Population Pharmacokinetic Analysis and Model-Based Simulations of Aripiprazole for a 1-Day Initiation Regimen for the Long-Acting Antipsychotic Aripiprazole Lauroxil.

PubMed

Hard, Marjie L; Wehr, Angela Y; Sadler, Brian M; Mills, Richard J; von Moltke, Lisa

2018-06-11

BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (AL NCD ) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of AL NCD , AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single AL NCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. AL NCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.

The Ellipta® in asthma and chronic obstructive pulmonary disease: device characteristics and patient acceptability.

PubMed

Jones, Thomas L; Neville, Daniel M; Chauhan, Anoop J

2018-02-01

Asthma and chronic obstructive pulmonary disease are primarily treated with inhaled medication, but delivery of that medication to its site of action is problematic; patients' ability to use inhalers will affect therapeutic response. Multiple inhaler devices are available but they are variably easy to use with consequent effects on compliance, intentional or otherwise. The Ellipta ® device is a novel blister strip dry powder inhaler with medium resistance and a consistent delivered dose across a range of inspiratory flow rates. The Ellipta has proven easy to use and is preferred by patients across several evaluations and compared with other inhaler devices. The Ellipta is used to administer multiple inhaled medications, all in single daily-dose regimens, making it ideal for patients who struggle with complex inhaled therapy regimens.

Low-dose hydrocortisone replacement is associated with improved arterial stiffness index and blood pressure dynamics in severely adrenocorticotrophin-deficient hypopituitary male patients.

PubMed

Behan, Lucy-Ann; Carmody, David; Rogers, Bairbre; Hannon, Mark J; Davenport, Colin; Tormey, William; Smith, Diarmuid; Thompson, Christopher J; Stanton, Alice; Agha, Amar

2016-06-01

Increased cardiovascular and cerebrovascular morbidity and mortality in hypopituitary subjects may be linked to inappropriate glucocorticoid exposure; however, the pathophysiology remains unclear. We aimed to examine the effect of three commonly prescribed hydrocortisone (HC) regimens on vascular risk factors. An open crossover study randomising ten hypopituitary men with severe adrenocorticotrophic hormone deficiency to three HC dose regimens: dose A (20mg mane and 10mg tarde), dose B (10mg mane and 10mg tarde) and dose C (10mg mane and 5mg tarde). Following 6 weeks on each regimen, participants underwent 24-h serum cortisol sampling, 24-h ambulatory blood pressure (BP) measurements, calculation of the Ambulatory Arterial Stiffness Index (AASI), oral glucose tolerance testing and fasting serum osteoprotegerin (OPG) sampling. There were no differences in 24-h BP between dose regimens and controls; however, low-dose HC replacement (dose C) was associated with the lowest AASI, indicating a less stiff arterial tree (P<0.05) compared with the other dose regimens. Loss of the physiologic nocturnal BP dip was more common in higher HC replacement regimens, although only significant for dose B compared with dose C (P=0.03). Twenty per cent of patients had abnormal glucose tolerance, but this was unrelated to dose regimen. OPG correlated strongly with 24-h BP in those on dose A only (r=0.65, P=0.04). Currently prescribed HC replacement doses do not result in significant differences in absolute BP levels or improvements in insulin sensitivity. However, lower HC doses may result in lower arterial stiffness and a more physiological nocturnal BP dip. Long-term studies are required to confirm these findings and evaluate their impact on vascular morbidity in this patient group. © 2016 European Society of Endocrinology.

Changes in Mipomersen Dosing Regimen Provide Similar Exposure With Improved Tolerability in Randomized Placebo‐Controlled Study of Healthy Volunteers

PubMed Central

Flaim, JoAnn D.; Grundy, John S.; Baker, Brenda F.; McGowan, Mary P.; Kastelein, John J. P.

2014-01-01

Background Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low‐density lipoprotein (LDL) cholesterol, non‐high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA‐approved subcutaneous dose of 200 mg once weekly. Methods and Results A short‐term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty‐four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post‐distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post‐dose elevation of C‐reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. Conclusions This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer‐term studies. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01061814. PMID:24627419

Changes in mipomersen dosing regimen provide similar exposure with improved tolerability in randomized placebo-controlled study of healthy volunteers.

PubMed

Flaim, Joann D; Grundy, John S; Baker, Brenda F; McGowan, Mary P; Kastelein, John J P

2014-03-13

Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA-approved subcutaneous dose of 200 mg once weekly. A short-term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty-four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post-distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post-dose elevation of C-reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer-term studies. http://www.clinicaltrials.gov. Unique identifier: NCT01061814.

Effect of (+)-Methamphetamine on Path Integration Learning, Novel Object Recognition, and Neurotoxicity in Rats

PubMed Central

Herring, Nicole R.; Schaefer, Tori L.; Gudelsky, Gary A.; Vorhees, Charles V.; Williams, Michael T.

2008-01-01

Rationale Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems, but few associated cognitive effects. Objectives Since, questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens. Methods Rats were treated with one of two regimens, one the typical neurotoxic regimen (4 × 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho et al. 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 ×1.67 mg/kg once every 15 min); matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior. Results On markers of neurotoxicity, MA showed decreased DA and 5-HT, and increased glial fibrillary acidic protein and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple-T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained. Conclusions MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity. PMID:18509623

Effect of +-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats.

PubMed

Herring, Nicole R; Schaefer, Tori L; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T

2008-09-01

Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems but few associated cognitive effects. Since questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens. Rats were treated with one of the two regimens: one based on the typical neurotoxic regimen (4 x 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho AK, Melega WP, Kuczenski R, Segal DS Synapse 39:161-166, 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 x 1.67 mg/kg once every 15 min) matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior. On markers of neurotoxicity, MA showed decreased dopamine (DA) and 5-HT, increased glial fibrillary acidic protein, and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained. MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity.

Evidence for the changing regimens of acetylcysteine.

PubMed

Chiew, Angela L; Isbister, Geoffrey K; Duffull, Stephen B; Buckley, Nicholas A

2016-03-01

Paracetamol overdose prior to the introduction of acetylcysteine was associated with significant morbidity. Acetylcysteine is now the mainstay of treatment for paracetamol poisoning and has effectively reduced rates of hepatotoxicity and death. The current three-bag intravenous regimen with an initial high loading dose was empirically derived four decades ago and has not changed since. This regimen is associated with a high rate of adverse effects due mainly to the high initial peak acetylcysteine concentration. Furthermore, there are concerns that the acetylcysteine concentration is not adequate for 'massive' overdoses and that the dose and duration may need to be altered. Various novel regimens have been proposed, looking to address these issues. Many of these modified regimens aim to decrease the rate of adverse reactions by slowing the loading dose and thereby decrease the peak concentration. We used a published population pharmacokinetic model of acetylcysteine to simulate these modified regimens. We determined mean peak and 20 h acetylcysteine concentrations and area under the under the plasma concentration-time curve to compare these regimens. Those regimens that resulted in a lower peak acetylcysteine concentration have been shown in studies to have a lower rate of adverse events. However, these studies were too small to show whether they are as effective as the traditional regimen. Further research is still needed to determine the optimum dose and duration of acetylcysteine that results in the fewest side-effects and treatment failures. Indeed, a more patient-tailored approach might be required, whereby the dose and duration are altered depending on the paracetamol dose ingested or paracetamol concentrations. © 2015 The British Pharmacological Society.

Effects of sodium in hydration solution on plasma methotrexate concentrations following high-dose methotrexate in children with acute lymphoblastic leukemia.

PubMed

Kinoshita, Akitoshi; Kurosawa, Yoshihiro; Kondoh, Kensuke; Suzuki, Toshio; Manabe, Atsushi; Inukai, Takeshi; Sugita, Kanji; Nakazawa, Shinpei

2003-03-01

To test whether a higher sodium dose in the hydration solution may facilitate faster methotrexate (MTX) elimination as compared with a lower sodium dose following high-dose MTX (HDMTX) treatment. Intravenous solutions with alternate doses of sodium (regimen A 70 mEq/l, regimen B 100 mEq/l) were given to 30 children with acute lymphoblastic leukemia in two courses of HDMTX in a randomized crossover fashion. The plasma MTX concentrations every 24 h from the beginning of MTX administration and the adverse events associated with HDMTX were compared between the two hydration regimens. The plasma MTX concentrations were similar in the two hydration regimens at 24 h (A 50.9+/-7.4 vs B 40.9+/-5.4 microM, means+/- SE, P=0.17), but was significantly lower in regimen B at 48 and 72 h (A 0.65+/-0.17 vs B 0.27+/-0.03 microM, P=0.04; and A 0.14+/-0.03 vs B 0.05+/-0.01 microM, P=0.003). The time during which MTX plasma concentrations exceeded 0.1 microM was significantly longer in regimen A than in regimen B (A 3.83+/-0.18 vs B 3.13+/-0.06 days, P=0.001). The incidences of adverse events were similar between the two regimens ( P=0.78), and severe adverse events were not seen in either regimen. Hydration with a higher sodium dose facilitated faster MTX elimination following HDMTX. Sodium may have a beneficial effect on MTX-induced nephrotoxicity.

Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier.

PubMed

Langford-Smith, Kia J; Sandiford, Zara; Langford-Smith, Alex; Wilkinson, Fiona L; Jones, Simon A; Wraith, J Ed; Wynn, Robert F; Bigger, Brian W

2013-01-01

Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.

Patient adherence to prescribed antimicrobial drug dosing regimens.

