gland irradiation can result in functional deficits or rectal toxicities or both. A controversial alternative approach for this patient cohort is the use of focal therapy, where the treatment is focussed on an identified dominant index lesion (DIL). This work aims to investigate the treatment parameters for focal SBRT of the prostate under which clinically acceptable rectal NTCP levels can be achieved. For eachmore » of 25 low risk CaP patients, a hypothetical 2 cc DIL was modeled in the right-posterior quadrant of the prostate, and was used to build a PTV as the target for SBRT simulation. An SBRT prescriptions of 41 Gy and 37 Gy in 5 fractions were chosen, corresponding to the boost levels used in previous CaP dose escalation studies. DVH data were exported and used to calculate rectal NTCP values based on the Lyman-Kutcher-Burman (LKB) model using the QUANTEC reccommended model parameters. Rectal NTCP dependence on DIL-to-rectum separation, dose level, and DIL volume were investigated. The final goal of this ongoing work is to create a map of the maximum allowable prescription dose for a given patient geometry that achieves a clinically acceptable rectal NTCP level.« less

[Clinical experience of carbon ion radiotherapy for malignant tumors].

PubMed

Ishikawa, Hitoshi; Tsuji, Hiroshi; Tsujii, Hirohiko

2006-04-01

The carbon ion (C-ion) beams provide unique advantageous biological and physical properties in radiotherapy (RT) for malignant tumors. C-ion beams have a high relative biological effectiveness (RBE) resulting from the high linear energy transfer (LET). In terms of their physical characteristics, C-ion beams exhibit a spread-out Bragg peak (SOBP) and make for a better dose distribution of the target volume by specified beam modulations. Between June 1994 and August 2005, a total of 2,371 patients with malignant tumors were registered in phase I/II dose-escalation studies and clinical phase II trials using C-ion beams generated at Heavy Ion Medical Accelerator in Chiba (HIMAC). In the initial dose-escalation studies, grade 3 or more late rectal complications had developed in some patients. However, the adverse effects were resolved because of the use of appropriate dose levels and modification of the radiation technique. C-ion beams can carry out hypofractionated radiotherapy with a large fraction dose and reduce the overall treatment times compared with conventional radiotherapy. They can also achieve better local tumor control even for radio-resistant tumors such as malignant melanoma, hepatocellular carcinoma and bone and soft tissue sarcomas with minimal morbidity to the normal surrounding tissues.

QT effect of semagacestat at therapeutic and supratherapeutic doses.

PubMed

Zhang, Wei; Ayan-Oshodi, Mosun; Willis, Brian A; Annes, William; Hall, Stephen D; Chiesa, Joseph; Seger, Mary

2012-04-01

This thorough QT/ QT interval corrected for heart rate (QTc) study was designed to assess the potential of semagacestat, a functional gamma-secretase inhibitor, to delay cardiac repolarization. In this Phase I, single-dose, randomized, 4-period crossover study, semagacestat was compared with placebo in 54 healthy male and female subjects between the ages of 19 and 63 years, inclusive. Each study period included single oral-dose administrations of semagacestat 140 mg, semagacestat 280 mg, moxifloxacin 400 mg, or placebo. Study subjects and the investigator were blinded to the identity of semagacestat and placebo; however, moxifloxacin was administered as open-label. Moxifloxacin was compared with placebo for assay sensitivity analysis. Pharmacokinetic parameters were also assessed. For each QTc, the upper bound of the 2-sided 90% confidence interval (CI) for the least squares mean difference between semagacestat (at both the 140- and 280-mg dose levels) and placebo was < 10 msec at all time points, and thus, within the limits set for clinical relevance in regulatory guidelines. The results of this study indicate that single doses of 140 and 280 mg semagacestat did not prolong QTc to a clinically significant degree.

Clinical evaluation of rosoxacin for the treatment of chancroid.

PubMed Central

Haase, D A; Ndinya-Achola, J O; Nash, R A; D'Costa, L J; Hazlett, D; Lubwama, S; Nsanze, H; Ronald, A R

1986-01-01

One hundred seven men with Haemophilus ducreyi-positive chancroid were assigned to receive 300 mg of rosoxacin as a single dose or 150 mg twice daily for 3 days. Ulcers and buboes were followed clinically and bacteriologically for 1 month. Of 40 evaluable males on the 3-day regimen, 38 (95%) were cured, while only 14 of 23 (61%) males on the single-dose regimen were cured; this regimen was discontinued. There was one ulcer relapse at day 21 in both groups; the one relapse in the single-dose group had a persistent culture-positive bubo. Eight of nine (89%) buboes followed to the endpoint on the 3-day rosoxacin regimen were cured, versus three of six (50%) on the single-dose regimen. Adverse effects were mainly related to the central nervous system but were minor and did not require intervention. None of the treatment failures was due to organisms resistant to rosoxacin, and failure of the single-dose regimen presumably was related to duration of tissue levels rather than to drug resistance. Administration of 150 mg of rosoxacin twice daily for 3 days is an effective regimen for the therapy of chancroid and is a reasonable alternative to other short-course regimens. PMID:3489439

Bortezomib for acute humoral rejection treatment at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City: an update.

PubMed

Leyva, Sergio; Marino, Lluvia A; Alberú, Josefina; Morales-Buenrostro, Luis E

2010-01-01

The use of bortezomib as a treatment modality of AHR improved and stabilized graft function (clinical response) in the majority of patients. Its use in single dose, even combined with rituximab, does not seem to be useful to obtain a sustained clinical response, or to reduce HLAabs level. The use of 4 doses of bortezomib in days 1, 4, 7, and 10 (1.3 mg/m2 BSA each) plus plasmapheresis produced both a good clinical response and a reduction in DSA. Moving forward, it will be necessary to define the long-term effectiveness of bortezomib and whether rituximab administration is indispensable to achieve this goal. Until now, it is evident that many patients needed retreatment and they were well tolerated.

Quantifying exploratory low dose compounds in humans with AMS

PubMed Central

Dueker, Stephen R.; Vuong, Le T.; Lohstroh, Peter N.; Giacomo, Jason A.; Vogel, John S.

2010-01-01

Accelerator Mass Spectrometry is an established technology whose essentiality extends beyond simply a better detector for radiolabeled molecules. Attomole sensitivity reduces radioisotope exposures in clinical subjects to the point that no population need be excluded from clinical study. Insights in human physiochemistry are enabled by the quantitative recovery of simplified AMS processes that provide biological concentrations of all labeled metabolites and total compound related material at non-saturating levels. In this paper, we review some of the exploratory applications of AMS 14C in toxicological, nutritional, and pharmacological research. This body of research addresses the human physiochemistry of important compounds in their own right, but also serves as examples of the analytical methods and clinical practices that are available for studying low dose physiochemistry of candidate therapeutic compounds, helping to broaden the knowledge base of AMS application in pharmaceutical research. PMID:21047543

Steady-state serum salicylate levels in hospitalized patients with rheumatoid arthritis. Comparison of two dosage schedules of choline magnesium trisalicylate.

PubMed

Cassell, S; Furst, D; Dromgoole, S; Paulus, H

1979-04-01

When the total daily drug dose was individualized to produce a steady-state serum salicylate concentration between 20 and 35 mg/dl, clinically acceptable fluctuations of serum concentrations occurred during both twice daily and three times daily administration. In 6 rheumatoid arthritis patients receiving choline magnesium trisalicylate, mean steady-state serum levels were the same, and the ranges of hourly mean concentrations during 8 and 12 hour dosage intervals were 19 to 27 mg/dl and 17 to 30 mg/dl, respectively. Changing the dosing interval from 8 to 12 hours required a 50% increase in the fractional doses, but resulted in an increase of only 3 mg/dl in mean peak concentration and a ddecrease of 1 mg/dl in mean minimum concentration.

Anticholinergics and Central Nervous System Effects: Are We Confused?

PubMed Central

Staskin, David R; Zoltan, Edward

2007-01-01

The central nervous system (CNS) effects of anticholinergic agents have been documented in various patient populations and to varying degrees in case reports, brain-activity surrogates, and computerized cognitive testing. The older patient population with overactive bladder represents a group at increased risk of cognitive impairment and other CNS side effects associated with antimuscarinic agents. The complexity of the effect of anticholinergic agents on CNS function requires an increased level of careful investigation. Studies need to be performed in the at-risk population with multiple, validated tests at clinically prescribed doses in acute and chronic situations. These studies need to take into account the effect of commonly prescribed dosing regimens, with doses selected to represent with equivalent bladder potency. The alterations in the serum levels and parent/metabolite effects contributed by metabolic issues or drug delivery systems require special attention. PMID:18231615

A comparison of the convolution and TMR10 treatment planning algorithms for Gamma Knife® radiosurgery

PubMed Central

Wright, Gavin; Harrold, Natalie; Bownes, Peter

2018-01-01

Aims To compare the accuracies of the convolution and TMR10 Gamma Knife treatment planning algorithms, and assess the impact upon clinical practice of implementing convolution-based treatment planning. Methods Doses calculated by both algorithms were compared against ionisation chamber measurements in homogeneous and heterogeneous phantoms. Relative dose distributions calculated by both algorithms were compared against film-derived 2D isodose plots in a heterogeneous phantom, with distance-to-agreement (DTA) measured at the 80%, 50% and 20% isodose levels. A retrospective planning study compared 19 clinically acceptable metastasis convolution plans against TMR10 plans with matched shot times, allowing novel comparison of true dosimetric parameters rather than total beam-on-time. Gamma analysis and dose-difference analysis were performed on each pair of dose distributions. Results Both algorithms matched point dose measurement within ±1.1% in homogeneous conditions. Convolution provided superior point-dose accuracy in the heterogeneous phantom (-1.1% v 4.0%), with no discernible differences in relative dose distribution accuracy. In our study convolution-calculated plans yielded D99% 6.4% (95% CI:5.5%-7.3%,p<0.001) less than shot matched TMR10 plans. For gamma passing criteria 1%/1mm, 16% of targets had passing rates >95%. The range of dose differences in the targets was 0.2-4.6Gy. Conclusions Convolution provides superior accuracy versus TMR10 in heterogeneous conditions. Implementing convolution would result in increased target doses therefore its implementation may require a revaluation of prescription doses. PMID:29657896

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

PubMed

McKeand, William

2017-09-01

Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation. Food did not seem to have any clinically relevant impact on pharmacokinetic parameters. Bazedoxifene had an estimated oral bioavailability of ~6% and was safe and well tolerated in the range of doses evaluated. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: A simulation study based on phase 3 trial data.

PubMed

Fassoni, Artur C; Baldow, Christoph; Roeder, Ingo; Glauche, Ingmar

2018-06-28

Continuing tyrosine kinase inhibitor mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia and allows for a sustained disease control in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of the optimally responding patients, a systematic assessment of long-term tyrosine kinase inhibitor dose de-escalation is missing. We use a mathematical model to analyze and consistently describe biphasic treatment responses from tyrosine kinase inhibitor treated patients from two independent clinical phase-3 trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this mathematical framework to investigate the influence of different dosing regimens on the treatment outcome. We provide strong evidence suggesting that tyrosine kinase inhibitor dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, which have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitoring provides patient-specific predictions of an optimal reduced dose not decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose halving should be considered as a long-term treatment option for well-responding chronic myeloid leukemia patients under continuing maintenance therapy with tyrosine kinase inhibitors. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and therapy costs. Copyright © 2018, Ferrata Storti Foundation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, J. Martin, E-mail: mbrown@stanford.edu; Carlson, David J.; Brenner, David J.

Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), are rapidly becoming accepted practice for the radiation therapy of certain tumors. Typically, SRS and SBRT involve the delivery of 1 or a few large-dose fractions of 8 to 30 Gy per fraction: a major paradigm shift from radiation therapy practice over the past 90 years, when, with relatively large amounts of normal tissues receiving high doses, the goal was to maximize tumor response for an acceptable level of normal tissue injury. The development of SRS and SBRT have come about because ofmore » technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumors with reduced margins and high gradients outside the target, thereby minimizing doses to surrounding normal tissues. Because the results obtained with SRS and SBRT have been impressive, they have raised the question whether classic radiobiological modeling, and the linear-quadratic (LQ) model, are appropriate for large doses per fraction. In addition to objections to the LQ model, the possibility of additional biological effects resulting from endothelial cell damage, enhanced tumor immunity, or both have been raised to account for the success of SRS and SBRT. In this review, we conclude that the available preclinical and clinical data do not support a need to change the LQ model or to invoke phenomena over and above the classic 5 Rs of radiobiology and radiation therapy, with the likely exception that for some tumors high doses of irradiation may produce enhanced antitumor immunity. Thus, we suggest that for most tumors, the standard radiobiology concepts of the 5 Rs are sufficient to explain the clinical data, and the excellent results obtained from clinical studies are the result of the much larger biologically effective doses that are delivered with SRS and SBRT.« less

A Double-Blind Clinical Study to Investigate the Effects of a Fungal Protease Enzyme System on Metabolic, Hepato-renal, and Cardiovascular Parameters Following 30 Days of Supplementation in Active, Healthy Men.