PubMed

Vrijens, Bernard; Urquhart, John

2005-05-01

The aim of this article is to review current knowledge about the clinical impact of patients' variable adherence to prescribed anti-infective drug dosing regimens, with the aim of renewing interest and exploration of this important but largely neglected area of therapeutics. Central to the estimation of a patient's adherence to a prescribed drug regimen is a reliably compiled drug dosing history. Electronic monitoring methods have emerged as the virtual 'gold standard' for compiling drug dosing histories in ambulatory patients. Reliably compiled drug dosing histories are consistently downwardly skewed, with varying degrees of under-dosing. In particular, the consideration of time intervals between protease inhibitor doses has revealed that ambulatory patients' variable execution of prescribed dosing regimens is a leading source of variance in viral response. Such analyses reveal the need for a new discipline, called pharmionics, which is the study of how ambulatory patients use prescription drugs. Properly analysed, reliable data on the time-course of patients' actual intake of prescription drugs can eliminate a major source of unallocated variance in drug responses, including the non-response that occurs and is easily misinterpreted when a patient's complete non-execution of a prescribed drug regimen is unrecognized clinically. As such, reliable compilation of ambulatory patients' drug dosing histories has the promise of being a key step in reducing unallocated variance in drug response and in improving the informational yield of clinical trials. It is also the basis for sound, measurement-guided steps taken to improve a patient's execution of a prescribed dosing regimen.

Principles for designing future regimens for multidrug-resistant tuberculosis.

PubMed

Brigden, Grania; Nyang'wa, Bern-Thomas; du Cros, Philipp; Varaine, Francis; Hughes, Jennifer; Rich, Michael; Horsburgh, C Robert; Mitnick, Carole D; Nuermberger, Eric; McIlleron, Helen; Phillips, Patrick P J; Balasegaram, Manica

2014-01-01

Fewer than 20% of patients with multidrug-resistant (MDR) tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.

Therapeutic efficacy of AS2077715 against experimental tinea pedis in guinea pigs in comparison with terbinafine.

PubMed

Ohsumi, Keisuke; Murai, Hidetsugu; Nakamura, Ikko; Watanabe, Masato; Fujie, Akihiko

2014-10-01

AS2077715 is a novel antifungal metabolite produced by the newly isolated fungal strain Capnodium sp. 339855. This compound has potent inhibitory activity against Trichophyton mentagrophytes mitochondrial cytochrome bc1 complex (complex III) and potent fungicidal activity against T. mentagrophytes, as measured in vitro. Here, we compared the effects of AS2077715 and terbinafine in a guinea pig model of tinea pedis. In a treatment regimen started from the day 7 after infection, 10 daily oral doses of 10 and 20 mg kg(-1) AS2077715 and 20 mg kg(-1) of terbinafine significantly decreased fungal colony-forming units (CFUs) in foot pad skin. In a treatment regimen started from the day 11 after infection, 20 mg kg(-1) AS2077715 significantly reduced fungal CFUs in foot pad skin after 7 daily doses in comparison with 20 mg kg(-1) terbinafine-treated guinea pigs. Our findings suggest that in vivo potency and efficacy of AS2077715 are equal to or greater than that of terbinafine, positioning AS2077715 as a good candidate for use in treating trichophytosis.

Twice-Daily versus Once-Daily Pramipexole Extended Release Dosage Regimens in Parkinson's Disease.

PubMed

Yun, Ji Young; Kim, Young Eun; Yang, Hui-Jun; Kim, Han-Joon; Jeon, Beomseok

2017-01-01

This open-label study aimed to compare once-daily and twice-daily pramipexole extended release (PER) treatment in Parkinson's disease (PD). PD patients on dopamine agonist therapy, but with unsatisfactory control, were enrolled. Existing agonist doses were switched into equivalent PER doses. Subjects were consecutively enrolled into either once-daily-first or twice-daily-first groups and received the prescribed amount in one or two, respectively, daily doses for 8 weeks. For the second period, subjects switched regimens in a crossover manner. The forty-four patients completed a questionnaire requesting preference during their last visit. We measured the UPDRS-III, Hoehn and Yahr stages (H&Y) in medication-on state, Parkinson's disease sleep scale (PDSS), and Epworth Sleepiness Scale. Eighteen patients preferred a twice-daily regimen, 12 preferred a once-daily regimen, and 14 had no preference. After the trial, 14 subjects wanted to be on a once-daily regimen, 25 chose a twice-daily regimen, and 5 wanted to maintain the prestudy regimen. Main reasons for choosing the twice-daily regimen were decreased off-duration, more tolerable off-symptoms, and psychological stability. The mean UPDRS-III, H&Y, and PDSS were not different. Daytime sleepiness was significantly high in the once-daily regimen, whereas nocturnal hallucinations were more common in the twice-daily. Multiple dosing should be considered if once-daily dosing is unsatisfactory. This study is registered as NCT01515774 at ClinicalTrials.gov.

Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

PubMed

Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper

2015-06-01

Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients

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

Penoncello, Gregory P.; Ding, George X., E-mail: george.ding@vanderbilt.edu

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, andmore » 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2 cm{sup 3} for head and neck plans and brain plans and a contiguous volume of 5 cm{sup 3} for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens.« less

Weekly infusional high-dose 5-fluorouracil and leucovorin and biweekly cisplatin: a convenient treatment option in advanced gastric cancer.

PubMed

Kundel, Yulia; Purim, Ofer; Figer, Arie; Stemmer, Salomon M; Tichler, Thomas; Sulkes, Jaqueline; Sulkes, Aaron; Brenner, Baruch

2008-04-01

To summarize our experience using a regimen of weekly 5-FU and leucovorin (LV) and biweekly cisplatin (CDDP) in advanced gastric cancer (AGC). Patients had previously untreated histologically confirmed AGC. Treatment consisted of intravenous weekly infusional 5-FU and LV and biweekly CDDP, given for 6 weeks followed by a 2-week rest. Initially, a lower dose level was used (5-FU 2000 mg/m(2), LV 500 mg/m(2), CDDP 40 mg/m(2)), which was later increased (5-FU 2600 mg/m(2), LV 500 mg/m(2), CDDP 50 mg/m(2)). Forty-five patients were treated, 18 at the lower dose level and 27 at the higher dose level. The median age was 67 years and 55% were male. Grade > or =3 toxicity was documented in 37% of patients but toxicity related hospitalizations or treatment discontinuation occurred in only 22% and 13%, respectively. There were no toxic deaths. The most common hematological toxicities were anemia and neutropenia and the most common non-hematological toxicities were nausea, vomiting and fatigue. Of the 39 patients evaluable for response, 13 (33%) had partial response (PR) and 11 (28%) had stable disease (SD). Control of disease (PR+SD) was achieved in 61%. The higher dose level was associated with a higher response rate (p=0.07) and an increased toxicity (p=0.01), mostly hematological and gastrointestinal. Median progression-free survival and overall survival were 3.5 and 9.2 months, respectively. This regimen appears safe, with a manageable toxicity profile. Efficacy data resemble those reported for more complex and toxic regimens. The higher dose level had enhanced activity, at the expense of increased toxicity.

Oxytocin regimen for labor augmentation, labor progression, and perinatal outcomes.

PubMed

Zhang, Jun; Branch, D Ware; Ramirez, Mildred M; Laughon, S Katherine; Reddy, Uma; Hoffman, Mathew; Bailit, Jennifer; Kominiarek, Michelle; Chen, Zhen; Hibbard, Judith U

2011-08-01

To examine the effects and safety of high-dose (compared with low-dose) oxytocin regimen for labor augmentation on perinatal outcomes. Data from the Consortium on Safe Labor were used. A total of 15,054 women from six hospitals were eligible for the analysis. Women were grouped based on their oxytocin starting dose and incremental dosing of 1, 2, and 4 milliunits/min. Duration of labor and a number of maternal and neonatal outcomes were compared among these three groups stratified by parity. Multivariable logistic regression and generalized linear mixed model were used to adjust for potential confounders. Oxytocin regimen did not affect the rate of cesarean delivery or other perinatal outcomes. Compared with 1 milliunit/min, the regimens starting with 2 milliunits/min and 4 milliunits/min reduced the duration of first stage by 0.8 hours (95% confidence interval 0.5-1.1) and 1.3 hours (1.0-1.7), respectively, in nulliparous women. No effect was observed on the second stage of labor. Similar patterns were observed in multiparous women. High-dose regimen was associated with a reduced risk of meconium stain, chorioamnionitis, and newborn fever in multiparous women. High-dose oxytocin regimen (starting dose at 4 milliunits/min and increment of 4 millliunits/min) is associated with a shorter duration of first-stage of labor for all parities without increasing the cesarean delivery rate or adversely affecting perinatal outcomes. II.

Fewer doses of HPV vaccine result in immune response similar to three-dose regimen

Cancer.gov

NCI scientists report that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody levels against two of the most carcinogenic types of HPV (16 and 18), compared to a standard three dose regimen.

New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease.

PubMed

Rao, Gauri G; Ly, Neang S; Haas, Curtis E; Garonzik, Samira; Forrest, Alan; Bulitta, Jurgen B; Kelchlin, Pamela A; Holden, Patricia N; Nation, Roger L; Li, Jian; Tsuji, Brian T

2014-01-01

Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10(8) CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2 of 14.8 h) disease. Front-loaded regimens (n=5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n=14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.

Retrospective evaluation of the MEAM regimen as a conditioning regimen before autologous peripheral blood stem cell transplantation for lymphoma in two centers with different dosing schedules of melphalan.