PubMed

Anderson, Mark L

2013-05-01

Research on the role of digestion in overall health has driven increasing interest in the use of digestive enzymes, which may improve nutrient absorption and reduce gastrointestinal symptoms. Sales of digestive aids and enzymes have grown over 8% in 2009, with enzymes accounting for $69 million of this growing category. Recent clinical research reported that acute dosing of Aminogen®, a patented blend of digestive protease enzymes isolated from Aspergillus and blended with whey protein concentrate, increased the rate of protein absorption. The results indicated a faster rate of amino acid absorption reflected in significantly higher blood levels of amino acids, increased nitrogen retention, and significantly reduced levels of C-reactive protein. Few studies, however, have examined the safety of repeated dosing of oral enzymes with an appropriate substrate. The purpose of this study, therefore, was to evaluate basic measures of clinical safety during 30 days of continuous, repeated dosing of Aminogen® and whey protein supplementation in healthy, active men maintaining a regimen of resistance training. Parameters evaluated include various markers of general physical health, metabolic function, hepato-renal function, and cardiovascular health including fasting blood lipids. Forty healthy, resistance-trained men (27.1 ± 7.9 years) were recruited for this double-blind, randomized study. Group A ingested two 40-g doses of whey protein per day containing Aminogen®. Group B ingested two 40-g doses of whey protein per day. No significant changes were noted in measures of general physical health, metabolic function, cardiovascular health, and hepato-renal function within or between groups. However, total cholesterol, LDL cholesterol, and serum calcium significantly increased ( P  < 0.05) in group B. In group A, whey protein containing Aminogen® was well tolerated with no adverse reactions reported. No differences in serum markers of clinical safety and an improved blood lipid profile are also reported.

Carotid endarterectomy--an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

PubMed

Chaturvedi, S; Bruno, A; Feasby, T; Holloway, R; Benavente, O; Cohen, S N; Cote, R; Hess, D; Saver, J; Spence, J D; Stern, B; Wilterdink, J

2005-09-27

To assess the efficacy of carotid endarterectomy for stroke prevention in asymptomatic and symptomatic patients with internal carotid artery stenosis. Additional clinical scenarios, such as use of endarterectomy combined with cardiac surgery, are also reviewed. The authors selected nine important clinical questions. A systematic search was performed for articles from 1990 (the year of the last statement) until 2001. Additional articles from 2002 through 2004 were included using prespecified criteria. Two reviewers also screened for other relevant articles from 2002 to 2004. Case reports, review articles, technical studies, and single surgeon case series were excluded. For several questions, high quality randomized clinical trials had been completed. Carotid endarterectomy reduces the stroke risk compared to medical therapy alone for patients with 70 to 99% symptomatic stenosis (16% absolute risk reduction at 5 years). There is a smaller benefit for patients with 50 to 69% symptomatic stenosis (absolute risk reduction 4.6% at 5 years). There is a small benefit for asymptomatic patients with 60 to 99% stenosis if the perioperative complication rate is low. Aspirin in a dose of 81 to 325 mg per day is preferred vs higher doses (650 to 1,300 mg per day) in patients undergoing endarterectomy. Evidence supports carotid endarterectomy for severe (70 to 99%) symptomatic stenosis (Level A). Endarterectomy is moderately useful for symptomatic patients with 50 to 69% stenosis (Level B) and not indicated for symptomatic patients with <50% stenosis (Level A). For asymptomatic patients with 60 to 99% stenosis, the benefit/risk ratio is smaller compared to symptomatic patients and individual decisions must be made. Endarterectomy can reduce the future stroke rate if the perioperative stroke/death rate is kept low (<3%) (Level A). Low dose aspirin (81 to 325 mg) is preferred for patients before and after carotid endarterectomy to reduce the rate of stroke, myocardial infarction, and death (Level A).

'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jetten, Marlon J.A.; Gaj, Stan; Ruiz-Aracama, Ainhoa

2012-03-15

Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome humanmore » miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques outperformed classic clinical chemistry tests. ► Metabolomic analyses led to the detection of five new acetaminophen metabolites. ► Low dose APAP changed immune and oxidative stress related gene expression in blood. ► APAP-induced full-genome human blood miRNA profiles were assessed for the first time.« less

Preclinical toxicity profile of oral bilastine.

PubMed

Lucero, María Luisa; Arteche, Joseba K; Sommer, E W; Casadesus, Agustín

2012-06-01

As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastine-associated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage.

Low-Dose of Bergamot-Derived Polyphenolic Fraction (BPF) Did Not Improve Metabolic Parameters in Second Generation Antipsychotics-Treated Patients: Results from a 60-days Open-Label Study.

PubMed

Bruno, Antonio; Pandolfo, Gianluca; Crucitti, Manuela; Cacciola, Massimo; Santoro, Vincenza; Spina, Edoardo; Zoccali, Rocco A; Muscatello, Maria R A

2017-01-01

Objectives: The nutraceutical approach to the management of metabolic syndrome (MetS) might be a promising strategy in the prevention of cardio-metabolic risk. Low-dose bergamot-derived polyphenolic fraction (BPF) has been proven effective in patients with MetS, as demonstrated by a concomitant improvement in lipemic and glycemic profiles. The present study was aimed to further explore, in a sample of subjects receiving second generation antipsychotics (SGAs), the effects on body weight and metabolic parameters of a low dose of BPF (500 mg/day) administered for 60 days. Methods: Twenty-eight outpatients treated with SGAs assumed BPF at single daily dose of 500 mg/day for 60 days. Body weight, BMI, fasting levels of glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides were determined; moreover, Brief Psychiatric Rating Scale (BPRS) was administered. Results: Low-dose BPF administration did not change clinical and metabolic parameters, as well as clinical symptoms in the study sample. At the end of the trial, among completers ( n = 24) only nine patients (37.5%) reached an LDL reduction >0 but <50%. Conclusions: Our results demonstrate that patients treated with SGAs may need higher BPF doses for obtaining the positive effects on body weight and metabolic parameters previously found in the general population at lower doses.

Low-Dose of Bergamot-Derived Polyphenolic Fraction (BPF) Did Not Improve Metabolic Parameters in Second Generation Antipsychotics-Treated Patients: Results from a 60-days Open-Label Study

PubMed Central

Bruno, Antonio; Pandolfo, Gianluca; Crucitti, Manuela; Cacciola, Massimo; Santoro, Vincenza; Spina, Edoardo; Zoccali, Rocco A.; Muscatello, Maria R. A.

2017-01-01

Objectives: The nutraceutical approach to the management of metabolic syndrome (MetS) might be a promising strategy in the prevention of cardio-metabolic risk. Low-dose bergamot-derived polyphenolic fraction (BPF) has been proven effective in patients with MetS, as demonstrated by a concomitant improvement in lipemic and glycemic profiles. The present study was aimed to further explore, in a sample of subjects receiving second generation antipsychotics (SGAs), the effects on body weight and metabolic parameters of a low dose of BPF (500 mg/day) administered for 60 days. Methods: Twenty-eight outpatients treated with SGAs assumed BPF at single daily dose of 500 mg/day for 60 days. Body weight, BMI, fasting levels of glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides were determined; moreover, Brief Psychiatric Rating Scale (BPRS) was administered. Results: Low-dose BPF administration did not change clinical and metabolic parameters, as well as clinical symptoms in the study sample. At the end of the trial, among completers (n = 24) only nine patients (37.5%) reached an LDL reduction >0 but <50%. Conclusions: Our results demonstrate that patients treated with SGAs may need higher BPF doses for obtaining the positive effects on body weight and metabolic parameters previously found in the general population at lower doses. PMID:28443024

Single isotope evaluation of pulmonary capillary protein leak (ARDS model) using computerized gamma scintigraphy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tatum, J.L.; Strash, A.M.; Sugerman, H.J.

Using a canine oleic acid model, a computerized gamma scintigraphic technique was evaluated to determine 1) ability to detect pulmonary capillary protein leak in a model temporally consistent with clinical adult respiratory distress syndrome (ARDS), 2) the possibility of providing a quantitative index of leak, and 3) the feasibility of closely spaced repeat evaluations. Study animals received oleic acid (controls, n . 10; 0.05 ml/kg, n . 10; 0.10 ml/kg, n . 12; 0.15 ml/kg, n . 6) 3 hours prior to a tracer dose of technetium-99m (/sup 99/mTc) HSA. One animal in each dose group also received two repeatmore » tracer injections spaced a minimum of 45 minutes apart. Digital images were obtained with a conventional gamma camera interfaced to a dedicated medical computer. Lung: heart ratio versus time curves were generated, and a slope index was calculated for each curve. Slope index values for all doses were significantly greater than control values (P(t) less than 0.0001). Each incremental dose increase was also significantly greater than the previous dose level. Oleic acid dose versus slope index fitted a linear regression model with r . 0.94. Repeat dosing produced index values with standard deviations less than the group sample standard deviations. We feel this technique may have application in the clinical study of pulmonary permeability edema.« less

A randomized clinical trial of the efficacy of single versus double-daily dose of oral iron for prevention of iron deficiency anemia in women with twin gestations.

PubMed

Ali, Mohammed K; Abbas, Ahmed M; Abdelmagied, Ahmed M; Mohammed, Ghada E; Abdalmageed, Osama S

2017-12-01

The study aims to assess the efficacy of single versus double-daily oral iron dose on prevention of iron deficiency anemia in women with twin gestations. A randomized controlled trial (NCT02858505) conducted at Woman's Health Hospital, Assiut, Egypt, between August 2015 and June 2016 included 120 non-anemic pregnant women with twin gestations in the first trimester. Women were randomly assigned to either group I (27 mg elemental iron) or group II (54 mg elemental iron) daily starting from 12 weeks of pregnancy till 36 weeks. The primary outcomes included the mean level of hemoglobin, hematocrit and serum ferritin at 36 weeks' gestation. Both iron doses maintained the mean hemoglobin and hematocrit within the normal level from 12 weeks to 36 weeks (p = 0.378 and p = 0.244, respectively). However, the mean serum ferritin level was higher in group II than group I (p = 0.000) at 36 weeks' gestation. Moreover, women in group II reported more side effects than group I at 36 weeks' gestation. Doubling the prophylactic iron dose is comparable to single dose in the prevention of iron deficiency anemia among women with twin gestations with more side effects.

Pulmonary nodules: effect of adaptive statistical iterative reconstruction (ASIR) technique on performance of a computer-aided detection (CAD) system-comparison of performance between different-dose CT scans.

PubMed

Yanagawa, Masahiro; Honda, Osamu; Kikuyama, Ayano; Gyobu, Tomoko; Sumikawa, Hiromitsu; Koyama, Mitsuhiro; Tomiyama, Noriyuki

2012-10-01

To evaluate the effects of ASIR on CAD system of pulmonary nodules using clinical routine-dose CT and lower-dose CT. Thirty-five patients (body mass index, 22.17 ± 4.37 kg/m(2)) were scanned by multidetector-row CT with tube currents (clinical routine-dose CT, automatically adjusted mA; lower-dose CT, 10 mA) and X-ray voltage (120 kVp). Each 0.625-mm-thick image was reconstructed at 0%-, 50%-, and 100%-ASIR: 0%-ASIR is reconstructed using only the filtered back-projection algorithm (FBP), while 100%-ASIR is reconstructed using the maximum ASIR and 50%-ASIR implies a blending of 50% FBP and ASIR. CAD output was compared retrospectively with the results of the reference standard which was established using a consensus panel of three radiologists. Data were analyzed using Bonferroni/Dunn's method. Radiation dose was calculated by multiplying dose-length product by conversion coefficient of 0.021. The consensus panel found 265 non-calcified nodules ≤ 30 mm (ground-glass opacity [GGO], 103; part-solid, 34; and solid, 128). CAD sensitivity was significantly higher at 100%-ASIR [clinical routine-dose CT, 71% (overall), 49% (GGO); lower-dose CT, 52% (overall), 67% (solid)] than at 0%-ASIR [clinical routine-dose CT, 54% (overall), 25% (GGO); lower-dose CT, 36% (overall), 50% (solid)] (p<0.001). Mean number of false-positive findings per examination was significantly higher at 100%-ASIR (clinical routine-dose CT, 8.5; lower-dose CT, 6.2) than at 0%-ASIR (clinical routine-dose CT, 4.6; lower-dose CT, 3.5; p<0.001). Effective doses were 10.77 ± 3.41 mSv in clinical routine-dose CT and 2.67 ± 0.17 mSv in lower-dose CT. CAD sensitivity at 100%-ASIR on lower-dose CT is almost equal to that at 0%-ASIR on clinical routine-dose CT. ASIR can increase CAD sensitivity despite increased false-positive findings. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania

PubMed Central

Isanaka, Sheila; Mugusi, Ferdinand; Hawkins, Claudia; Spiegelman, Donna; Okuma, James; Aboud, Said; Guerino, Chalamilla; Fawzi, Wafaie W.

2013-01-01

Context Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. Objective To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. Design, Setting, and Participants A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. Intervention The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. Main Outcome Measure The composite of HIV disease progression or death from any cause. Results The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96–1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11–1.87) vs standard-dose supplementation. Conclusion In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. Trial Registration clinicaltrials.gov Identifier: NCT00383669 PMID:23073950

Helium ion beam imaging for image guided ion radiotherapy.