PubMed

Sugimoto, Miyuki; Ito, Shoko; Mashima, Kiyomi; Umino, Kento; Minakata, Daisuke; Nakano, Hirofumi; Yamasaki, Ryoko; Kawasaki, Yasufumi; Ashizawa, Masahiro; Yamamoto, Chihiro; Fujiwara, Shin-Ichiro; Okazuka, Kiyoshi; Hatano, Kaoru; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Muroi, Kazuo; Kako, Shinichi; Kanda, Yoshinobu

2016-09-01

The BEAM regimen consisting of carmustine (BCNU), etoposide, cytarabine, and melphalan (MEL) is widely used before autologous hematopoietic stem cell transplantation (auto-HSCT) for lymphoma. However, intravenous BCNU is not available in Japan, and therefore, ranimustine (MCNU) has been used instead of BCNU (the MEAM regimen). We retrospectively analyzed the outcome of 79 adult patients who underwent auto-HSCT for lymphoma using this regimen in two centers, with 1- and 2-day dosing of MEL, respectively. Three-year overall survival (OS) and progression-free survival (PFS) probabilities were 77.3 and 56.5 % in the entire population and 71.7 and 58.0 % in patients with diffuse large B cell lymphoma. These outcomes were at least equivalent to those with the BEAM regimen. There was no regimen-related pulmonary toxicity. In a multivariate analysis, older age was the only factor that was significantly associated with for OS. In a comparison of the two MEL dosing schedules, while there was no significant differences in either OS or PFS, diarrhea was observed more frequently with 1-day dosing of MEL. In conclusion, the MEAM regimen appeared to be a promising conditioning regimen in auto-HSCT for lymphoma. A large prospective study is warranted to confirm the current findings.

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients.

PubMed

Penoncello, Gregory P; Ding, George X

2016-01-01

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2cm(3) for head and neck plans and brain plans and a contiguous volume of 5cm(3) for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens. Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Terbinafine in combination with other antifungal agents for treatment of resistant or refractory mycoses: investigating optimal dosing regimens using a physiologically based pharmacokinetic model.

PubMed

Dolton, Michael J; Perera, Vidya; Pont, Lisa G; McLachlan, Andrew J

2014-01-01

Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.

Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy.

PubMed

Meille, Christophe; Barbolosi, Dominique; Ciccolini, Joseph; Freyer, Gilles; Iliadis, Athanassios

2016-08-01

Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen.

Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET.

PubMed

Fouda, Usama M; Sayed, Ahmed M

2011-12-01

To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3-7) combined with HPuFSH-GnRHant protocol. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

Safety, Adherence and Acceptability of Intermittent Tenofovir/Emtricitabine as HIV Pre-Exposure Prophylaxis (PrEP) among HIV-Uninfected Ugandan Volunteers Living in HIV-Serodiscordant Relationships: A Randomized, Clinical Trial

PubMed Central

Kibengo, Freddie M.; Ruzagira, Eugene; Katende, David; Bwanika, Agnes N.; Bahemuka, Ubaldo; Haberer, Jessica E.; Bangsberg, David R.; Barin, Burc; Rooney, James F.; Mark, David; Chetty, Paramesh; Fast, Patricia; Kamali, Anatoli; Priddy, Frances H.

2013-01-01

Background Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens. Design Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment. Methods Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT. Results Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen. Conclusions Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing. Registration Clinicaltrials.gov number NCT00931346 PMID:24086333

Medication Regimen Complexity Measured by MRCI: A Systematic Review to Identify Health Outcomes.

PubMed

Alves-Conceição, Vanessa; Rocha, Kérilin Stancine Santos; Silva, Fernanda Vilanova Nascimento; Silva, Rafaella Oliveira Santos; Silva, Daniel Tenório da; Lyra-Jr, Divaldo Pereira de

2018-05-01

To perform a systematic review to identify health outcomes related to medication regimen complexity as measured by the Medication Regimen Complexity Index (MRCI) instrument. Cochrane Library, LILACS, PubMed, Scopus, EMBASE, Open Thesis, and Web of Science were searched from January 1, 2004, until April 02, 2018, using the following search terms: outcome assessment, drug therapy, and Medication Regimen Complexity Index and their synonyms in different combinations. Studies that used the MRCI instrument to measure medication regimen complexity and related it to clinical, humanistic, and/or economic outcomes were evaluated. Two reviewers independently carried out the analysis of the titles, abstracts, and complete texts according to the eligibility criteria, performed data extraction, and evaluated study quality. A total of 23 studies met the inclusion criteria; 18 health outcomes related to medication regimen complexity were found. The health outcomes most influenced by medication regimen complexity were hospital readmission, medication adherence, hospitalization, adverse drug events, and emergency sector visit. Only one study related medication regimen complexity with humanistic outcomes, and no study related medication regimen complexity to economic outcomes. Most of the studies were of good methodological quality. Relevance to Patient Care and Clinical Practice: Health care professionals should pay attention to medication regimen complexity of the patients because this may influence health outcomes. This study identified some health outcomes that may be influenced by medication regimen complexity: hospitalization, hospital readmission, and medication adherence were more prevalent, showing a significant association between MRCI increase and these health outcomes.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

PubMed

Kampouraki, Emmanouela; Avery, Peter J; Wynne, Hilary; Biss, Tina; Hanley, John; Talks, Kate; Kamali, Farhad

2017-09-01

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients. © 2017 John Wiley & Sons Ltd.

Expert opinion on a flexible extended regimen of drospirenone/ethinyl estradiol contraceptive.

PubMed

Han, Leo; Jensen, Jeffrey T

2014-10-01

Oral contraceptives are often prescribed in extended or continuous forms in order to manage menstrual bleeding and menstrual-related side effects. However, with extended regimens, unscheduled intracycle bleeding can become problematic. Flexible extended dosing of a contraceptive containing drospirenone (DRSP) and ethinyl estradiol (EE) was designed to improve bleeding profiles during extended cycles through active management of bleeding symptoms. We examine the rationale for flexible extended dosing as well as review the dosing regimen. We will focus on the findings of the two most important clinical trials regarding flexible extended DRSP/EE (3 mg/20 μg), including the bleeding profiles of women in those trials. Pharmacology, mechanisms of action, efficacy as well as safety of DRSP containing pills will also be reviewed. Flexible extended dosing of DRSP/EE (3 mg/20 μg) has similar pharmacokinetics and contraceptive efficacy of both conventional and fixed extended regimens. However, it has the added benefit of fewer days of bleeding/spotting compared to conventional and fixed extended regimens.

Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage.

PubMed

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Muller, Vincent; Llosa, Augusto E; Uzzeni, Florent; Luquero, Francisco J; Ciglenecki, Iza; Azman, Andrew S

2017-06-01

In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68-0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

Magnesium sulphate for prevention of eclampsia: are intramuscular and intravenous regimens equivalent? A population pharmacokinetic study.

PubMed

Salinger, D H; Mundle, S; Regi, A; Bracken, H; Winikoff, B; Vicini, P; Easterling, T

2013-06-01

To compare magnesium sulphate concentrations achieved by intramuscular and intravenous regimens used for the prevention of eclampsia. Low-resource obstetric hospitals in Nagpur and Vellore, India. Pregnant women at risk for eclampsia due to hypertensive disease. A pharmacokinetic study was performed as part of a randomised trial that enrolled 300 women comparing intramuscular and intravenous maintenance regimens of magnesium dosing. Data from 258 enrolled women were analysed in the pharmacokinetic study. A single sample was drawn per woman with the expectation of using samples in a pooled data analysis. Pharmacokinetic parameters of magnesium distribution and clearance. Magnesium clearance was estimated to be 48.1 dl/hour, volume of distribution to be 156 dl and intramuscular bioavailability to be 86.2%. The intramuscular regimen produced higher initial serum concentrations, consistent with a substantially larger loading dose. At steady state, magnesium concentrations in the intramuscular and intravenous groups were comparable. With either regimen, a substantial number of women would be expected to have serum concentrations lower than those generally held to be therapeutic. Clinical implications were that a larger loading dose for the intravenous regimen should be considered; where feasible, individualised dosing of magnesium sulphate would reduce the variability in serum concentrations and might result in more women with clinically effective magnesium concentrations; and lower dose magnesium sulphate regimens should be considered with caution. © 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.

Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model

PubMed Central

Dolton, Michael J.; Perera, Vidya; Pont, Lisa G.

2014-01-01

Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens. PMID:24126579

Single Dose Versus 3 Doses of Intramuscular Benzathine Penicillin for Early Syphilis in HIV: A Randomized Clinical Trial.

PubMed

Andrade, Roberto; Rodriguez-Barradas, Maria C; Yasukawa, Kosuke; Villarreal, Erick; Ross, Michael; Serpa, Jose A

2017-03-15

Patients coinfected with syphilis and human immunodeficiency virus (HIV) may have a slower decrease in rapid plasma reagin (RPR) titers. Currently a single dose of 2.4 million units of intramuscular benzathine penicillin G (BPG) is recommended for the treatment of early syphilis. Some observational studies have suggested that this regimen may lead to high failure rates in coinfected patients. We conducted an open-label randomized clinical trial to compare the efficacy of single-dose and 3-dose regimens of BPG for the treatment of early syphilis in HIV-infected individuals. RPR titers were monitored every 3 months. Treatment success was defined as a decrease in RPR titers of ≥2 dilutions (4-fold) during a 12-month follow-up period. Sixty-four patients were included. In the intention-to-treat analysis, treatment success rates were 80% (28 of 35 subjects) and 93% (27 of 29 subjects) in the single-dose and 3-dose regimens, respectively (absolute difference, 13% [95% confidence interval {CI}, -5% to 30%; P = .17). In the per-protocol analysis, success rates were 93% (27 of 29) and 100% in the single-dose and 3-dose regimens, respectively (absolute difference, 7% [95% CI, -7% to 22%]; P = .49). CD4 T-cell count, RPR titer and syphilis stage did not affect treatment results. When compared with a single dose of BPG, a 3-dose regimen did not improve syphilis serological outcomes. Our results support the Centers for Disease Control and Prevention recommendation of a single dose of BPG in HIV-infected patients with early syphilis. NCT02611765. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes.