PubMed

Martišíková, M; Gehrke, T; Berke, S; Aricò, G; Jäkel, O

2018-06-14

Ion beam radiotherapy provides potential for increased dose conformation to the target volume. To translate it into a clinical advantage, it is necessary to guarantee a precise alignment of the actual internal patient geometry with the treatment beam. This is in particular challenging for inter- and intrafractional variations, including movement. Ion beams have the potential for a high sensitivity imaging of the patient geometry. However, the research on suitable imaging methods is not conclusive yet. Here we summarize the research activities within the "Clinical research group heavy ion therapy" funded by the DFG (KFO214). Our aim was to develop a method for the visualization of a 1 mm thickness difference with a spatial resolution of about 1 mm at clinically applicable doses. We designed and built a dedicated system prototype for ion radiography using exclusively the pixelated semiconductor technology Timepix developed at CERN. Helium ions were chosen as imaging radiation due to their decreased scattering in comparison to protons, and lower damaging potential compared to carbon ions. The data acquisition procedure and a dedicated information processing algorithm were established. The performance of the method was evaluated at the ion beam therapy facility HIT in Germany with geometrical phantoms. The quality of the images was quantified by contrast-to-noise ratio (CNR) and spatial resolution (SR) considering the imaging dose. Using the unique method for single ion identification, degradation of the images due to the inherent contamination of the outgoing beam with light secondary fragments (hydrogen) was avoided. We demonstrated experimentally that the developed data processing increases the CNR by 350%. Consideration of the measured ion track directions improved the SR by 150%. Compared to proton radiographs at the same dose, helium radiographs exhibited 50% higher SR (0.56 ± 0.04lp/mm vs. 0.37 ± 0.02lp/mm) at a comparable CNR in the middle of the phantom. The clear visualization of the aimed inhomogeneity at a diagnostic dose level demonstrates a resolution of 0.1 g/cm 2 or 0.6% in terms of water-equivalent thickness. We developed a dedicated method for helium ion radiography, based exclusively on pixelated semiconductor detectors. The achievement of a clinically desired image quality in simple phantoms at diagnostic dose levels was demonstrated experimentally.

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

High-order noise analysis for low dose iterative image reconstruction methods: ASIR, IRIS, and MBAI

NASA Astrophysics Data System (ADS)

Do, Synho; Singh, Sarabjeet; Kalra, Mannudeep K.; Karl, W. Clem; Brady, Thomas J.; Pien, Homer

2011-03-01

Iterative reconstruction techniques (IRTs) has been shown to suppress noise significantly in low dose CT imaging. However, medical doctors hesitate to accept this new technology because visual impression of IRT images are different from full-dose filtered back-projection (FBP) images. Most common noise measurements such as the mean and standard deviation of homogeneous region in the image that do not provide sufficient characterization of noise statistics when probability density function becomes non-Gaussian. In this study, we measure L-moments of intensity values of images acquired at 10% of normal dose and reconstructed by IRT methods of two state-of-art clinical scanners (i.e., GE HDCT and Siemens DSCT flash) by keeping dosage level identical to each other. The high- and low-dose scans (i.e., 10% of high dose) were acquired from each scanner and L-moments of noise patches were calculated for the comparison.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Bryostatin Effects on Cognitive Function and PKCɛ in Alzheimer's Disease Phase IIa and Expanded Access Trials.

PubMed

Nelson, Thomas J; Sun, Miao-Kun; Lim, Chol; Sen, Abhik; Khan, Tapan; Chirila, Florin V; Alkon, Daniel L

2017-01-01

Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus -1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

Glycemic control and insulin requirements in type 1 diabetic patients depending on the clinical characteristics at diabetes onset.

PubMed

Beato-Víbora, Pilar Isabel; Tormo-García, M Ángeles

2014-01-01

The long-term prognosis of type 1 diabetes (T1DM) was evaluated in relation to the clinical characteristics at the time of diabetes onset. We examined retrospectively the clinical and laboratory characteristics present at the time of diagnosis in 301 adult patients (187 men) consecutively admitted to hospital with T1DM onset and evaluated the clinical outcome of T1DM during 6 ± 4.8 years following diagnosis. Women needed a greater insulin dose per kg of body weight over the first 2 years following diagnosis. Younger patients at diagnosis had greater insulin requirements during follow-up. Patients with at least one positive pancreatic antibody needed a greater insulin dose 2 years after diagnosis and developed poorer glycemic control during follow-up than patients with no detectable pancreatic antibodies at onset. Diabetic ketoacidosis at onset was associated with greater insulin requirements over the first 2 years of follow-up and with poorer glycemic control during the course of the illness. C-peptide levels at diagnosis correlated with insulin requirements during the first 2 years of follow-up. Patients with higher HbA1c levels at diagnosis had greater insulin requirements in the first year of follow-up. A correlation was found between the HbA1c levels at the consecutive years of follow-up. Female sex, younger age, humoral pancreatic autoimmunity, diabetic ketoacidosis, lower pancreatic reserve and higher HbA1c levels at onset could predict a poor long-term clinical outcome of T1DM in terms of insulin requirements and glycemic control.

Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial.

PubMed

Gheorghiade, Mihai; Greene, Stephen J; Butler, Javed; Filippatos, Gerasimos; Lam, Carolyn S P; Maggioni, Aldo P; Ponikowski, Piotr; Shah, Sanjiv J; Solomon, Scott D; Kraigher-Krainer, Elisabeth; Samano, Eliana T; Müller, Katharina; Roessig, Lothar; Pieske, Burkert

2015-12-01

Worsening chronic heart failure (HF) is a major public health problem. To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively. Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. clinicaltrials.gov Identifier: NCT01951625.

Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

PubMed

Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

2014-05-01

In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

Higher hydrocortisone dose increases bilirubin in hypopituitary patients- results from an RCT.

PubMed

Werumeus Buning, Jorien; Kootstra-Ros, Jenny E; Brummelman, Pauline; van den Berg, Gerrit; van der Klauw, Melanie; Wolffenbuttel, Bruce H R; van Beek, André P; Dullaart, Robin P F

2016-05-01

Bilirubin has anti-oxidative and anti-inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients. A randomized double-blind cross-over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10-week exposure to a higher hydrocortisone dose (0·4-0·6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0·2-0·3 mg/kg body weight)]. Plasma total bilirubin was increased by 10% from 7 to 8 μM in response to the higher hydrocortisone dose (P = 0·033). This effect was inversely related to age (P = 0·042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0·006) and aspartate aminotransferase activities (P = 0·001). Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro-inflammatory state and enhanced liver fat accumulation. © 2016 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

Dose reduction with adaptive statistical iterative reconstruction for paediatric CT: phantom study and clinical experience on chest and abdomen CT.

PubMed

Gay, F; Pavia, Y; Pierrat, N; Lasalle, S; Neuenschwander, S; Brisse, H J

2014-01-01

To assess the benefit and limits of iterative reconstruction of paediatric chest and abdominal computed tomography (CT). The study compared adaptive statistical iterative reconstruction (ASIR) with filtered back projection (FBP) on 64-channel MDCT. A phantom study was first performed using variable tube potential, tube current and ASIR settings. The assessed image quality indices were the signal-to-noise ratio (SNR), the noise power spectrum, low contrast detectability (LCD) and spatial resolution. A clinical retrospective study of 26 children (M:F = 14/12, mean age: 4 years, range: 1-9 years) was secondarily performed allowing comparison of 18 chest and 14 abdominal CT pairs, one with a routine CT dose and FBP reconstruction, and the other with 30 % lower dose and 40 % ASIR reconstruction. Two radiologists independently compared the images for overall image quality, noise, sharpness and artefacts, and measured image noise. The phantom study demonstrated a significant increase in SNR without impairment of the LCD or spatial resolution, except for tube current values below 30-50 mA. On clinical images, no significant difference was observed between FBP and reduced dose ASIR images. Iterative reconstruction allows at least 30 % dose reduction in paediatric chest and abdominal CT, without impairment of image quality. • Iterative reconstruction helps lower radiation exposure levels in children undergoing CT. • Adaptive statistical iterative reconstruction (ASIR) significantly increases SNR without impairing spatial resolution. • For abdomen and chest CT, ASIR allows at least a 30 % dose reduction.

Bioavailability of sulforaphane from two broccoli sprout beverages: Results of a short term, cross-over clinical trial in Qidong, China

PubMed Central

Egner, Patricia A.; Chen, Jian Guo; Wang, Jin Bing; Wu, Yan; Sun, Yan; Lu, Jian Hua; Zhu, Jian; Zhang, Yong Hui; Chen, Yong Sheng; Friesen, Marlin D.; Jacobson, Lisa P.; Muñoz, Alvaro; Ng, Derek; Qian, Geng Sun; Zhu, Yuan Rong; Chen, Tao Yang; Botting, Nigel P.; Zhang, Qingzhi; Fahey, Jed W.; Talalay, Paul; Groopman, John D; Kensler, Thomas W.

2011-01-01

One of several challenges in design of clinical chemoprevention trials is the selection of the dose, formulation and dose schedule of the intervention agent. Therefore, a cross-over clinical trial was undertaken to compare the bioavailability and tolerability of sulforaphane from two of broccoli sprout-derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR). Sulforaphane was generated from glucoraphanin contained in GRR by gut microflora or formed by treatment of GRR with myrosinase from daikon (Raphanus sativus) sprouts to provide SFR. Fifty healthy, eligible participants were requested to refrain from crucifer consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period, 7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane and sulforaphane thiol conjugates in urine samples collected daily throughout the study. Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites (in approximately 12 hour collections after dosing), was substantially greater with the SFR (mean = 70%) than with GRR (mean = 5%) beverages. Interindividual variability in excretion was considerably lower with SFR than GRR beverage. Elimination rates were considerably slower with GRR allowing for achievement of steady state dosing as opposed to bolus dosing with SFR. Optimal dosing formulations in future studies should consider blends of sulforaphane and glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of some targets and prolonged inhibition of others implicated in the protective actions of sulforaphane. PMID:21372038

NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

PubMed Central

Mansky, Patrick J.; Sannes, Timothy S.; Johnson, Laura Lee; Blackman, Marc R.; Grem, Jean L.; Swain, Sandra M.; Monahan, Brian P.

2013-01-01

Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone. PMID:24285980

A comprehensive analysis of the IMRT dose delivery process using statistical process control (SPC)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerard, Karine; Grandhaye, Jean-Pierre; Marchesi, Vincent

The aim of this study is to introduce tools to improve the security of each IMRT patient treatment by determining action levels for the dose delivery process. To achieve this, the patient-specific quality control results performed with an ionization chamber--and which characterize the dose delivery process--have been retrospectively analyzed using a method borrowed from industry: Statistical process control (SPC). The latter consisted in fulfilling four principal well-structured steps. The authors first quantified the short term variability of ionization chamber measurements regarding the clinical tolerances used in the cancer center ({+-}4% of deviation between the calculated and measured doses) by calculatingmore » a control process capability (C{sub pc}) index. The C{sub pc} index was found superior to 4, which implies that the observed variability of the dose delivery process is not biased by the short term variability of the measurement. Then, the authors demonstrated using a normality test that the quality control results could be approximated by a normal distribution with two parameters (mean and standard deviation). Finally, the authors used two complementary tools--control charts and performance indices--to thoroughly analyze the IMRT dose delivery process. Control charts aim at monitoring the process over time using statistical control limits to distinguish random (natural) variations from significant changes in the process, whereas performance indices aim at quantifying the ability of the process to produce data that are within the clinical tolerances, at a precise moment. The authors retrospectively showed that the analysis of three selected control charts (individual value, moving-range, and EWMA control charts) allowed efficient drift detection of the dose delivery process for prostate and head-and-neck treatments before the quality controls were outside the clinical tolerances. Therefore, when analyzed in real time, during quality controls, they should improve the security of treatments. They also showed that the dose delivery processes in the cancer center were in control for prostate and head-and-neck treatments. In parallel, long term process performance indices (P{sub p}, P{sub pk}, and P{sub pm}) have been analyzed. Their analysis helped defining which actions should be undertaken in order to improve the performance of the process. The prostate dose delivery process has been shown statistically capable (0.08% of the results is expected to be outside the clinical tolerances) contrary to the head-and-neck dose delivery process (5.76% of the results are expected to be outside the clinical tolerances).« less

A comprehensive analysis of the IMRT dose delivery process using statistical process control (SPC).

PubMed

Gérard, Karine; Grandhaye, Jean-Pierre; Marchesi, Vincent; Kafrouni, Hanna; Husson, François; Aletti, Pierre

2009-04-01

The aim of this study is to introduce tools to improve the security of each IMRT patient treatment by determining action levels for the dose delivery process. To achieve this, the patient-specific quality control results performed with an ionization chamber--and which characterize the dose delivery process--have been retrospectively analyzed using a method borrowed from industry: Statistical process control (SPC). The latter consisted in fulfilling four principal well-structured steps. The authors first quantified the short-term variability of ionization chamber measurements regarding the clinical tolerances used in the cancer center (+/- 4% of deviation between the calculated and measured doses) by calculating a control process capability (C(pc)) index. The C(pc) index was found superior to 4, which implies that the observed variability of the dose delivery process is not biased by the short-term variability of the measurement. Then, the authors demonstrated using a normality test that the quality control results could be approximated by a normal distribution with two parameters (mean and standard deviation). Finally, the authors used two complementary tools--control charts and performance indices--to thoroughly analyze the IMRT dose delivery process. Control charts aim at monitoring the process over time using statistical control limits to distinguish random (natural) variations from significant changes in the process, whereas performance indices aim at quantifying the ability of the process to produce data that are within the clinical tolerances, at a precise moment. The authors retrospectively showed that the analysis of three selected control charts (individual value, moving-range, and EWMA control charts) allowed efficient drift detection of the dose delivery process for prostate and head-and-neck treatments before the quality controls were outside the clinical tolerances. Therefore, when analyzed in real time, during quality controls, they should improve the security of treatments. They also showed that the dose delivery processes in the cancer center were in control for prostate and head-and-neck treatments. In parallel, long-term process performance indices (P(p), P(pk), and P(pm)) have been analyzed. Their analysis helped defining which actions should be undertaken in order to improve the performance of the process. The prostate dose delivery process has been shown statistically capable (0.08% of the results is expected to be outside the clinical tolerances) contrary to the head-and-neck dose delivery process (5.76% of the results are expected to be outside the clinical tolerances).

Valproic acid induced hyperammonaemic encephalopathy.

PubMed

Amanat, Saima; Shahbaz, Naila; Hassan, Yasmin

2013-01-01

To observe clinical and laboratory features of valproic acid-induced hyperammonaemic encephalopathy in patients taking valproic acid. Observational study was conducted at the Neurology Department, Dow University of Health Sciences, Civil Hospital, Karachi, from February 26, 2010 to March 20, 2011. Ten patients on valproic acid therapy of any age group with idiopathic or secondary epilepsy, who presented with encephalopathic symptoms, were registered and followed up during the study. Serum ammonia level, serum valproic acid level, liver function test, cerebrospinal fluid examination, electroencephalogram and brain imaging of all the patients were done. Other causes of encephalopathy were excluded after clinical and appropriate laboratory investigations. Microsoft Excell 2007 was used for statistical analysis. Hyperammonaemia was found in all patients with encephalopathic symptoms. Rise in serum ammonia was independent of dose and serum level of valproic acid. Liver function was also found to be normal in 80% (n = 8) of the patients. Valproic acid was withdrawn in all patients. Three (30%) patients improved only after the withdrawal of valproic acid. Six (60%) patients improved after L-Carnitine replacement, one (10%) after sodium benzoate. On followup, serum ammonia had reduced to normal in five (50%) patients and to more than half of the baseline level in two (20%) patients. Three (30%) patients were lost to followup after complete clinical improvement. Within therapeutic dose and serum levels, valproic acid can cause symptomatic hyperammonaemia resulting in encephalopathy. All patients taking valproic acid presenting with encephalopathic symptoms must be monitored for the condition.

The mechanisms of delayed onset type adverse reactions to oseltamivir

PubMed Central

Hama, Rokuro

2016-01-01

Abstract Oseltamivir is recommended for the treatment and prophylaxis of influenza in persons at higher risk for influenza complications such as individuals with diabetes, neuropsychiatric illnesses, and respiratory, cardiac, renal, hepatic or haematological diseases. However, a recent Cochrane review reported that reduction of antibody production, renal disorders, hyperglycaemia, psychiatric disorders, and QT prolongation may be related to oseltamivir use. The underlying mechanisms are reviewed. There is decisive evidence that administration of a clinically compatible dose of oseltamivir in mice challenged by a respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed symptom-relieving effects and inhibition of viral clearance. These effects were accompanied by decreased level of T cell surface sialoglycosphingolipid (ganglioside) GM1 that is regulated by the endogenous neuraminidase in response to viral challenge. Clinical and non-clinical evidence supports the view that the usual dose of oseltamivir suppresses pro-inflammatory cytokines such as interferon-gamma, interleukin-6, and tumour necrosis factor-alpha almost completely with partial suppression of viral shedding in human influenza virus infection experiment. Animal toxicity tests support the clinical evidence with regard to renal and cardiac disorders (bradycardia and QT prolongation) and do not disprove the metabolic effect. Reduction of antibody production and cytokine induction and renal, metabolic, cardiac, and prolonged psychiatric disorders after oseltamivir use may be related to inhibition of the host’s endogenous neuraminidase. While the usual clinical dose of zanamivir may not have this effect, a higher dose or prolonged administration of zanamivir and other neuraminidase inhibitors may induce similar delayed reactions, including reduction of the antibody and/or cytokine production. PMID:27251370

Characterization of a new transmission detector for patient individualized online plan verification and its influence on 6MV X-ray beam characteristics.

PubMed

Thoelking, Johannes; Sekar, Yuvaraj; Fleckenstein, Jens; Lohr, Frank; Wenz, Frederik; Wertz, Hansjoerg

2016-09-01

Online verification and 3D dose reconstruction on daily patient anatomy have the potential to improve treatment delivery, accuracy and safety. One possible implementation is to recalculate dose based on online fluence measurements with a transmission detector (TD) attached to the linac. This study provides a detailed analysis of the influence of a new TD on treatment beam characteristics. The influence of the new TD on surface dose was evaluated by measurements with an Advanced Markus Chamber (Adv-MC) in the build-up region. Based on Monte Carlo simulations, correction factors were determined to scale down the over-response of the Adv-MC close to the surface. To analyze the effects beyond dmax percentage depth dose (PDD), lateral profiles and transmission measurements were performed. All measurements were carried out for various field sizes and different SSDs. Additionally, 5 IMRT-plans (head & neck, prostate, thorax) and 2 manually created test cases (3×3cm(2) fields with different dose levels, sweeping gap) were measured to investigate the influence of the TD on clinical treatment plans. To investigate the performance of the TD, dose linearity as well as dose rate dependency measurements were performed. With the TD inside the beam an increase in surface dose was observed depending on SSD and field size (maximum of +11%, SSD = 80cm, field size = 30×30cm(2)). Beyond dmax the influence of the TD on PDDs was below 1%. The measurements showed that the transmission factor depends slightly on the field size (0.893-0.921 for 5×5cm(2) to 30×30cm(2)). However, the evaluation of clinical IMRT-plans measured with and without the TD showed good agreement after using a single transmission factor (γ(2%/2mm) > 97%, δ±3% >95%). Furthermore, the response of TD was found to be linear and dose rate independent (maximum difference <0.5% compared to reference measurements). When placed in the path of the beam, the TD introduced a slight, clinically acceptable increase of the skin dose even for larger field sizes and smaller SSDs and the influence of the detector on the dose beyond dmax as well as on clinical IMRT-plans was negligible. Since there was no dose rate dependency and the response was linear, the device is therefore suitable for clinical use. Only its absorption has to be compensated during treatment planning, either by the use of a single transmission factor or by including the TD in the incident beam model. Copyright © 2015. Published by Elsevier GmbH.

Sci-Fri AM: MRI and Diagnostic Imaging - 02: Quality Improvement: Diagnostic Reference Levels for Interior Health CT exams – L-Spine, Chest/Abdomen/pelvis, Abdomen/Pelvis, Head

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bjarnason, Thorarin

Diagnostic Reference Levels are used to optimize patient dose and image quality in the clinical setting. It is assumed that the majority of exams are of diagnostic quality, or the radiologists would request protocol adjustments. By investigating the dose indicator distributions from all scanners, the upper DRL can be set to the 75th percentile of the distribution and a lower DRL can be set to the 10th percentile. Scanners using doses consistently outside the upper/lower DRL range can be adjusted accordingly. 11 CT scanners, all contributing to the American College of Radiology Dose Index Registry (ACR DIR) were used inmore » this study. Dose indicator data were compiled from the ACR DIR data and local DRLs established. Scanners with median doses outside the upper/lower DRL were followed-up with. Using effective dose and exam volumes, collective dose was determined before and after protocol adjustments to evaluate the effect of this quality improvement effort. The quality initiative is complete for L-spine and Chest/Abdomen/Pelvis exams and only initial surveys were completed for Head and Abdomen/Pelvis examsg. Median Scanner Dose reductions were 8.8 and 4.9 % for L-spine and Chest/Abdomen/Pelvis exams, respectively, resulting with collective dose reductions of 0.7 and 3.2 person•Sv/yr. Follow-up is ongoing for Abdomen/Pelvis and Head exams.« less

In vivo dosimetry using a linear Mosfet-array dosimeter to determine the urethra dose in 125I permanent prostate implants.

PubMed

Bloemen-van Gurp, Esther J; Murrer, Lars H P; Haanstra, Björk K C; van Gils, Francis C J M; Dekker, Andre L A J; Mijnheer, Ben J; Lambin, Philippe

2009-01-01

In vivo dosimetry during brachytherapy of the prostate with (125)I seeds is challenging because of the high dose gradients and low photon energies involved. We present the results of a study using metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters to evaluate the dose in the urethra after a permanent prostate implantation procedure. Phantom measurements were made to validate the measurement technique, determine the measurement accuracy, and define action levels for clinical measurements. Patient measurements were performed with a MOSFET array in the urinary catheter immediately after the implantation procedure. A CT scan was performed, and dose values, calculated by the treatment planning system, were compared to in vivo dose values measured with MOSFET dosimeters. Corrections for temperature dependence of the MOSFET array response and photon attenuation in the catheter on the in vivo dose values are necessary. The overall uncertainty in the measurement procedure, determined in a simulation experiment, is 8.0% (1 SD). In vivo dose values were obtained for 17 patients. In the high-dose region (> 100 Gy), calculated and measured dose values agreed within 1.7% +/- 10.7% (1 SD). In the low-dose region outside the prostate (< 100 Gy), larger deviations occurred. MOSFET detectors are suitable for in vivo dosimetry during (125)I brachytherapy of prostate cancer. An action level of +/- 16% (2 SD) for detection of errors in the implantation procedure is achievable after validation of the detector system and measurement conditions.

Pharmacokinetic and pharmacodynamic drug interactions of carbamazepine and glibenclamide in healthy albino Wistar rats

PubMed Central

Prashanth, S.; Kumar, A. Anil; Madhu, B.; Rama, N.; Sagar, J. Vidya

2011-01-01

Aims: To find out the pharmacokinetic and pharmacodynamic drug interaction of carbamazepine, a protype drug used to treat painful diabetic neuropathy with glibenclamide in healthy albino Wistar rats following single and multiple dosage treatment. Materials and Methods: Therapeutic doses (TD) of glibenclamide and TD of carbamazepine were administered to the animals. The blood glucose levels were estimated by GOD/POD method and the plasma glibenclamide concentrations were estimated by a sensitive RP HPLC method to calculate pharmacokinetic parameters. Results: In single dose study the percentage reduction of blood glucose levels and glibenclamide concentrations of rats treated with both carbamazepine and glibenclamide were significantly increased when compared with glibenclamide alone treated rats and the mechanism behind this interaction may be due to inhibition of P-glycoprotein mediated transport of glibenclamide by carbamazepine, but in multiple dose study the percentage reduction of blood glucose levels and glibenclamide concentrations were reduced and it may be due to inhibition of P-glycoprotein mediated transport and induction of CYP2C9, the enzyme through which glibenclamide is metabolised. Conclusions: In the present study there is a pharmacokinetic and pharmacodynamic interaction between carbamazepine and glibenclamide was observed. The possible interaction involves both P-gp and CYP enzymes. To investigate this type of interactions pre-clinically are helpful to avoid drug-drug interactions in clinical situation. PMID:21701639

Impact of gastroesophageal reflux control through tailored proton pump inhibition therapy or fundoplication in patients with Barrett's esophagus.

PubMed

Baldaque-Silva, Francisco; Vieth, Michael; Debel, Mumen; Håkanson, Bengt; Thorell, Anders; Lunet, Nuno; Song, Huan; Mascarenhas-Saraiva, Miguel; Pereira, Gisela; Lundell, Lars; Marschall, Hanns-Ulrich

2017-05-07

To determine the impact of upwards titration of proton pump inhibition (PPI) on acid reflux, symptom scores and histology, compared to clinically successful fundoplication. Two cohorts of long-segment Barrett's esophagus (BE) patients were studied. In group 1 ( n = 24), increasing doses of PPI were administered in 8-wk intervals until acid reflux normalization. At each assessment, ambulatory 24 h pH recording, endoscopy with biopsies and symptom scoring (by a gastroesophageal reflux disease health related quality of life questionnaire, GERD/HRLQ) were performed. Group 2 ( n = 30) consisted of patients with a previous fundoplication. In group 1, acid reflux normalized in 23 of 24 patients, resulting in improved GERD/HRQL scores ( P = 0.001), which were most pronounced after the starting dose of PPI ( P < 0.001). PPI treatment reached the same level of GERD/HRQL scores as after a clinically successful fundoplication ( P = 0.5). Normalization of acid reflux in both groups was associated with reduction in papillary length, basal cell layer thickness, intercellular space dilatation, and acute and chronic inflammation of squamous epithelium. This study shows that acid reflux and symptom scores co-vary throughout PPI increments in long-segment BE patients, especially after the first dose of PPI, reaching the same level as after a successful fundoplication. Minor changes were found among GERD markers at the morphological level.

A randomized clinical trial comparing metabolic parameters after 48 weeks of standard- and low-dose stavudine therapy and tenofovir disoproxil fumarate therapy in HIV-infected South African patients.