PubMed

Hatorp, V; Huang, W C; Strange, P

1999-04-01

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.

Successful use of full-dose dexamethasone, high-dose cytarabine, and cisplatin as part of initial therapy in non-hodgkin and hodgkin lymphoma with severe hepatic dysfunction.

PubMed

McCarthy, Jeanne; Gopal, Ajay K

2009-04-01

Anthracycline-based chemotherapy is the cornerstone of modern curative regimens for aggressive lymphomas; however, these drugs cannot be safely administered in the setting of severe hepatic dysfunction. Alternative regimens for this setting are required. We describe 2 patients with newly diagnosed advanced aggressive lymphoma (diffuse large B-cell lymphoma [DLBCL] and classic Hodgkin lymphoma [HL]) presenting with severe hepatic dysfunction with hyperbilirubinemia (4.3-13.2 mg/dL). Because of the inability to safely administer unattenuated doses of anthracycline-based regimens, dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was used at full doses (along with rituximab for the DLBCL patient) until hepatic function normalized (1-5 cycles). The treatment was then converted to R-CHOP (rituximab/cyclophosphamide/ doxorubicin/vincristine/prednisone) and ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) for the DLBCL and HL patient, respectively, to complete therapy. The patients had a partial remission and complete remission, respectively. These data suggest that DHAP is a safe and effective regimen that can be used without dose modification as part of initial therapy in the setting of aggressive lymphoma and hepatic failure. The literature on the use of treatment regimens for aggressive lymphoma in the setting of hepatic dysfunction is reviewed.

Relationship between Fosfomycin Exposure and Amplification of Escherichia coli Subpopulations with Reduced Susceptibility in a Hollow-Fiber Infection Model.

PubMed

VanScoy, Brian; McCauley, Jennifer; Bhavnani, Sujata M; Ellis-Grosse, Evelyn J; Ambrose, Paul G

2016-09-01

Understanding the relationship between antibiotic exposure and amplification of bacterial subpopulations with reduced drug susceptibility over time is important for evaluating the adequacy of dosing regimens. We utilized a hollow-fiber infection model to identify the fosfomycin intravenous dosing regimens that prevented the amplification of Escherichia coli bacterial subpopulations with reduced fosfomycin susceptibility. The challenge isolate was E. coli ATCC 25922 (agar MIC with glucose-6-phosphate, 1 mg/liter; agar MIC without glucose-6-phosphate, 32 mg/liter). The fosfomycin dosing regimens studied were 1 to 12 g every 8 h for 10 days to approximate that planned for clinical use. The studies included a no-treatment control regimen. Two bacterial subpopulations were identified, one with reduced susceptibility with agar MIC values ranging from 32 to 128 mg/liter and the other resistant with agar MIC values of 256 to >1,024 mg/liter on plates containing 5× and 256× the baseline MIC value, respectively. An inverted-U-shaped function best described the relationship between the amplification of the two bacterial subpopulations and drug exposure. The lowest fosfomycin dosing regimen that did not amplify a bacterial subpopulation with reduced susceptibility was 4 g administered every 8 h. Nearly immediate amplification of bacterial subpopulations with reduced susceptibility was observed with fosfomycin dosing regimens consisting of 1 to 2 g every 8 h. These data will be useful to support the selection of fosfomycin dosing regimens that minimize the potential for on-therapy amplification of bacterial subpopulations with reduced susceptibility. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Vitamin D: Daily vs. Monthly Use in Children and Elderly-What Is Going On?

PubMed

Dalle Carbonare, Luca; Valenti, Maria Teresa; Del Forno, Francesco; Caneva, Elena; Pietrobelli, Angelo

2017-06-24

Vitamin D deficiency is highly prevalent among children and adults worldwide. Agreement exists that vitamin D deficiency should be corrected. However, the definitions of vitamin deficiency and effective vitamin D replacement therapy are inconsistent in the literature. Not only is the dosing regimen still under debate, but also the time and period of administration (i.e., daily vs. monthly dose). In pediatric as well as elderly subjects, dosing regimens with high vitamin D doses at less frequent intervals were proposed to help increase compliance to treatment: these became widespread in clinical practice, despite mounting evidence that such therapies are not only ineffective but potentially harmful, particularly in elderly subjects. Moreover, in the elderly, high doses of vitamin D seem to increase the risk of functional decline and are associated with a higher risk of falls and fractures. Achieving good adherence to recommended prophylactic regimens is definitely one of the obstacles currently being faced in view of the wide segment of the population liable to the treatment and the very long duration of prophylaxis. The daily intake for extended periods is in fact one of the frequent causes of therapeutic drop-outs, while monthly doses of vitamin D may effectively and safely improve patient compliance to the therapy. The aim of our paper is a quasi-literature review on dosing regimens among children and elderly. These two populations showed a particularly significant beneficial effect on bone metabolism, and there could be different outcomes with different dosing regimens.

Human Papillomavirus Vaccine Effectiveness Against Incident Genital Warts Among Female Health-Plan Enrollees, United States.

PubMed

Hariri, Susan; Schuler, Megan S; Naleway, Allison L; Daley, Matthew F; Weinmann, Sheila; Crane, Bradley; Newcomer, Sophia R; Tolsma, Dennis; Markowitz, Lauri E

2018-02-01

We examined the effectiveness of human papillomavirus vaccination by dose number and spacing against incident genital warts in a cohort of 64,517 female health-plan enrollees in the United States during 2006-2012. Eligible recipients were classified into groups by regimen: 0, 1, 2 (<6 months apart), 2 (≥6 months apart), or 3 doses. They were followed until a genital wart diagnosis, loss to follow-up, or the end of study. Propensity score weights were used to balance baseline differences across groups. To account for latent genital warts before vaccination, we applied 6- and 12-month buffer periods from last and first vaccine dose, respectively. Incidence rates and hazard ratios were calculated using Poisson regression and Cox models. The propensity score-weighted incidence rate per 100,000 person-years was 762 among unvaccinated participants. Using 6- and 12-month buffer periods, respectively, incidence rates were 641 and 257 for 1 dose, 760 and 577 for the 2-dose (<6-month interval) regimen, 313 and 194 for the 2-dose (≥6-month interval) regimen, and 199 and 162 among 3-dose vaccinees; vaccine effectiveness was 68% and 76% for the 2-dose (≥6-month interval) regimen and 77% and 80% in 3-dose vaccinees compared with unvaccinated participants. Vaccine effectiveness was not significant among vaccinees receiving 1-dose and 2-dose (<6-month interval) regimens compared with unvaccinated participants. Our findings contribute to a better understanding of the real-world effectiveness of HPV vaccination. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Dosimetric impact of cylinder size in high-dose rate vaginal cuff brachytherapy (VCBT) for primary endometrial cancer.

PubMed

Zhang, Hualin; Gopalakrishnan, Mahesh; Lee, Plato; Kang, Zhuang; Sathiaseelan, Vythialingam

2016-09-08

The purpose of this study was to evaluate the dosimetric impact of cylinder size in high-dose-rate (HDR) vaginal cuff brachytherapy (VCBT). Sample plans of HDR VCBT in a list of cylinders ranging from 2.5 to 4 cm in diameter at 0.5 cm incre-ment were created and analyzed. The doses were prescribed either at the 0.5cm depth with 5.5 Gy for 4 fractions or at the cylinder surface with 8.8 Gy for 4 frac-tions, in various treatment lengths. A 0.5 cm shell volume called PTV_Eval was contoured for each plan and served as the target volume for dosimetric evaluation. The cumulative and differential dose volume histograms (c-DVH and d-DVH), mean doses (D-mean) and the doses covering 90% (D90), 10% (D10), and 5% (D5) of PTV_Eval were calculated. In the 0.5 cm depth regimen, the DVH curves were found to have shifted toward the lower dose zone when a larger cylinder was used, but in the surface regimen the DVH curves shifted toward the higher dose zone as the cylinder size increased. The D-means of the both regimens were between 6.9 and 7.8 Gy and dependent on the cylinder size but independent of the treatment length. A 0.5 cm variation of diameter could result in a 4% change of D-mean. Average D90s were 5.7 (ranging from 5.6 to 5.8 Gy) and 6.1 Gy (from 5.7 to 6.4 Gy), respectively, for the 0.5 cm and surface regimens. Average D10 and D5 were 9.2 and 11 Gy, respectively, for the 0.5 cm depth regimen, and 8.9 and 9.7 Gy, respectively, for the surface regimen. D-mean, D90, D10, and D5 for other prescription doses could be calculated from the lookup tables of this study. Results indicated that the cylinder size has moderate dosimetric impact, and that both regimens are comparable in dosimetric quality. © 2016 The Authors.

Effect of high-dose oral multivitamins and minerals in participants not treated with statins in the randomized Trial to Assess Chelation Therapy (TACT).

PubMed

Issa, Omar M; Roberts, Rhonda; Mark, Daniel B; Boineau, Robin; Goertz, Christine; Rosenberg, Yves; Lewis, Eldrin F; Guarneri, Erminia; Drisko, Jeanne; Magaziner, Allan; Lee, Kerry L; Lamas, Gervasio A

2018-01-01

In a prespecified subgroup analysis of participants not on statin therapy at baseline in the TACT, a high-dose complex oral multivitamins and multimineral regimen was found to have a large unexpected benefit compared with placebo. The regimen tested was substantially different from any vitamin regimen tested in prior clinical trials. To explore these results, we performed detailed additional analyses of participants not on statins at enrollment in TACT. TACT was a factorial trial testing chelation treatments and a 28-component high-dose oral multivitamins and multiminerals regimen versus placebo in post-myocardial infarction (MI) patients 50 years or older. There were 460 (27%) of 1,708 TACT participants not taking statins at baseline, 224 (49%) were in the active vitamin group and 236 (51%) were in the placebo group. Patients were enrolled at 134 sites around the United States and Canada. Daily high-dose oral multivitamins and multiminerals (6 tablets, active or placebo). The primary end point of TACT was time to the first occurrence of any component of the composite end point: all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for angina. The primary end point occurred in 137 nonstatin participants (30%), of which 51 (23%) of 224 were in the active group and 86 (36%) of 236 were taking placebo (hazard ratio, 0.62; 95% confidence interval, 0.44-0.87; P=.006). Results in the key TACT secondary end point, a combination of cardiovascular mortality, stroke, or recurrent MI, was consistent in favoring the active vitamin group (hazard ratio, 0.46; 95% confidence interval, 0.28-0.75; P=.002). Multiple end point analyses were consistent with these results. High-dose oral multivitamin and multimineral supplementation seem to decrease combined cardiac events in a stable, post-MI population not taking statin therapy at baseline. These unexpected findings are being retested in the ongoing TACT2. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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

The clinical pharmacology of alkylating agents in high-dose chemotherapy.

PubMed

Huitema, A D; Smits, K D; Mathôt, R A; Schellens, J H; Rodenhuis, S; Beijnen, J H

2000-08-01

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in high-dose chemotherapy. Differences between conventional and high doses will be discussed.

Intermittent minodronic acid treatment with sufficient bone resorption inhibition prevents reduction in bone mass and strength in ovariectomized rats with established osteopenia comparable with daily treatment.

PubMed

Kimoto, Aishi; Tanaka, Makoto; Nozaki, Kazutoshi; Mori, Masamichi; Fukushima, Shinji; Mori, Hiroshi; Shiroya, Tsutomu; Nakamura, Toshitaka

2013-07-01

This study examined and compared the effects of four-week intermittent and daily administrations of minodronic acid, a highly potent nitrogen-containing bisphosphonate, on bone mineral density (BMD), bone strength, bone turnover, and histomorphometry on established osteopenia in ovariectomized (OVX) rats. Fourteen-week-old female F344 rats were OVX or sham-operated. At 12 weeks post surgery, minodronic acid was orally administered once every 4 weeks at 0.2, 1, and 5 mg/kg and once daily at 0.006, 0.03, and 0.15 mg/kg for 12 months. The total dosing amount was comparable between the two dosing regimens. The levels of urinary deoxypyridinoline and serum osteocalcin were measured to assess bone turnover. BMD as assessed via dual-energy X-ray absorptiometry, bone structure and dynamical changes in vertebral trabecula and biomechanical properties were measured ex vivo at 12 months to assess bone content and material properties. Minodronic acid dose-dependently ameliorated the decrease in BMD of lumbar vertebrae and the femur in both treatment regimens similarly. Minodronic acid suppressed elevated urinary levels of deoxypyridinoline, a bone resorption marker, and reduced the serum levels of osteocalcin, a bone formation marker. In the mechanical test at 12 months of treatment, minodronic acid dose-dependently ameliorated the reduction in bone strength in femur and vertebral body. There is no significant difference in parameters between the two regimens except maximal load of lower doses in lumbar vertebral body and absorption energy of middle doses in femur. With these parameters with significant differences, values of the intermittent regimen were significantly lower than that of daily repeated regimen. Bone histomorphometric analysis of the lumbar vertebral body showed that minodronic acid significantly ameliorated the decrease in bone mass, trabecular thickness and number, and the increase in trabecular separation, bone resorption indices (Oc.S/BS and N.Oc/BS), and bone formation indices (BFR/BS, MAR and OV/BV) in both regimens. Minodronic acid suppressed OVX-induced increases in bone turnover at the tissue level and ameliorated all structural indices, thereby improving the deterioration of bone quality under osteoporotic disease conditions regardless of the regimen. In conclusion, a four-week intermittent treatment of minodronic acid suppressed increased bone resorption as daily treatment when considering the total administered dose in OVX rats with established osteopenia. The improvement of microarchitectural destruction in low dose of intermittent treatment was weaker than that observed in a daily repeated regimen; however the effects of high and middle doses of intermittent treatment were equivalent to that observed in daily repeated regimen accompanied by sufficient bone resorption inhibition in rats. These findings suggest that minodronic acid at an appropriate dose in an intermittent regimen may be as clinically useful in osteoporosis therapy as in daily treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

Brief Report: The Euro-Lupus Low-Dose Intravenous Cyclophosphamide Regimen Does Not Impact the Ovarian Reserve, as Measured by Serum Levels of Anti-Müllerian Hormone.

PubMed

Tamirou, Farah; Husson, Séverine Nieuwland; Gruson, Damien; Debiève, Frédéric; Lauwerys, Bernard R; Houssiau, Frédéric A

2017-06-01

The Euro-Lupus regimen of low-dose intravenous cyclophosphamide (IV CYC) (cumulative dose of 3 gm) was developed to reduce gonadal toxicity. To address the possibility of a marginal effect on the ovarian reserve, we measured serum titers of anti-Müllerian hormone (AMH) in patients with systemic lupus erythematosus (SLE) treated with the Euro-Lupus regimen and compared them with those measured in patients who were treated with higher doses of IV CYC or were never treated with IV CYC. Serum AMH levels were measured by enzyme-linked immunosorbent assay in a cohort of 155 premenopausal SLE patients; 30 of these patients had been treated with the Euro-Lupus regimen, and 24 had received higher doses of IV CYC. None had received oral CYC. AMH levels were age-adjusted using a slope computed from levels measured across the group of SLE patients who had not been treated with IV CYC. Demographic and clinical data were collected. Serum titers of AMH measured in SLE patients treated with the Euro-Lupus IV CYC regimen (median dose 1.46 ng/ml) did not differ from those measured in patients never treated with the cytotoxic drug (median 1.85 ng/ml). As expected, patients given >6 gm of IV CYC had significantly lower serum titers of AMH (median 0.83 ng/ml) compared with those never treated with IV CYC (P = 0.047). Median serum AMH titers did not change before (1.24 ng/ml) and after (2.50 ng/ml) treatment with the Euro-Lupus IV CYC regimen in the subset of patients for whom paired samples could be tested (P = 0.43). The Euro-Lupus regimen of low-dose IV CYC does not impact the ovarian reserve of SLE patients and can therefore be proposed as treatment in patients seeking to become pregnant. © 2017, American College of Rheumatology.

Current practice of antibiotic prophylaxis for surgical fixation of closed long bone fractures: a survey of 297 members of the Orthopaedic Trauma Association.

PubMed

Gans, Itai; Jain, Amit; Sirisreetreerux, Norachart; Haut, Elliott R; Hasenboehler, Erik A

2017-01-01

The risk of postoperative surgical site infection after long bone fracture fixation can be decreased with appropriate antibiotic use. However, there is no agreement on the superiority of a single- or multiple-dose perioperative regimen of antibiotic prophylaxis. The purpose of this study is to determine the following: 1) What are the current practice patterns of orthopaedic trauma surgeons in using perioperative antibiotics for closed long bone fractures? 2) What is the current knowledge of published antibiotic prophylaxis guidelines among orthopaedic trauma surgeons? 3) Are orthopaedic surgeons willing to change their current practices? A questionnaire was distributed via email between September and December 2015 to 955 Orthopaedic Trauma Association members, of whom 297 (31%) responded. Most surgeons (96%) use cefazolin as first-line infection prophylaxis. Fifty-nine percent used a multiple-dose antibiotic regimen, 39% used a single-dose regimen, and 2% varied this decision according to patient factors. Thirty-six percent said they were unfamiliar with Centers for Disease Control and Prevention (CDC) antibiotic prophylaxis guidelines; only 30% were able to select the correct CDC recommendation from a multiple-choice list. However, 44% of surgeons said they followed CDC recommendations. Fifty-six percent answered that a single-dose antibiotic prophylaxis regimen was not inferior to a multiple-dose regimen. If a level-I study comparing a single preoperative dose versus multiple perioperative antibiotic dosing regimen for treatment of closed long bone fractures were published, most respondents (64%) said they would fully follow these guidelines, and 22% said they would partially change their practice to follow these guidelines. There is heterogeneity in the use of single- versus multiple-dose antibiotic prophylaxis for surgical repair of closed long bone fractures. Many surgeons were unsure of current evidence-based recommendations regarding perioperative antibiotic use. Most respondents indicated they would be receptive to high-level evidence regarding the single- versus multiple-dose perioperative prophylactic antibiotics for the treatment of closed long bone fractures.

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.).

A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens.

PubMed

Darwish, Mona; Bond, Mary; Ricciotti, Nancy; Hsieh, Jennifer; Fiedler-Kelly, Jill; Grasela, Thaddeus

2014-11-01

Quartette (levonorgestrel [LNG]/ethinyl estradiol [EE] and EE) is an ascending-dose, extended-regimen combined oral contraceptive (COC) that consists of a constant dose of LNG 150 µg on days 1 to 84 with EE 20 µg on days 1 to 42, 25 µg on days 43 to 63, 30 µg on days 64 to 84, and 10 µg of EE monotherapy on days 85 to 91. A population pharmacokinetic (PK) model for EE was developed using nonlinear mixed-effects modeling to characterize the PK profile of EE administered in Quartette and other extended-regimen LNG/EE COCs. Model-predicted plasma concentration-time profiles demonstrated a stepwise increase in systemic exposure to EE during the first 84 days of the cycle following each EE dose change. Lower concentrations of EE were noted during the final 7-day period of EE 10 µg. Gradual increases in EE seen with Quartette may decrease the incidence of unscheduled bleeding frequently observed during early cycles of extended-regimen COCs. © The Author(s) 2014.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

PubMed

Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

2016-12-06

Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups (typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI -0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

PubMed Central

Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

2011-01-01

Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted. Trial Registration www.controlled-trials.com ISRCTN47375023 PMID:21980373

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: A randomized open-label study

PubMed Central

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016. PMID:25692350

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: a randomized open-label study.