PubMed

Menezes, C N; Crowther, N J; Duarte, R; Van Amsterdam, D; Evans, D; Dickens, C; Dix-Peek, T; Rassool, M; Prinsloo, A; Raal, F; Sanne, I

2014-01-01

Low-dose stavudine therapy may have a lower toxicity profile compared with standard dose. A randomized controlled trial comparing these two doses of stavudine with tenofovir disoproxil fumarate (tenofovir DF) was performed to assess the effects on anthropometry, markers of inflammation, and lipid and glucose metabolism in Black South African patients. Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or tenofovir DF (300 mg), each combined with lamivudine and efavirenz, for 48 weeks. Anthropometry, markers of inflammation, and lipid and glucose metabolism were assessed using standard techniques. In all three treatment arms, there was a significant increase in lipid levels over the study period. At 48 weeks, fasting glucose level (P < 0.005) and homeostasis model assessment (HOMA) score (P < 0.05) increased significantly in the standard-dose stavudine arm, as did insulin and C-peptide levels in both the standard- and low-dose stavudine arms. At week 48, a significant decrease (P < 0.05) in adiponectin was noted in the standard-dose stavudine arm, but there was an increase (P < 0.005) in the tenofovir DF arm. In both the stavudine arms, significant increases in anthropometric measures occurred at 24 weeks but these decreased by week 48. Mitochondrial toxicities occurred in both the stavudine arms. Immunological and virological outcomes were similar for all three arms. This study highlights the occurrence of metabolic abnormalities with both stavudine and tenofovir DF treatment. Awareness of the potential increased cardiovascular risk should be of concern with the use of both these therapies. © 2013 British HIV Association.

Impact of Paclitaxel Dose on Tissue Pharmacokinetics and Vascular Healing: A Comparative Drug-Coated Balloon Study in the Familial Hypercholesterolemic Swine Model of Superficial Femoral In-Stent Restenosis.

PubMed

Gongora, Carlos A; Shibuya, Masahiko; Wessler, Jeffrey D; McGregor, Jenn; Tellez, Armando; Cheng, Yanping; Conditt, Gerard B; Kaluza, Greg L; Granada, Juan F

2015-07-01

This study sought to compare the effect of paclitaxel-coated balloon (PCB) concentration on tissue levels and vascular healing using 3 different PCB technologies (In.Pact Pacific = 3 μg/mm(2), Lutonix = 2 μg/mm(2) and Ranger = 2 μg/mm(2)) in the experimental setting. The optimal therapeutic dose for PCB use has not been determined yet. Paclitaxel tissue levels were measured up to 60 days following PCB inflation (Ranger and In.Pact Pacific) in the superficial femoral artery of healthy swine (18 swine, 36 vessels). The familial hypercholesterolemic swine model of superficial femoral artery in-stent restenosis (6 swine, 24 vessels) was used in the efficacy study. Two weeks following bare-metal stent implantation, each in-stent restenosis site was randomly treated with a PCB or an uncoated control balloon (Sterling). Quantitative vascular analysis and histology evaluation was performed 28 days following PCB treatment. All PCB technologies displayed comparable paclitaxel tissue levels 4 h following balloon inflation. At 28 days, all PCB had achieved therapeutic tissue levels; however, the In.Pact PCB resulted in higher tissue concentrations than did the other PCB groups at all time points. Neointimal inhibition by histology was decreased in all PCB groups compared with the control group, with a greater decrease in the In.Pact group. However, the neointima was more mature and contained less peri-strut fibrin deposits in both 2-μg/mm(2) PCB groups. Compared with the clinically established PCB dose, lower-dose PCB technologies achieve lower long-term tissue levels but comparable degrees of neointimal inhibition and fewer fibrin deposits. The impact of these findings in restenosis reduction and clinical outcomes needs to be further investigated. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.

PubMed

Teinturier, C; Hartmann, O; Valteau-Couanet, D; Benhamou, E; Bougneres, P F

1998-11-01

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Sustained remission of Cushing's disease with mitotane and pituitary irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schteingart, D.E.; Tsao, H.S.; Taylor, C.I.

1980-05-01

Low doses of mitotane were given orally to 36 patients with Cushing's disease, concurrently with or after pituitary cobalt irradiation. Clinical and biochemical remission occurred in 29. The response to treatment occurred early in 17 patients and late in 12. The different pattern of response to mitotane was not related to the dose given or to its serum level. Early biochemical indicators of adrenal suppression with mitotane were a sharp decrease in adrenal response to the infusion of ACTH and in plasma levels of dehydroepiandrosterone sulfate. Although mitotane was given together with pituitary irradiation, initial remission was due mainly tomore » the adrenal effect of mitotane. Plasma ACTH levels were still elevated when cortisol had returned to normal. In seventeen of the 29 patients who responded to treatment drug therapy has been discontinued, and they remain in remission of Cushing's syndrome. Side-effects have been dose dependent, with anorexia, nausea, decreased memory, and gynecomastia in men being the commonest.« less

DETERMINATION OF NATIONAL DIAGNOSTIC REFERENCE LEVELS IN COMPUTED TOMOGRAPHY EXAMINATIONS OF IRAN BY A NEW QUALITY CONTROL-BASED DOSE SURVEY METHOD.

PubMed

Sohrabi, Mehdi; Parsi, Masoumeh; Mianji, Fereidoun

2018-05-01

National diagnostic reference levels (NDRLs) of Iran were determined for the four most common CT examinations including head, sinus, chest and abdomen/pelvis. A new 'quality control (QC)-based dose survey method', as developed by us, was applied to 157 CT scanners in Iran (2014-15) with different slice classes, models and geographic spread across the country. The NDRLs for head, sinus, chest and abdomen/pelvis examinations are 58, 29, 12 and 14 mGy for CTDIVol and 750, 300, 300 and 650 mGy.cm for DLP, respectively. The 'QC-based dose survey method' was further proven that it is a simple, accurate and practical method for a time and cost-effective NDRLs determination. One effective approach for optimization of the CT examination protocols at the national level is the provision of an adequate standardized training of the radiologists, technicians and medical physicists on the patient radiation protection principles and implementation of the DRL concept in clinical practices.

Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study).

PubMed

Friedman, A B; Brown, S J; Bampton, P; Barclay, M L; Chung, A; Macrae, F A; McKenzie, J; Reynolds, J; Gibson, P R; Hanauer, S B; Sparrow, M P

2018-04-01

Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x10 8 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity. © 2018 John Wiley & Sons Ltd.

SU-F-J-64: Comparison of Dosimetric Robustness Between Proton Therapy and IMRT Plans Following Tumor Regression for Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teng, C; Ainsley, C; Teo, B

Purpose: In the light of tumor regression and normal tissue changes, dose distributions can deviate undesirably from what was planned. As a consequence, replanning is sometimes necessary during treatment to ensure continued tumor coverage or to avoid overdosing organs at risk (OARs). Proton plans are generally thought to be less robust than photon plans because of the proton beam’s higher sensitivity to changes in tissue composition, suggesting also a higher likely replanning rate due to tumor regression. The purpose of this study is to compare dosimetric deviations between forward-calculated double scattering (DS) proton plans with IMRT plans upon tumor regression,more » and assesses their impact on clinical replanning decisions. Methods: Ten consecutive locally advanced NSCLC patients whose tumors shrank > 50% in volume and who received four or more CT scans during radiotherapy were analyzed. All the patients received proton radiotherapy (6660 cGy, 180 cGy/fx). Dosimetric robustness during therapy was characterized by changes in the planning objective metrics as well as by point-by-point root-mean-squared differences for the entire PTV, ITV, and OARs (heart, cord, esophagus, brachial plexus and lungs) DVHs. Results: Sixty-four pairs of DVHs were reviewed by three clinicians, who requested a replanning rate of 16.7% and 18.6% for DS and IMRT plans, respectively, with a high agreement between providers. Robustness of clinical indicators was found to depend on the beam orientation and dose level on the DVH curve. Proton dose increased most in OARs distal to the PTV along the beam path, but these changes were primarily in the mid to low dose levels. In contrast, the variation in IMRT plans occurred primarily in the high dose region. Conclusion: Robustness of clinical indicators depends where on the DVH curves comparisons are made. Similar replanning rates were observed for DS and IMRT plans upon large tumor regression.« less

Methodological improvements in quantifying cognitive change in clinical trials: an example with single-dose administration of donepezil.

PubMed

Pietrzak, R H; Maruff, P; Snyder, P J

2009-03-01

Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer's disease (AD). Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day. Early phase I clinical trial. 15 healthy older adults; 14 older adults with mild Alzheimer's disease. Single acute dose of 5mg donepezil. Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring. A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing). The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.

Hepatitis C virus RNA elimination and development of resistance in replicon cells treated with BMS-790052.

PubMed

Wang, Chunfu; Huang, Haichang; Valera, Lourdes; Sun, Jin-Hua; O'Boyle, Donald R; Nower, Peter T; Jia, Lingling; Qiu, Dike; Huang, Xin; Altaf, Aneela; Gao, Min; Fridell, Robert A

2012-03-01

BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 to 5. This exceptional potency translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped to the N-terminal region of NS5A. To further characterize the antiviral activity of BMS-790052, HCV replicon elimination and colony formation assays were performed. Replicon was cleared from genotype 1a and 1b replicon cells in a time- and dose-dependent manner. Elimination of the genotype 1a replicon required longer treatment durations and higher concentrations of BMS-790052 than those for the genotype1b replicon. Single amino acid substitutions that conferred relatively low levels of resistance were observed at early time points and at low doses. Higher doses and longer treatment durations yielded mutations that conferred greater levels of resistance, including linked amino acid substitutions. Replicon cells that survived inhibitor treatment remained fully sensitivity to pegylated alpha interferon (pegIFN-α) and other HCV inhibitors. Moreover, genotype 1a replicon elimination was markedly enhanced when pegIFN-α and BMS-790052 were combined. Resistant variants observed in this study were very similar to those observed in a multiple ascending dose (MAD) monotherapy trial of BMS-790052, validating replicon elimination studies as a model to predict clinical resistance. Insights gained from the in vitro anti-HCV activity and resistance profiles of BMS-790052 will be used to help guide the clinical development of this novel HCV inhibitor.

Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization

PubMed Central

Kim, Edwin H.; Bird, J. Andrew; Kulis, Michael; Laubach, Susan; Pons, Laurent; Shreffler, Wayne; Steele, Pamela; Kamilaris, Janet; Vickery, Brian; Burks, A. Wesley

2011-01-01

Background There are no treatments currently available for peanut allergy. Sublingual immunotherapy is a novel approach to the treatment of peanut allergy. Objective To investigate the safety, clinical effectiveness and immunologic changes with sublingual immunotherapy in peanut-allergic children. Methods In this double-blind, placebo-controlled study, subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind, placebo-controlled food challenge. Results Eighteen children ages 1 to 11 years completed 12 months of dosing and the food challenge. Dosing side effects were primarily oropharyngeal and uncommonly required treatment. During the double-blind, placebo-controlled food challenge, the treatment group safely ingested 20 times more peanut protein than the placebo group (median 1710 mg vs. 85 mg, p=0.011). Mechanistic studies demonstrated a decrease in prick skin test wheal size (p=0.020) and decreased basophil responsiveness after stimulation with 10−2 mcg/ml (p=0.009) and 10−3 mcg/ml (p=0.009) of peanut. Peanut-specific IgE increased over the initial 4 months (p=0.002) then steadily decreased over the remaining 8 months (p=0.003) while peanut-specific IgG4 increased during the 12 months (p=0.014). Lastly, IL-5 levels decreased after 12 months (p=0.015). No statistically significant changes were found in IL-13 levels, the percent of T regulatory cells, or IL-10 and IFN-gamma production. Conclusion Peanut sublingual immunotherapy is able to safely induce clinical desensitization in peanut allergic children with evidence of immunologic changes suggesting a significant change in the allergic response. Further study is required to determine if continued peanut sublingual immunotherapy is able to induce long-term immune tolerance. PMID:21281959

SU-E-T-509: Validation of the Use of OSLD for Carbon Beam Remote Dosimetry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Summers, P; Lowenstein, J; Alvarez, P

2014-06-01

Purpose: To describe the commissioning of Aluminum Oxide Optically Stimulated Luminescent Dosimeters (OSLD) for the use in Carbon beam remote dosimetry for centers participating in NCI-funded cooperative group clinical trials. Methods: As Carbon therapy centers express interest in participating in cooperative group clinical trials, the Imaging and Radiation Oncology Core Group (IROC) Houston QA Center (formerly RPC) is developing a way to remotely monitor the machine output of these Carbon facilities. OSLD have been commissioned for photon, electron and proton dosimetry, so an experiment was designed to commission the same dosimeters for Carbon. OSLD were irradiated in a Carbon therapymore » beam produced by the Siemens synchrotron at the Heidelberg Ion Therapy facility in Heidelberg, Germany. The OSLD were placed in acrylic phantoms, imaged with a CT scanner, and plans were developed using the Siemens treatment planning system. The OSLD were irradiated in uniform fields with maximum energies of 216, 301, and 402 MeV and at dose levels of 50, 100, 200 and 300 cGy. Results: The response of the OSLD in the Carbon beam, as compared to the Cobalt-60 reference condition, required an energy correction of 1.85 to account for the particle correction. OSLD dose calculations typically have a linearity correction to account for the change in response relative to the change in dose delivered. However, the response of the OSLD in the Carbon beam was found to be independent of the dose level; thus the linearity correction is 1.00. Conclusion: IROC Houston has commissioned OSLD for the use of remote output checks for Carbon therapy facilities to help ensure consistency across clinical trial participants. Work supported by grant CA10953 (NCI, DHHS)« less

Toxicokinetics and toxicity of atorvastatin in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herron, C.E.; Brueckner, C.C.; Chism, J.P.

HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose–exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemicmore » exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use. - Highlights: • Atorvastatin is given to reduce cholesterol and is available as a generic drug. • Co-dosing of multiple products to treat hypercholesterolemia is increasing. • This work characterized the toxicokinetics and toxicity of atorvastatin in dogs. • The toxicokinetics of two hydroxylated metabolites were determined. • Recommendations on the dose–exposure relationship in dog are provided.« less

Immunological Effect of aGV Rabies Vaccine Administered Using the Essen and Zagreb Regimens: A Double-Blind, Randomized Clinical Trial.

PubMed

Miao, Li; Shi, Liwei; Yang, Yi; Yan, Kunming; Sun, Hongliang; Mo, Zhaojun; Li, Li

2018-04-01

This study evaluated the immunological effect of an aGV rabies virus strain using the Essen and Zagreb immunization programs. A total of 1,944 subjects were enrolled and divided into three groups: the Essen test group, Essen control group, and Zagreb test group. Neutralizing antibody levels and antibody seroconversion rates were determined at 7 and 14 days after the initial inoculations and then 14 days after the final inoculation in all of the subjects. The seroconversion rates for the Essen test group, Essen control group, and Zagreb test group, which were assessed 7 days after the first dosing in a susceptible population, were 35.74%, 26.92%, and 45.49%, respectively, and at 14 days, the seroconversion rates in this population were 100%, 100%, and 99.63%, respectively. At 14 days after the final dosing, the seroconversion rates were 100% in all three of the groups. The neutralizing serum antibody levels of the Essen test group, Essen control group, and Zagreb test group at 7 days after the first dosing in the susceptible population were 0.37, 0.26, and 0.56 IU/mL, respectively, and at 14 days after the initial dosing, these levels were 16.71, 13.85, and 16.80 IU/mL. At 14 days after the final dosing, the neutralizing antibody levels were 22.9, 16.3, and 18.62 IU/mL, respectively. The results of this study suggested that the aGV rabies vaccine using the Essen program resulted in a good serum immune response, and the seroconversion rates and the neutralizing antibody levels generated with the Zagreb regimen were higher than those with the Essen regimen when measured 7 days after the first dose.

AUC versus peak-trough dosing of vancomycin: applying new pharmacokinetic paradigms to an old drug.

PubMed

Brown, Daniel L; Lalla, Christina D; Masselink, Andrew J

2013-08-01

To compare and contrast the pharmacokinetic/pharmacodynamic foundations of traditional "peak-trough" vancomycin dosing methods versus newer "area under the curve" (AUC) strategies. To propose a new AUC-based dosing chart for empirically determining an initial vancomycin dosing regimen designed to achieve a desired AUC24 using the minimum inhibitory concentration (MIC), creatinine clearance (CrCl), and vancomycin clearance (ClVanco). Peak-trough vancomycin dosing is designed to achieve a Cpeak of 20-40 mg/L and a Ctrough of 10-15 or 15-20 mg/L, depending on the severity of the infection and the nature of the pathogen. New treatment guidelines for vancomycin suggest that therapy should achieve an AUC24/MIC of ≥400. AUC-based vancomycin dosing derives the daily dose from ClVanco, MIC, and the desired AUC24/MIC, without consideration of the patient's weight. A vancomycin dosing chart is proposed that estimates ClVanco using the following formula developed by Matzke et al: ClVanco in L/h = [(CrClmL/min × 0.689) + 3.66] × 0.06, which simplifies to (CrClmL/min × 0.41) + 0.22. Two levels of dosing are included-high dose (Ctrough: 15-20 mg/L) and moderate dose (Ctrough: 10-15 mg/L). Although the chart has not been validated clinically, it represents the product of standard dosing equations that are used to determine a starting dosing regimen based on well-established vancomycin pharmacokinetic parameters. An understanding of pharmacokinetic and pharmacodynamic principles, including the relevance of AUC in relation to MIC, enables clinicians to make the best use of vancomycin dosing options. The proposed dosing chart is pharmacokinetically valid but has yet to be applied clinically. It provides a foundation for further study of how clinicians can determine an optimal AUC-based starting vancomycin dosing regimen without having to derive ClVanco or AUC24.

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study

PubMed Central

Rosenblad, Carl; af Edholm Arvidsson, Karolina; Wictorin, Klas; Keywood, Charlotte; Shankar, Bavani; Lowe, David A.; Björklund, Anders; Widner, Håkan

2015-01-01

In advanced stages of Parkinson’s disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson’s disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson’s disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson’s Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [–1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [–0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [–1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson’s Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson’s disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias. PMID:25669730

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

PubMed

Taylor, Hugh S; Giudice, Linda C; Lessey, Bruce A; Abrao, Mauricio S; Kotarski, Jan; Archer, David F; Diamond, Michael P; Surrey, Eric; Johnson, Neil P; Watts, Nelson B; Gallagher, J Chris; Simon, James A; Carr, Bruce R; Dmowski, W Paul; Leyland, Nicholas; Rowan, Jean P; Duan, W Rachel; Ng, Juki; Schwefel, Brittany; Thomas, James W; Jain, Rita I; Chwalisz, Kristof

2017-07-06

Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

Efficacy of two once-daily methylphenidate formulations compared across dose levels at different times of the day: preliminary indications from a secondary analysis of the COMACS study data.

PubMed

Sonuga-Barke, Edmund J S; Swanson, James M; Coghill, David; DeCory, Heleen H; Hatch, Simon J

2004-09-30

Methylphenidate (MPH) is commonly prescribed in the treatment of Attention-Deficit/Hyperactivity Disorder or ADHD. Concerta and Metadate CD are once-daily formulations of MPH using different delivery mechanisms resulting in different pharmacokinetic profiles. A recent study (COMACS) showed that for near-milligram (mg) equivalent daily doses, Metadate CD provides greater symptom control in the morning (1.5 through 4.5 hours post-dose), while Concerta provides greater control in the early evening (12 hours post-dose). Non-inferential comparison of effects for different dose levels of the two formulations suggested that equivalent levels of morning symptom control could be obtained with lower daily doses of Metadate CD than Concerta; the situation being reversed in the evening. The current paper presents a secondary analysis that provides a statistical test of these observations. The COMACS study was a multi-center, double-blind crossover study of Metadate CD, Concerta and placebo with each treatment administered for 1 week. Children were assigned on the basis of their pre-trial dosage to either high (Metadate CD 60 mg; Concerta 54 mg), medium (Metadate CD 40 mg; Concerta 36 mg) or low doses (Metadate CD 20 mg; Concerta 18 mg) of MPH, and attended a laboratory school on the 7th day for assessment at 7 sessions across the day. For the post-hoc comparisons across dose levels presented here, total SKAMP scores with the active treatments (adjusted for placebo response) were analyzed using an analysis of covariance, with a combined measure modeling placebo response across all time period as the covariate. Symptom control from 1.5 through 6.0 hours post-dose was as good with lower doses of Metadate CD (20 and 40 mg) as with higher doses of Concerta (36 and 54 mg, respectively). Lower daily doses of Concerta (18 and 36 mg) and higher doses of Metadate CD (40 and 60 mg, respectively) gave equivalent control at 7.5 and 12 hours with Metadate CD giving better control from1.5 through 6.0 hours post-dose. Different delivery profiles of Metadate CD and Concerta can be exploited to limit total daily exposure to MPH while at the same targeting a specific, especially clinically significant, period of the day. These results need to be confirmed in a study in which children are randomly allocated to different dose levels of the two formulations and plasma MPH concentrations are assessed simultaneously.

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent.

PubMed

Allen, Joshua E; Crowder, Roslyn N; Crowder, Roslyn; El-Deiry, Wafik S

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer.

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent

PubMed Central

Allen, Joshua E.; Crowder, Roslyn; El-Deiry, Wafik S.

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer. PMID:26580220

Chronic lead poisoning in horses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dollahite, J.W.; Younger, R.L.; Crookshank, H.R.

1978-06-01

Lead Acetate was fed to 4 groups of 2 horses each to study chronic lead intoxication. A 5th group of 3 horses was maintained as controls. The lead was fed in capsules, with the minimum dosage of 6.25 mg/kg/day of lead as lead acetate (group I). The dose was increased from group I through group IV in an approximate geometric series, with each group being given about 125% of the dose given the previous group. These doses were given for 105 days, a period designated as phase 1. Since clinical signs were not observed after 105 days, the doses weremore » increased and fed for an additional 190 days (days 106 to 295). This period was designated phase 2. The smallest daily dose in phase 2 was set at about 125% of the largest daily dose in phase 1. The doses in each group was increased by about 125% of that of the previous group, as was done in phase 1. Seven horses died or were euthanatized after 18 to 190 days of phase 2 (123 to 295 days after the 1st dose). One horse in group I did not develop any clinical signs of intoxication. Dose-related responses were unnoticed with doses larger than 15.3 mg/kg/day. All horses given lead had increased blood lead and serum iron concentrations. During phase 2, the hematocrit and hemoglobin contents were depressed. The lead concentration in kidney, liver, spleen, pancreas, brain, bone, and heart was increased in the treated horses. The dose level required to produce lead intoxication was greater than that reported for cattle and that estimated in epizootiologic studies of horses.« less

Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

PubMed

Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

2016-05-01

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract

PubMed Central

Atwell, Lauren L.; Hsu, Anna; Wong, Carmen P.; Stevens, Jan F.; Bella, Deborah; Yu, Tian-Wei; Pereira, Clifford B.; Löhr, Christiane V.; Christensen, John Mark; Dashwood, Roderick H.; Williams, David E.; Shannon, Jackilen; Ho, Emily

2015-01-01

Scope Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults. Methods and results Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 μmol SFN daily, as a single dose and as two 100-μmol doses taken 12 h apart. Using HPLC-MS/MS, we detected ~3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21). Conclusion We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials. PMID:25522265

Physics of vascular brachytherapy.

PubMed

Jani, S K

1999-08-01

Basic physics plays an important role in understanding the clinical utility of radioisotopes in brachytherapy. Vascular brachytherapy is a very unique application of localized radiation in that dose levels very close to the source are employed to treat tissues within the arterial wall. This article covers basic physics of radioactivity and differentiates between beta and gamma radiations. Physical parameters such as activity, half-life, exposure and absorbed dose have been explained. Finally, the dose distribution around a point source and a linear source is described. The principles of basic physics are likely to play an important role in shaping the emerging technology and its application in vascular brachytherapy.

A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations.

PubMed

Fiedler, Walter; Kayser, Sabine; Kebenko, Maxim; Janning, Melanie; Krauter, Jürgen; Schittenhelm, Marcus; Götze, Katharina; Weber, Daniela; Göhring, Gudrun; Teleanu, Veronica; Thol, Felicitas; Heuser, Michael; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut; Schlenk, Richard F

2015-06-01

Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara-C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara-C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity (DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level -1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones. © 2015 John Wiley & Sons Ltd.

Persistent increase of blood lead level and suppression of δ-ALAD activity in northern bobwhite quail orally dosed with even a single 2-mm spent lead shot.

PubMed

Holladay, S D; Kerr, R; Holladay, J P; Meldrum, B; Williams, S M; Gogal, R M

2012-10-01

Birds that display grit ingestion behavior are potentially at risk of lead (Pb) poisoning from mistaken ingestion of spent Pb shot pellets. The majority of available studies designed to assess such risk have used unspent shot pellets rather than field-obtained spent shot, which is oxidized and otherwise changed by weathering. Available studies also often administered more or heavier shot pellets to a bird than it might be expected to ingest. The current study dosed northern bobwhite quail (Colinus virginianus) weighing 194.6 ± 23.1 g (female birds) and 199.3 ± 12.2 g (male birds) with one to three spent no. 9 Pb shot collected from a skeet range, with particular interest in the toxicity that may occur from ingestion of a single 2-mm, 50 mg shot. An 8 week post-dosing clinical observation period was employed, over which feed consumption, body weight, blood Pb levels, and a battery of blood physiological parameters were made. Weight loss occurred in the birds, including male birds dosed with one Pb pellet. Erythrocyte delta aminolevulinic acid dehydratase (δ-ALAD) levels were decreased for the duration of the study across exposures and to levels associated with injury in wild bird populations. Decreased ALAD was particularly severe in female birds dosed with one Pb pellet and was still 92 % decreased at 8 weeks after dosing. Together, these results suggest that inadvertent ingestion of a single no. 9 Pb shot pellet can adversely affect the health of northern bobwhite quail.

Effect of agomelatine treatment on C-reactive protein levels in patients with major depressive disorder: an exploratory study in "real-world," everyday clinical practice.