PubMed

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.

Total Skin Electron Beam for Primary Cutaneous T-cell Lymphoma

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

Elsayad, Khaled; Kriz, Jan; Moustakis, Christos

Purpose: Recent trials with low-dose total skin electron beam (TSEB) therapy demonstrated encouraging results for treating primary cutaneous T-cell lymphoma (PCTCL). In this study, we assessed the feasibility of different radiation doses and estimated survival rates of different pathologic entities and stages. Methods and Materials: We retrospectively identified 45 patients with PCTCL undergoing TSEB therapy between 2000 and 2015. Clinical characteristics, treatment outcomes, and toxicity were assessed. Results: A total of 49 courses of TSEB therapy were administered to the 45 patients. There were 26 pathologically confirmed cases of mycosis fungoides (MF) lymphoma, 10 cases of Sézary syndrome (SS), andmore » 9 non-MF/SS PCTCL patients. In the MF patients, the overall response rate (ORR) was 92% (50% complete remission [CR]), 70% ORR in SS patients (50% CR), and 89% ORR in non-MF/SS patients (78% CR). The ORR for MF/SS patients treated with conventional dose (30-36 Gy) regimens was 92% (63% CR) and 75% (25% CR) for low-dose (<30-Gy) regimens (P=.09). In MF patients, the overall survival (OS) was 77 months with conventional dose regimens versus 14 months with low-dose regimens (P=.553). In SS patients, the median OS was 48 versus 16 months (P=.219), respectively. Median event-free survival (EFS) for MF in conventional dose patients versus low-dose patients was 15 versus 8 months, respectively (P=.264) and 19 versus 3 months for SS patients (P=.457). Low-dose regimens had shorter treatment time (P=.009) and lower grade 2 adverse events (P=.043). A second TSEB course was administered in 4 MF patients with 100% ORR. There is a possible prognostic impact of supplemental/boost radiation (P<.001); adjuvant treatment (P<.001) and radiation tolerability (P=.021) were detected. Conclusions: TSEB therapy is an efficacious treatment modality in the treatment of several forms of cutaneous T-cell lymphoma. There is a nonsignificant trend to higher and longer clinical benefit for MF and SS patients receiving conventional dose. Low-dose TSEB regimens are well tolerated and achieve short-term palliation.« less

The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting.

PubMed

De Stefano, Valerio; Rocca, Bianca; Tosetto, Alberto; Soldati, Denise; Petrucci, Giovanna; Beggiato, Eloise; Bertozzi, Irene; Betti, Silvia; Carli, Giuseppe; Carpenedo, Monica; Cattaneo, Daniele; Cavalca, Viviana; Dragani, Alfredo; Elli, Elena; Finazzi, Guido; Iurlo, Alessandra; Lanzarone, Giuseppe; Lissandrini, Laura; Palandri, Francesca; Paoli, Chiara; Rambaldi, Alessandro; Ranalli, Paola; Randi, Maria Luigia; Ricco, Alessandra; Rossi, Elena; Ruggeri, Marco; Specchia, Giorgina; Timillero, Andrea; Turnu, Linda; Vianelli, Nicola; Vannucchi, Alessandro M; Rodeghiero, Francesco; Patrono, Carlo

2018-06-01

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A 2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB 2 , a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB 2 as a reliable end point for dose-finding studies of novel aspirin regimens.

Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers.

PubMed

Mutua, Gaudensia; Sanders, Eduard; Mugo, Peter; Anzala, Omu; Haberer, Jessica E; Bangsberg, David; Barin, Burc; Rooney, James F; Mark, David; Chetty, Paramesh; Fast, Patricia; Priddy, Frances H

2012-01-01

Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63-92] for daily dosing and 55% [IQR:28-78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14-50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. ClinicalTrials.gov NCT00971230.

Uncertainties in estimating heart doses from 2D-tangential breast cancer radiotherapy.

PubMed

Lorenzen, Ebbe L; Brink, Carsten; Taylor, Carolyn W; Darby, Sarah C; Ewertz, Marianne

2016-04-01

We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002. Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left-sided patients, mean heart dose was related to maximum heart distance in the medial field. For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from <1Gy to >8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always <1Gy and maximum dose always <5Gy for all three regimens. The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT-scans. Copyright © 2016. Published by Elsevier Ireland Ltd.

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013.

PubMed

Taylor, Carolyn W; Wang, Zhe; Macaulay, Elizabeth; Jagsi, Reshma; Duane, Frances; Darby, Sarah C

2015-11-15

Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this "mean heart dose." In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose. Copyright © 2015 Elsevier Inc. All rights reserved.

A randomized, double-blind, crossover study comparing two- and four-dose hydrocortisone regimen with regard to quality of life, cortisol and ACTH profiles in patients with primary adrenal insufficiency.

PubMed

Ekman, Bertil; Bachrach-Lindström, Margareta; Lindström, Torbjörn; Wahlberg, Jeanette; Blomgren, Johan; Arnqvist, Hans J

2012-07-01

Current guidelines on how to divide the daily cortisol substitution dose in patients with primary adrenal insufficiency (PAI) are controversial and mainly based on empirical data. To assess how an equal dose of hydrocortisone (HC) given either four times daily or twice daily influence diurnal profiles of cortisol and ACTH, patient preferences and health-related quality of life (HRQoL). Double blind, crossover. Fifteen patients with PAI (six women) were included. Capsules of HC or placebo were given at 07:00, 12:00, 16:00 and 22:00 h in 4-week treatment periods: either one period with four doses (10 + 10 + 5 + 5 mg) or one period with two doses (20 + 0 + 10 + 0 mg). Diurnal profiles of cortisol and ACTH were collected, and area under the curve (AUC) was calculated. Questionnaires were used to evaluate patient preferences and HRQoL. The four-dose regimen gave a higher serum cortisol before tablet intake in the morning (P = 0·027) and a higher 24-h cortisol(AUC) (P < 0·0001) compared with the two-dose period. In contrast, a lower median plasma ACTH in the morning before tablet intake (P = 0·003) and a lower 24-h ln(ACTH(AUC) ) were found during the four-dose period. The patients preferred the four-dose regimen (P = 0·03), and the HRQoL scores tended to be higher (high score indicates better HRQoL) for the four-dose period. In summary, a four-dose regimen gives increased availability of cortisol and an enhanced effect with a less elevated ACTH in the morning in comparison with a two-dose regimen but the effect on HRQoL remains inconclusive. © 2012 Blackwell Publishing Ltd.

Dashboard systems: Pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies.

PubMed

Mould, Diane R; Dubinsky, Marla C

2015-03-01

Many marketed drugs exhibit high variability in exposure and response. While these drugs are efficacious in their approved indications, finding appropriate dose regimens for individual patients is not straightforward. Similar dose adjustment problems are also seen with drugs that have a complex relationship between exposure and response and/or a narrow therapeutic window. This is particularly true for monoclonal antibodies, where prolonged dosing at a sub-therapeutic dose can also elicit anti-drug antibodies which will further compromise safety and efficacy. Thus, finding appropriate doses quickly would represent a substantial improvement in healthcare. Dashboard systems, which are decision-support tools, offer an improved, convenient means of tailoring treatment for individual patients. This article reviews the clinical need for this approach, particularly with monoclonal antibodies, the design, development, and testing of such systems, and the likely benefits of dashboard systems in clinical practice. We focus on infliximab for reference. © 2015, The American College of Clinical Pharmacology.

76 FR 12972 - Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-09

.../phone line to learn about possible modifications before coming to the meeting. Agenda: On May 17 and 18... children less than 2 years of age. In addition, the committees will consider adding a weight-based dosing regimen to the existing age-based dosing regimen for children 2 to 12 years of age. Dosing for children 12...

Treatment-time regimen of hypertension medications significantly affects ambulatory blood pressure and clinical characteristics of patients with resistant hypertension.

PubMed

Hermida, Ramón C; Ríos, María T; Crespo, Juan J; Moyá, Ana; Domínguez-Sardiña, Manuel; Otero, Alfonso; Sánchez, Juan J; Mojón, Artemio; Fernández, José R; Ayala, Diana E

2013-03-01

Patients with resistant hypertension (RH) are at greater risk for stroke, renal insufficiency, and cardiovascular disease (CVD) events than are those for whom blood pressure (BP) is responsive to and well controlled by therapeutic interventions. Although all chronotherapy trials have compared the effects on BP regulation of full daily doses of medications when ingested in the morning versus at bedtime, prescription of the same medications in divided doses twice daily (BID) is frequent. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and laboratory medicine parameters of RH patients evaluated by 48-h ambulatory BP monitoring (ABPM). This cross-sectional study evaluated 2899 such patients (1701 men/1198 women), 64.2 ± 11.8 (mean ± SD) yrs of age, enrolled in the Hygia Project. Among the participants, 1084 were ingesting all hypertension medications upon awakening (upon-awakening regimen), 1436 patients were ingesting the full daily dose of ≥1 of them at bedtime (bedtime regimen), and 379 were ingesting split doses of ≥1 medications BID upon awakening and at bedtime (BID regimen). Patients of the bedtime regimen compared with the other two treatment-time regimens had lower likelihood of microalbuminuria and chronic kidney disease; significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; plus higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. The bedtime regimen was also significantly associated with lower asleep systolic (SBP) and diastolic (DBP) BP means than the upon-awakening and BID regimens. The sleep-time relative SBP and DBP decline was significantly attenuated by the upon-awakening and BID regimens (p < .001), resulting in significantly higher prevalence of non-dipping in these two treatment-time regimen groups (80.5% and 77.3%, respectively) than in the bedtime regimen (54.4%; p < .001 between groups). Additionally, the prevalence of the riser BP pattern, associated with highest CVD risk, was much greater, 31.0% and 29.8%, respectively, among patients of the upon-awakening and BID-treatment regimens, compared with the bedtime regimen (17.6%; p < .001 between groups). Patients of the bedtime regimen also showed significantly higher prevalence of properly controlled ambulatory BP (p < .001) as a result of a greater proportion of them showing complete control of asleep SBP and DBP means. Our findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of blunted nighttime BP decline, i.e., lower prevalence of CVD risk markers, in RH patients ingesting the full daily dose of ≥1 hypertension medications at bedtime than in those ingesting all of them upon awakening or ≥1 of them as split doses BID. In RH, ingesting the same medications BID neither improves ambulatory BP control nor reduces the prevalence of non-dipping, and cannot be considered chronotherapy. Collectively, findings of this study indicate that a bedtime hypertension medication regimen, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of true RH and avoid treatment-induced nocturnal hypotension, should be the therapeutic scheme of choice for patients who, by conventional cuff methods (and in the absence of ABPM) and the morning-treatment regimen, have been mistakenly judged to be resistant to therapy.