PubMed

De Berardis, Domenico; Fornaro, Michele; Orsolini, Laura; Iasevoli, Felice; Tomasetti, Carmine; de Bartolomeis, Andrea; Serroni, Nicola; De Lauretis, Ida; Girinelli, Gabriella; Mazza, Monica; Valchera, Alessandro; Carano, Alessandro; Vellante, Federica; Matarazzo, Ilaria; Perna, Giampaolo; Martinotti, Giovanni; Di Giannantonio, Massimo

2017-08-01

Agomelatine is a newer antidepressant but, to date, no studies have been carried out investigating its effects on C-reactive protein (CRP) levels in major depressive disorder (MDD) before and after treatment. The present study aimed (i) to investigate the effects of agomelatine treatment on CRP levels in a sample of patients with MDD and (ii) to investigate if CRP variations were correlated with clinical improvement in such patients. 30 adult outpatients (12 males, 18 females) with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of MDD were recruited in "real-world," everyday clinical practice and treated with a flexible dose of agomelatine for 12 weeks. The Hamilton Rating Scale for Depression (HAM-D) and the Snaith-Hamilton Pleasure Scale (SHAPS) were used to evaluate depressive symptoms and anhedonia, respectively. Moreover, serum CRP was measured at baseline and after 12 weeks of treatment. Agomelatine was effective in the treatment of MDD, with a significant reduction in HAM-D and SHAPS scores from baseline to endpoint. CRP levels were reduced in the whole sample, with remitters showing a significant difference in CRP levels after 12 weeks of agomelatine. A multivariate stepwise linear regression analysis showed that higher CRP level variation was associated with higher baseline HAM-D scores, controlling for age, gender, smoking, BMI, and agomelatine dose. Agomelatine's antidepressant properties were associated with a reduction in circulating CRP levels in MDD patients who achieved remission after 12 weeks of treatment. Moreover, more prominent CRP level variation was associated with more severe depressive symptoms at baseline.

Randomized clinical trial to comparing efficacy of daily, weekly and monthly administration of vitamin D3.

PubMed

Takács, István; Tóth, Béla E; Szekeres, László; Szabó, Boglárka; Bakos, Bence; Lakatos, Péter

2017-01-01

The comparative efficacy and safety profiles of selected daily 1000 IU, weekly 7000 IU and monthly 30,000 IU vitamin D 3 -not previously investigated-will be evaluated. Here, a prospective, randomized clinical trial, comparing efficacy and safety of a daily single dose of 1000 IU (group A) to a once-weekly 7000 IU dose (group B), or monthly 30,000 IU dose (group C) of vitamin D 3 . The present study is a controlled, randomized, open-label, multicenter clinical trial, 3  months in duration. Sixty-four adult subjects with vitamin D deficiency (25OHD<20 ng/ml), were included according to the inclusion and exclusion criteria. Dose-responses for increases in serum vitamin 25OHD were statistically equivalent for each of the three groups: A, B and C. Outcomes were 13.0 ± 1.5; 12.6 ± 1.1 and 12.9 ± 0.9 ng/ml increases in serum 25OHD per 1000 IU, daily, weekly and monthly, respectively. The treatment of subjects with selected doses restored 25OHD values to levels above 20 ng/ml in all groups. Treatment with distinct administration frequency of vitamin D 3 did not exhibit any differences in safety parameters. The daily, weekly and monthly administrations of daily equivalent of 1000 IU of vitamin D 3 provide equal efficacy and safety profiles.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

PubMed

Kloprogge, Frank; Workman, Lesley; Borrmann, Steffen; Tékété, Mamadou; Lefèvre, Gilbert; Hamed, Kamal; Piola, Patrice; Ursing, Johan; Kofoed, Poul Erik; Mårtensson, Andreas; Ngasala, Billy; Björkman, Anders; Ashton, Michael; Friberg Hietala, Sofia; Aweeka, Francesca; Parikh, Sunil; Mwai, Leah; Davis, Timothy M E; Karunajeewa, Harin; Salman, Sam; Checchi, Francesco; Fogg, Carole; Newton, Paul N; Mayxay, Mayfong; Deloron, Philippe; Faucher, Jean François; Nosten, François; Ashley, Elizabeth A; McGready, Rose; van Vugt, Michele; Proux, Stephane; Price, Ric N; Karbwang, Juntra; Ezzet, Farkad; Bakshi, Rajesh; Stepniewska, Kasia; White, Nicholas J; Guerin, Philippe J; Barnes, Karen I; Tarning, Joel

2018-06-01

The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Intraperitoneal Vancomycin Concentrations During Peritoneal Dialysis–Associated Peritonitis: Correlation with Serum Levels

PubMed Central

Fish, Richard; Nipah, Robert; Jones, Chris; Finney, Hazel; Fan, Stanley L.S.

2012-01-01

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally. ♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels. ♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R2 = 0.18). ♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children). PMID:22045102

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast.

PubMed

Miller, Jessica A; Thompson, Patricia A; Hakim, Iman A; Lopez, Ana Maria; Thomson, Cynthia A; Chew, Wade; Hsu, Chiu-Hsieh; Chow, H-H Sherry

2012-10-01

Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing. We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy. We conducted a mouse disposition study to determine whether limonene would be bio available in the mammary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also conducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination. The mouse disposition study showed that topical and oral orange oil administration resulted in similar mammary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application. Our studies showed that limonene is bio available in mammary tissue after topical orange oil application in mice and this novel route of administration to the breast is safe and feasible in healthy women.

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast

PubMed Central

Miller, Jessica A.; Thompson, Patricia A.; Hakim, Iman A.; Lopez, Ana Maria; Thomson, Cynthia A.; Chew, Wade; Hsu, Chiu-Hsieh; Chow, H.-H. Sherry

2013-01-01

Background Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing. We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy. Materials and Methods We conducted a mouse disposition study to determine whether limonene would be bio available in the mammary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also conducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination. Results The mouse disposition study showed that topical and oral orange oil administration resulted in similar mammary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application. Conclusions Our studies showed that limonene is bio available in mammary tissue after topical orange oil application in mice and this novel route of administration to the breast is safe and feasible in healthy women. PMID:24236248

Pharmacogenomics of warfarin in populations of African descent.

PubMed

Suarez-Kurtz, Guilherme; Botton, Mariana R

2013-02-01

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These 'Black' populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are 'friendly' enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity.

PubMed

Mennenga, Sarah E; Gerson, Julia E; Koebele, Stephanie V; Kingston, Melissa L; Tsang, Candy W S; Engler-Chiurazzi, Elizabeth B; Baxter, Leslie C; Bimonte-Nelson, Heather A

2015-04-01

Ethinyl Estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. We evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory as well as basal forebrain cholinergic integrity using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; tonic delivery of low EE, a dose that corresponds to the most popular doses used in the clinic today, did not impact cognition on any measure. Both medium and high injection doses of EE reduced the number of ChAt-immunoreactive cells in the basal forebrain, and cell population estimates in the vertical/diagonal bands negatively correlated with working memory errors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

PubMed

Stott, David J; Rodondi, Nicolas; Kearney, Patricia M; Ford, Ian; Westendorp, Rudi G J; Mooijaart, Simon P; Sattar, Naveed; Aubert, Carole E; Aujesky, Drahomir; Bauer, Douglas C; Baumgartner, Christine; Blum, Manuel R; Browne, John P; Byrne, Stephen; Collet, Tinh-Hai; Dekkers, Olaf M; den Elzen, Wendy P J; Du Puy, Robert S; Ellis, Graham; Feller, Martin; Floriani, Carmen; Hendry, Kirsty; Hurley, Caroline; Jukema, J Wouter; Kean, Sharon; Kelly, Maria; Krebs, Danielle; Langhorne, Peter; McCarthy, Gemma; McCarthy, Vera; McConnachie, Alex; McDade, Mairi; Messow, Martina; O'Flynn, Annemarie; O'Riordan, David; Poortvliet, Rosalinde K E; Quinn, Terence J; Russell, Audrey; Sinnott, Carol; Smit, Jan W A; Van Dorland, H Anette; Walsh, Kieran A; Walsh, Elaine K; Watt, Torquil; Wilson, Robbie; Gussekloo, Jacobijn

2017-06-29

The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

PubMed

van den Eertwegh, Alfons J M; Versluis, Jurjen; van den Berg, H Pieter; Santegoets, Saskia J A M; van Moorselaar, R Jeroen A; van der Sluis, Tim M; Gall, Helen E; Harding, Thomas C; Jooss, Karin; Lowy, Israel; Pinedo, Herbert M; Scheper, Rik J; Stam, Anita G M; von Blomberg, B Mary E; de Gruijl, Tanja D; Hege, Kristen; Sacks, Natalie; Gerritsen, Winald R

2012-05-01

The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam. Copyright © 2012 Elsevier Ltd. All rights reserved.

Clinical concerns of immunogenicity produced at cellular levels by biopharmaceuticals following their parenteral administration into human body.

PubMed

Tamilvanan, Shunmugaperumal; Raja, Natarajan Livingston; Sa, Biswanath; Basu, Sanat Kumar

2010-08-01

Similar to the low molecular weight traditional drugs, biopharmaceuticals are capable of producing not only therapeutic effects but also side effects provided if the dose of these compounds exceeds certain concentration and/or if the exposure duration of these compounds at subtoxic doses is being lengthened. In addition, a major drawback of biopharmaceuticals is the risk of antibody formation. Following the administration of biopharmaceuticals into human body, the formation of antidrug-antibody (ADA) or neutralizing antibody and other general immune system effects (including allergy, anaphylaxis, or serum sickness) are of clinical concern regarding therapeutic efficacy and patient safety. For example, drug-induced neutralizing antibodies to erythropoietin (EPO) result in pure red cell aplasia, whereas drug-induced acquired anti-factor VIII antibodies worsen the pathology associated with hemophilia. Since most of the already developed or under development biopharmaceuticals are to some extent immunogenic, the regulatory agencies insist to conduct potential ADA formation during the drug development process itself. This review encompasses a short overview on the clinical concerns of immunogenicity produced at cellular levels by growth hormone, interferon-alpha, EPO, factor VIII, and factor IX following their parenteral administration into human body. Clinical concerns related to immunogenicity produced by the biosimilar versions of these drugs are also presented wherever possible.

Reproducibility of three-dimensional cephalometric landmarks in cone-beam and low-dose computed tomography.

PubMed

Olszewski, R; Frison, L; Wisniewski, M; Denis, J M; Vynckier, S; Cosnard, G; Zech, F; Reychler, H

2013-01-01

The purpose of this study is to compare the reproducibility of three-dimensional cephalometric landmarks on three-dimensional computed tomography (3D-CT) surface rendering using clinical protocols based on low-dose (35-mAs) spiral CT and cone-beam CT (I-CAT). The absorbed dose levels for radiosensitive organs in the maxillofacial region during exposure in both 3D-CT protocols were also assessed. The study population consisted of ten human dry skulls examined with low-dose CT and cone-beam CT. Two independent observers identified 24 cephalometric anatomic landmarks at 13 sites on the 3D-CT surface renderings using both protocols, with each observer repeating the identification 1 month later. A total of 1,920 imaging measurements were performed. Thermoluminescent dosimeters were placed at six sites around the thyroid gland, the submandibular glands, and the eyes in an Alderson phantom to measure the absorbed dose levels. When comparing low-dose CT and cone-beam CT protocols, the cone-beam CT protocol proved to be significantly more reproducible for four of the 13 anatomical sites. There was no significant difference between the protocols for the other nine anatomical sites. Both low-dose and cone-beam CT protocols were equivalent in dose absorption to the eyes and submandibular glands. However, thyroid glands were more irradiated with low-dose CT. Cone-beam CT was more reproducible and procured less irradiation to the thyroid gland than low-dose CT. Cone-beam CT should be preferred over low-dose CT for developing three-dimensional bony cephalometric analyses.

A retrospective analysis for patient-specific quality assurance of volumetric-modulated arc therapy plans.

PubMed

Li, Guangjun; Wu, Kui; Peng, Guang; Zhang, Yingjie; Bai, Sen

2014-01-01

Volumetric-modulated arc therapy (VMAT) is now widely used clinically, as it is capable of delivering a highly conformal dose distribution in a short time interval. We retrospectively analyzed patient-specific quality assurance (QA) of VMAT and examined the relationships between the planning parameters and the QA results. A total of 118 clinical VMAT cases underwent pretreatment QA. All plans had 3-dimensional diode array measurements, and 69 also had ion chamber measurements. Dose distribution and isocenter point dose were evaluated by comparing the measurements and the treatment planning system (TPS) calculations. In addition, the relationship between QA results and several planning parameters, such as dose level, control points (CPs), monitor units (MUs), average field width, and average leaf travel, were also analyzed. For delivered dose distribution, a gamma analysis passing rate greater than 90% was obtained for all plans and greater than 95% for 100 of 118 plans with the 3%/3-mm criteria. The difference (mean ± standard deviation) between the point doses measured by the ion chamber and those calculated by TPS was 0.9% ± 2.0% for all plans. For all cancer sites, nasopharyngeal carcinoma and gastric cancer have the lowest and highest average passing rates, respectively. From multivariate linear regression analysis, the dose level (p = 0.001) and the average leaf travel (p < 0.001) showed negative correlations with the passing rate, and the average field width (p = 0.003) showed a positive correlation with the passing rate, all indicating a correlation between the passing rate and the plan complexity. No statistically significant correlation was found between MU or CP and the passing rate. Analysis of the results of dosimetric pretreatment measurements as a function of VMAT plan parameters can provide important information to guide the plan parameter setting and optimization in TPS. Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.

PubMed

Osterman, Mark T; Aberra, Faten N; Cross, Raymond; Liakos, Steven; McCabe, Robert; Shafran, Ira; Wolf, Douglas; Hardi, Robert; Nessel, Lisa; Brensinger, Colleen; Gilroy, Erin; Lewis, James D

2014-11-01

Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 μg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 μg/g. Secondary outcomes were continued remission with FC <100 μg/g or <200 μg/g (among patients with pre-randomization values above these levels). The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 μg/g (P = .04) and 200 μg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 μg/g compared with those with FC <200 μg/g (P = .01). Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

A retrospective analysis for patient-specific quality assurance of volumetric-modulated arc therapy plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Guangjun; Wu, Kui; Peng, Guang

2014-01-01

Volumetric-modulated arc therapy (VMAT) is now widely used clinically, as it is capable of delivering a highly conformal dose distribution in a short time interval. We retrospectively analyzed patient-specific quality assurance (QA) of VMAT and examined the relationships between the planning parameters and the QA results. A total of 118 clinical VMAT cases underwent pretreatment QA. All plans had 3-dimensional diode array measurements, and 69 also had ion chamber measurements. Dose distribution and isocenter point dose were evaluated by comparing the measurements and the treatment planning system (TPS) calculations. In addition, the relationship between QA results and several planning parameters,more » such as dose level, control points (CPs), monitor units (MUs), average field width, and average leaf travel, were also analyzed. For delivered dose distribution, a gamma analysis passing rate greater than 90% was obtained for all plans and greater than 95% for 100 of 118 plans with the 3%/3-mm criteria. The difference (mean ± standard deviation) between the point doses measured by the ion chamber and those calculated by TPS was 0.9% ± 2.0% for all plans. For all cancer sites, nasopharyngeal carcinoma and gastric cancer have the lowest and highest average passing rates, respectively. From multivariate linear regression analysis, the dose level (p = 0.001) and the average leaf travel (p < 0.001) showed negative correlations with the passing rate, and the average field width (p = 0.003) showed a positive correlation with the passing rate, all indicating a correlation between the passing rate and the plan complexity. No statistically significant correlation was found between MU or CP and the passing rate. Analysis of the results of dosimetric pretreatment measurements as a function of VMAT plan parameters can provide important information to guide the plan parameter setting and optimization in TPS.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leichner, P.K.

This report summarizes research in beta-particle dosimetry, quantitative single-photon emission computed tomography (SPECT), the clinical implementation of these two areas of research in radioimmunotherapy (RIT), and postgraduate training provided since the inception of this grant on July 15, 1989. To improve beta-particle dosimetry, a point source function was developed that is valid for a wide range of beta emitters. Analytical solutions for beta-particle dose rates within out outside slabs of finite thickness were validated in experimental tumors and are now being used in clinical RIT. Quantitative SPECT based on the circular harmonic transform (CHT) algorithm was validated in phantom, experimental,more » and clinical studies. This has led to improved macrodosimetry in clinical RIT. In dosimetry at the multi-cellular level studies were made of the HepG2 human hepatoblastoma grown subcutaneously in nude mice. Histologic sections and autoradiographs were prepared to quantitate activity distributions of radiolabeled antibodies. Absorbed-dose calculations are being carried out for {sup 131}I and {sup 90}Y beta particles for these antibody distributions.« less

A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats.

PubMed

Cancel, Aida M; Dillberger, John E; Kelly, Catherine M; Bolte, Henry F; Creasy, Dianne M; Sokal, David C

2010-03-01

This study investigated if quinacrine can induce a tumorigenic response in rats when administered in a manner similar to the intended human use for female non-surgical sterilization. Young sexually mature female rats received two doses of quinacrine (or 1% methylcellulose control) into each uterine horn approximately 21 days apart, and were observed for 23 months after the second dose administration. Dose levels were 0/0, 0/0, 10/10, 70/70, and 70/250-350 mg/kg (first dose/second dose), which represent local doses in the uterus at approximate multiples of 1x, 8x and 40x the human dose (mg quinacrine/g uterine weight) used for female non-surgical sterilization. Rats were observed for viability, clinical signs of toxicity, and changes in body weight and food consumption. At necropsy, selected organs were weighed, macroscopic observations were recorded, and tissues were collected, fixed, processed, and examined for microscopic pathologic findings. Acute quinacrine toxicity was evident during the dosing period but did not affect long-term survival. Non-neoplastic findings were more common in treated animals than controls, providing evidence of the appropriateness of the bioassay. The incidence of uncommon tumors of the reproductive tract was similar to controls at doses of 10/10mg/kg but increased with dose level and was significantly greater than controls at >or=70/70 mg/kg. We conclude that two doses of quinacrine administered approximately 21 days apart into the uterus of young sexually mature rats at a local dose approximately 8 times the human dose used for non-surgical female sterilization increased the lifetime risk of tumor development in the reproductive tract. (c) 2009 Elsevier Inc. All rights reserved.

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial.

PubMed

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-03-01

Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was -41.3% ± 26.1% (p < 0.001) in the regular-dose group and -21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria.

Effect of low-dose valsartan on proteinuria in normotensive immunoglobulin A nephropathy with minimal proteinuria: a randomized trial

PubMed Central

Jo, Young-Il; Na, Ha-Young; Moon, Ju-Young; Han, Sang-Woong; Yang, Dong-Ho; Lee, Sang-Ho; Park, Hyeong-Cheon; Choi, Hoon-Young; Lim, So-Dug; Kie, Jeong-Hae; Lee, Yong-Kyu; Shin, Sug-Kyun

2016-01-01

Background/Aims: Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Methods: Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Results: Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was −41.3% ± 26.1% (p < 0.001) in the regular-dose group and −21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Conclusions: Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria. PMID:26874511

An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection.

PubMed

Saber, Haleh; Del Valle, Pedro; Ricks, Tiffany K; Leighton, John K

2017-11-01

We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe. Published by Elsevier Inc.

Design of a multicentre randomized controlled trial to assess the safety and efficacy of dose titration by specialized nurses in patients with heart failure. ETIFIC study protocol

PubMed Central

García‐Garrido, LLuisa; Nebot Margalef, Magdalena; Lekuona, Iñaki; Comin‐Colet, Josep; Manito, Nicolás; Roure, Julia; Ruiz Rodriguez, Pilar; Enjuanes, Cristina; Latorre, Pedro; Torcal Laguna, Jesús; García‐Gutiérrez, Susana

2017-01-01

Abstract Aims Heart failure (HF) is associated with many hospital admissions and relatively high mortality, rates decreasing with administration of beta‐blockers (BBs), angiotensin‐converting‐enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists. The effect is dose dependent, suboptimal doses being common in clinical practice. The 2012 European guidelines recommend close monitoring and dose titration by HF nurses. Our main aim is to compare BB doses achieved by patients after 4 months in intervention (HF nurse‐managed) and control (cardiologist‐managed) groups. Secondary aims include comparing doses of the other aforementioned drugs achieved after 4 months, adverse events, and outcomes at 6 months in the two groups. Methods We have designed a multicentre (20 hospitals) non‐inferiority randomized controlled trial, including patients with new‐onset HF, left ventricular ejection fraction ≤40%, and New York Heart Association class II–III, with no contraindications to BBs. We will also conduct qualitative analysis to explore potential barriers to and facilitators of dose titration by HF nurses. In the intervention group, HF nurses will implement titration as prescribed by cardiologists, following a protocol. In controls, cardiologists will both prescribe and titrate doses. The study variables are doses of each of the drugs after 4 months relative to the target dose (%), New York Heart Association class, left ventricular ejection fraction, N‐terminal pro B‐type natriuretic peptide levels, 6 min walk distance, comorbidities, renal function, readmissions, mortality, quality of life, and psychosocial characteristics. Conclusions The trial seeks to assess whether titration by HF nurses of drugs recommended in practice guidelines is safe and not inferior to direct management by cardiologists. The results could have an impact on clinical practice. PMID:29154427

Analysis of uncertainties in Monte Carlo simulated organ dose for chest CT

NASA Astrophysics Data System (ADS)

Muryn, John S.; Morgan, Ashraf G.; Segars, W. P.; Liptak, Chris L.; Dong, Frank F.; Primak, Andrew N.; Li, Xiang

2015-03-01

In Monte Carlo simulation of organ dose for a chest CT scan, many input parameters are required (e.g., half-value layer of the x-ray energy spectrum, effective beam width, and anatomical coverage of the scan). The input parameter values are provided by the manufacturer, measured experimentally, or determined based on typical clinical practices. The goal of this study was to assess the uncertainties in Monte Carlo simulated organ dose as a result of using input parameter values that deviate from the truth (clinical reality). Organ dose from a chest CT scan was simulated for a standard-size female phantom using a set of reference input parameter values (treated as the truth). To emulate the situation in which the input parameter values used by the researcher may deviate from the truth, additional simulations were performed in which errors were purposefully introduced into the input parameter values, the effects of which on organ dose per CTDIvol were analyzed. Our study showed that when errors in half value layer were within ± 0.5 mm Al, the errors in organ dose per CTDIvol were less than 6%. Errors in effective beam width of up to 3 mm had negligible effect (< 2.5%) on organ dose. In contrast, when the assumed anatomical center of the patient deviated from the true anatomical center by 5 cm, organ dose errors of up to 20% were introduced. Lastly, when the assumed extra scan length was longer by 4 cm than the true value, dose errors of up to 160% were found. The results answer the important question: to what level of accuracy each input parameter needs to be determined in order to obtain accurate organ dose results.

Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms

PubMed Central

Lai, Stephen Y.; Koppikar, Priya; Thomas, Sufi M.; Childs, Erin E.; Egloff, Ann Marie; Seethala, Raja R.; Branstetter, Barton F.; Gooding, William E.; Muthukrishnan, Ashok; Mountz, James M.; Lui, Vivian W.Y.; Shin, Dong M.; Agarwala, Sanjiv S.; Johnson, Rita; Couture, Larry A.; Myers, Eugene N.; Johnson, Jonas T.; Mills, Gordon; Argiris, Athanassios; Grandis, Jennifer R.

2009-01-01

Purpose Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS. Patients and Methods Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 μg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry. Results Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively). Conclusion Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects. PMID:19204206

Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

PubMed

Samkoe, Kimberley S; Gunn, Jason R; Marra, Kayla; Hull, Sally M; Moodie, Karen L; Feldwisch, Joachim; Strong, Theresa V; Draney, Daniel R; Hoopes, P Jack; Roberts, David W; Paulsen, Keith; Pogue, Brian W

2017-08-01

ABY-029, a synthetic Affibody peptide, Z03115-Cys, labeled with a near-infrared fluorophore, IRDye® 800CW, targeting epidermal growth factor receptor (EGFR) has been produced under good manufacturing practices for a US Food and Drug Administration-approved first-in-use human study during surgical resection of glioma, as well as other tumors. Here, the pharmacology, phototoxicity, receptor activity, and biodistribution studies of ABY-029 were completed in rats, prior to the intended human use. Male and female Sprague Dawley rats were administered a single intravenous dose of varying concentrations (0, 245, 2449, and 24,490 μg/kg corresponding to 10×, 100×, and 1000× an equivalent human microdose level) of ABY-029 and observed for up to 14 days. Histopathological assessment of organs and tissues, clinical chemistry, and hematology were performed. In addition, pharmacokinetic clearance and biodistribution of ABY-029 were studied in subgroups of the animals. Phototoxicity and ABY-029 binding to human and rat EGFR were assessed in cell culture and on immobilized receptors, respectively. Histopathological assessment and hematological and clinical chemistry analysis demonstrated that single-dose ABY-029 produced no pathological evidence of toxicity at any dose level. No phototoxicity was observed in EGFR-positive and EGFR-negative glioma cell lines. Binding strength and pharmacokinetics of the anti-EGFR Affibody molecules were retained after labeling with the dye. Based on the successful safety profile of ABY-029, the 1000× human microdose 24.5 mg/kg was identified as the no observed adverse effect level following intravenous administration. Conserved binding strength and no observed light toxicity also demonstrated ABY-029 safety for human use.

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

DOE PAGES

Wang, Si-Si; Zimmermann, Maike; Zhang, Hongyong; ...

2017-04-24

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts—the pharmacodynamic drug-target complex for this class of drugs. In this paper, the feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [ 14C]carboplatin-DNA monoadduct levels in themore » cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC 50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R 2 = 0.95, p < 0.0001) and correlated with IC 50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p = 0.02 and p = 0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK) and [ 14C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [ 14C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [ 14C]carboplatin formulation for the microdose was 10 7 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Finally, additional accruals are required to significantly correlate adduct levels with response.« less

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Si-Si; Zimmermann, Maike; Zhang, Hongyong

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts—the pharmacodynamic drug-target complex for this class of drugs. In this paper, the feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [ 14C]carboplatin-DNA monoadduct levels in themore » cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC 50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R 2 = 0.95, p < 0.0001) and correlated with IC 50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p = 0.02 and p = 0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK) and [ 14C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [ 14C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [ 14C]carboplatin formulation for the microdose was 10 7 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Finally, additional accruals are required to significantly correlate adduct levels with response.« less