Molecular and Pharmacological Determinants of the Therapeutic Response to Artemether-Lumefantrine in Multidrug-Resistant Plasmodium falciparum Malaria

PubMed Central

Price, Ric N.; Uhlemann, Anne-Catrin; van Vugt, Michele; Al Brockman; Hutagalung, Robert; Nair, Shalini; Nash, Denae; Singhasivanon, Pratap; Anderson, Tim J. C.; Krishna, Sanjeev; White, Nicholas J.; Nosten, François

2015-01-01

Background Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). Methods On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. Results All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%–17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%–4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8–2.4-fold) increase in lumefantrine inhibitory concentration50 (P = .001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4–11; P = .008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5–53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. Conclusions The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic. PMID:16652314

Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.

PubMed

Price, Ric N; Uhlemann, Anne-Catrin; van Vugt, Michele; Brockman, Al; Hutagalung, Robert; Nair, Shalini; Nash, Denae; Singhasivanon, Pratap; Anderson, Tim J C; Krishna, Sanjeev; White, Nicholas J; Nosten, François

2006-06-01

Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.

In vitro and in vivo assessment of platelet function in healthy dogs during administration of a low-dose aspirin regimen.

PubMed

Haines, Jillian M; Thomason, John M; Seage, Eileen C; Wills, Robert W; Bulla, Camilo; Lunsford, Kari V; Mackin, Andrew J

2016-02-01

To assess the in vitro and in vivo platelet function of healthy dogs during administration of a low-dose aspirin regimen. 16 dogs. Dogs received aspirin (1 mg/kg, PO, q 24 h) for 7 days. Blood and urine samples were collected before (day 1; baseline) and on days 3 and 7 of the low-dose aspirin regimen. Platelet function was evaluated by use of turbidimetric and conventional impedance aggregometry, multiple-electrode impedance aggregometry, a platelet function analyzer (PFA), and determination of urine 11-dehydro-thromboxane B2 concentration. Turbidimetric aggregometry results were compared with the results obtained by the other 4 methods. Fourteen days after cessation of aspirin, platelet-rich plasma was incubated with acetylsalicylic acid and platelet function was assessed by turbidimetric aggregometry to determine whether this technique could accurately identify dogs that responded to the low-dose aspirin regimen. Of the 16 dogs, 13 had turbidimetric and conventional impedance aggregometry results that were decreased by > 25% from baseline on days 3 and 7, and 4 and 7 dogs had PFA closure times > 300 seconds on days 3 and 7, respectively. The median urine 11-dehydro-thromboxane B2 concentration-to-creatinine concentration ratio decreased by 49% between days 1 and 7. Turbidimetric aggregometry results were correlated with conventional impedance aggregometry results. There was poor agreement between the turbidimetric aggregometry and PFA results. The multiple-electrode impedance aggregometry protocol failed to reliably detect aspirin-induced platelet dysfunction. In vitro incubation of platelet-rich plasma with acetylsalicylic acid followed by turbidimetric aggregometry did not predict whether dogs responded to the low-dose aspirin regimen. Results indicated that the response to a low-dose aspirin regimen varied among healthy dogs.

Bleeding profile of a flexible extended regimen of ethinylestradiol/drospirenone in US women: an open-label, three-arm, active-controlled, multicenter study.

PubMed

Jensen, Jeffrey T; Garie, Sona Grossova; Trummer, Dietmar; Elliesen, Jörg

2012-08-01

Unscheduled bleeding may affect satisfaction and compliance with extended oral contraceptive (OC) regimens. The bleeding patterns of two variants of a flexible dosing regimen designed to manage intracyclic bleeding problems during extended cycles were compared with that of a conventional OC regimen. This was a 1-year, open-label, active-controlled, Phase 3 study conducted in the USA. Healthy women (18-45 years) received an ethinylestradiol (EE) 20 mcg/drospirenone 3 mg OC in two flexible extended regimens or in a conventional 24/4 (i.e., 28-day) regimen. The primary regimen [management of intracyclic bleeding (flexible(MIB)) regimen] was an extended dosing regimen that required subjects to initiate 4-day tablet-free intervals after 3 days of breakthrough bleeding/spotting. An alternative extended regimen [active period control (flexible(APC)) regimen] allowed subjects to initiate a 4-day tablet-free interval irrespective of the occurrence of bleeding. Bleeding profiles were compared between treatments. Efficacy and safety outcomes were also assessed. The full analysis set comprised 1864 women (flexible(MIB), N=1406; flexible(APC), N=232; conventional 24/4, N=226). Over 1 year, subjects in the flexible(MIB) group experienced significantly fewer (mean±SD, 40±30) bleeding/spotting days than those in the conventional 24/4 group (52±35). The corresponding value in the flexible(APC) group was 47±33 days. The pregnancy rate in the flexible(MIB) group was 1.65 per 100 woman-years (95% confidence interval, 0.96-2.65). All three regimens were well tolerated. A flexible(MIB) dosing regimen of EE 20 mcg/drospirenone 3 mg is associated with good contraceptive efficacy and fewer bleeding/spotting days than the conventional 24/4 regimen. Copyright © 2012 Elsevier Inc. All rights reserved.

Growth and development after hematopoietic cell transplant in children.

PubMed

Sanders, J E

2008-01-01

Hematopoietic cell transplantation (HCT) following high-dose chemotherapy or chemoradiotherapy for children with malignant or nonmalignant hematologic disorders has resulted in an increasing number of long-term disease-free survivors. The preparative regimens include high doses of alkylating agents, such as CY with or without BU, and may include TBI. These agents impact the neuroendocrine system in growing children and their subsequent growth and development. Children receiving high-dose CY or BUCY have normal thyroid function, but those who receive TBI-containing regimens may develop thyroid function abnormalities. Growth is not impacted by chemotherapy-only preparative regimens, but TBI is likely to result in growth hormone deficiency and decreased growth rates that need to be treated with synthetic growth hormone therapy. Children who receive high-dose CY-only have normal development through puberty, whereas those who receive BUCY have a high incidence of delayed pubertal development. Following fractionated TBI preparative regimens, approximately half of the patients have normal pubertal development. These data demonstrate that the growth and development problems after HCT are dependent upon the preparative regimen received. All children should be followed for years after HCT for detection of growth and development abnormalities that are treatable with appropriate hormone therapy.

Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial.

PubMed

St Peter, Shawn D; Tsao, Kuojen; Spilde, Troy L; Holcomb, George W; Sharp, Susan W; Murphy, J Patrick; Snyder, Charles L; Sharp, Ronald J; Andrews, Walter S; Ostlie, Daniel J

2008-06-01

Appendicitis is the most common emergency condition in children. Historically, a 3-drug regimen consisting of ampicillin, gentamicin, and clindamycin (AGC) has been used postoperatively for perforated appendicitis. A retrospective review at our institution has found single day dosing of ceftriaxone and metronidazole (CM) to be a more simple and cost-effective antibiotic strategy. Therefore, we performed a prospective, randomized trial to compare efficacy and cost-effectiveness of these 2 regimens. After internal review board approval (IRB no. 04 12-149), children found to have perforated appendicitis at appendectomy were randomized to either once daily dosing of CM (2 total doses per day) or standard dosing of AGC (11 total doses per day). Perforation was defined as an identifiable hole in the appendix. The operative approach (laparoscopic), length of antibiotic use, and criteria for discharge were standardized for the groups. Based on our retrospective analysis using length of postoperative hospitalization as a primary end point, a sample size of 100 patients was calculated for an alpha of .5 and a power of 0.82. One hundred patients underwent laparoscopic appendectomy for perforated appendicitis. On presentation, there were no differences in sex distribution, days of symptoms, temperature, or leukocyte count. There was no difference in abscess rate or wound infections between groups. The CM group resulted in significantly less antibiotic charges then the AGC group. Once daily dosing with the 2-drug regimen (CM) offers a more efficient, cost-effective antibiotic management in children with perforated appendicitis without compromising infection control when compared to a traditional 3-drug regimen.

Effective Antimicrobial Regimens for Use in Humans for Therapy of Bacillus anthracis Infections and Postexposure Prophylaxis†

PubMed Central

Deziel, Mark R.; Heine, Henry; Louie, Arnold; Kao, Mark; Byrne, William R.; Basset, Jennifer; Miller, Lynda; Bush, Karen; Kelly, Michael; Drusano, G. L.

2005-01-01

Expanded options for treatments directed against pathogens that can be used for bioterrorism are urgently needed. Treatment regimens directed against such pathogens can be identified only by using data derived from in vitro and animal studies. It is crucial that these studies reliably predict the efficacy of proposed treatments in humans. The objective of this study was to identify a levofloxacin treatment regimen that will serve as an effective therapy for Bacillus anthracis infections and postexposure prophylaxis. An in vitro hollow-fiber infection model that replicates the pharmacokinetic profile of levofloxacin observed in humans (half-life [t1/2], 7.5 h) or in animals, such as the mouse or the rhesus monkey (t1/2, ∼2 h), was used to evaluate a proposed indication for levofloxacin (500 mg once daily) for the treatment of Bacillus anthracis infections. The results obtained with the in vitro model served as the basis for the doses and the dose schedules that were evaluated in the mouse inhalational anthrax model. The effects of levofloxacin and ciprofloxacin treatment were compared to those of no treatment (untreated controls). The main outcome measure in the in vitro hollow-fiber infection model was a persistent reduction of culture density (≥4 log10 reduction) and prevention of the emergence of levofloxacin-resistant organisms. In the mouse inhalational anthrax model the main outcome measure was survival. The results indicated that levofloxacin given once daily with simulated human pharmacokinetics effectively sterilized Bacillus anthracis cultures. By using a simulated animal pharmacokinetic profile, a once-daily dosing regimen that provided a human-equivalent exposure failed to sterilize the cultures. Dosing regimens that “partially humanized” levofloxacin exposures within the constraints of animal pharmacokinetics reproduced the antimicrobial efficacy seen with human pharmacokinetics. In a mouse inhalational anthrax model, once-daily dosing was significantly inferior (survival end point) to regimens of dosing every 12 h or every 6 h with identical total daily levofloxacin doses. These results demonstrate the predictive value of the in vitro hollow-fiber infection model with respect to the success or the failure of treatment regimens in animals. Furthermore, the model permits the evaluation of treatment regimens that “humanize” antibiotic exposures in animal models, enhancing the confidence with which animal models may be used to reliably predict the efficacies of proposed antibiotic treatments in humans in situations (e.g., the release of pathogens as agents of bioterrorism or emerging infectious diseases) where human trials cannot be performed. A treatment regimen effective in rhesus monkeys was identified. PMID:16304178

Bioavailability of the Yuzpe and levonorgestrel regimens of emergency contraception: vaginal vs. oral administration.

PubMed

Kives, Sari; Hahn, Philip M; White, Emily; Stanczyk, Frank Z; Reid, Robert L

2005-03-01

Separate crossover studies compared the bioavailability of oral vs. vaginal routes of administration for the Yuzpe (n=5) and levonorgestrel regimens (n=4) of emergency contraception. Twice the standard dose of the Yuzpe regimen (200 microg of ethinyl estradiol, 1000 microg of levonorgestrel) or the levonorgestrel regimen (1500 microg of levonorgestrel) was self-administered vaginally. One week later, each subject received orally the standard dose of the assigned medication. Serial blood samples were collected over 24 h and assayed for levonorgestrel and ethinyl estradiol (for the Yuzpe regimen only). Paired t tests were used to compare oral vs. vaginal administration for maximum concentration (Cmax), time to maximum concentration (Tmax) and area under the curve over 24 h (AUC0-24). Relative bioavailability (vaginal/oral) was derived from AUC0-24. Vaginal administration of double the standard dose of the Yuzpe regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=14.6 ng/mL, p=.038) and a later Tmax (5.9 vs. 2.0 h, p=.066) for levonorgestrel, compared to oral administration. Corresponding ethinyl estradiol concentrations were higher (786 vs. 391 pg/mL, p=.039) and peaked later (4.0 vs. 1.9 hr, p=.154) with vaginal administration. Relative bioavailabilities for levonorgestrel and ethinyl estradiol were 58% and 175%, respectively. Similarly, vaginal administration of the levonorgestrel regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=15.2 ng/mL, p=.006) and a later Tmax (7.4 vs. 1.3 h, p=.037) for levonorgestel, compared to oral administration. The relative bioavailability was 62%. Our preliminary data suggest that vaginal administration of these emergency contraception regimens appears to require at least three times the standard oral dose to achieve equivalent systemic levonorgestrel concentrations.

Comparison of two melphalan protocols and evaluation of outcome and prognostic factors in multiple myeloma in dogs

PubMed Central

Fernández, Ricardo

2018-01-01

Background Multiple myeloma (MM) in dogs typically is treated with melphalan. A daily melphalan dosing schedule reportedly is well tolerated and associated with favorable outcome. Although anecdotally a pulse dose regimen has resulted in successful responses, little long‐term outcome and safety data is available regarding this dosing regimen for dogs with MM. Hypothesis/objectives (1) To compare outcome and adverse event profiles between pulse dose and daily dose melphalan schedules and (2) to report prognostic factors in dogs with MM treated with melphalan. We hypothesized that both protocols would have similar outcomes and tolerability. Animals Thirty‐eight client‐owned dogs diagnosed with MM receiving pulse dose (n = 17) or daily dose (n = 21) melphalan. Methods Retrospective cohort study assessing outcome and adverse events in dogs receiving either protocol. Risk factors were evaluated for their prognostic relevance. Results Both regimens were well tolerated and similarly effective, with an overall median survival time of 930 days. Renal disease and neutrophil‐to‐lymphocyte ratio (NLR) were negative prognostic factors, whereas hypercalcemia and osteolytic lesions were not prognostic factors in this study population. Conclusions and Clinical Importance Positive results support the use of either dosing regimen for the treatment of dogs with MM, and renal disease and NLR were negative prognostic factors. Prospective, controlled, and randomized studies are warranted to confirm these findings. PMID:29566439

Comparative toxicities of 3 platinum-containing chemotherapy regimens in relapsed/refractory lymphoma patients.

PubMed

Tixier, F; Ranchon, F; Iltis, A; Vantard, N; Schwiertz, V; Bachy, E; Bouafia-Sauvy, F; Sarkozy, C; Tournamille, J F; Gyan, E; Salles, G; Rioufol, C

2017-12-01

Optimal salvage chemotherapy regimen for patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma remains unclear but often based on platinum regimens. This retrospective study assesses in real life the toxicities profiles of patients with relapsed or refractory lymphoma treated with DHA (dexamethasone, high dose aracytine cytarabine) plus platinum salt (dexamethasone-High dose aracytine (cis)platin (DHAP), dexamethasone-High dose aracytine carboplatin (DHAC), or dexamethasone-High dose aracytine Oxaliplatin (DHAOX)), from February 2007 to May 2013 in 2 French hospitals. Toxicities were recorded from medical files and assessed according to the National Cancer Institute Common Toxicity Criteria version 3.0. Potential risk factors of renal insufficiency were tested by univariate analyses. A total of 276 patients were treated: 168 with DHAP (60.9%), 79 with DHAOX (28.6%), and 29 with DHAC (10.5%). Rituximab was associated in 80.1% of patients (n = 221). Renal failure was reported in 97 patients, mainly with cisplatin regimen (86.6%) leading to 8.9% grade III to IV renal failure (P = .001). Renal insufficiency was reversible in most patients but remained persistent in 24, with all of them being treated with DHAP except 1. Cisplatin-based regimen (50.0% versus 12.0%, P < .05) and female (44.6% versus 29.7%, P < .05) appeared to be at higher risks of renal failure. Platinum cumulative dose is a significant risk factor of nephrotoxicity. Hematologic toxicity was more frequent with carboplatin and cisplatin with at least 1 event (all toxicity grade) respectively in 79.3% and 71.4% of patients treated (P < .005). Auditory toxicity was mainly reported with cisplatin (n = 19; 4 grade I-II and 15 grade III-IV). Oxaliplatin was implicated in 77.6% of neurotoxicity (n = 59), mainly moderate (grade I-II). In conclusion, DHAOX and DHAC regimens have more favorable toxicity profile than DHAP regimen. Their lack of renal toxicity makes them attractive regimens, which may be interesting for patients eligible for autologous stem cell transplantation. Nevertheless, these results have to be confirmed by the therapeutic efficacy of these 3 regimens. Copyright © 2016 John Wiley & Sons, Ltd.

High-dose etoposide (VP-16)-containing preparatory regimens in allogeneic and autologous bone marrow transplantation for hematologic malignancies.

PubMed

Blume, K G; Forman, S J

1992-12-01

High-dose etoposide has been added to total body irradiation, cyclophosphamide, carmustine, or busulfan in preparatory regimens for allogeneic or autologous bone marrow transplantation for patients with leukemia, Hodgkin's disease, lymphoma, or multiple myeloma. The treatment results are encouraging, indicating that etoposide may be a valuable addition to the previously established regimens. Etoposide should be incorporated into collaborative, prospective trials to define its ultimate role in bone marrow transplantation.

Randomized controlled trial of a dose consolidation program.

PubMed

Delate, Thomas; Fairman, Kathleen A; Carey, Shelly M; Motheral, Brenda R

2004-01-01

To evaluate the effectiveness and financial impact of a drug dose consolidation (optimization) program using letter intervention. This pilot program in a large, mid-Atlantic health plan utilized a randomized controlled trial research design. A review of adjudicated pharmacy claims records was performed monthly for 3 consecutive months from November 2002 through February 2003 to identify inefficient (i.e., >once-daily) regimens for any one of 68 dosage strengths of 37 single-source maintenance drugs with once-daily dosing recommendations. Prescribers who had prescribed one or more inefficient regimens were identified and randomized to one of the 2 intervention arms or a control arm. Prescribers in both intervention arms were sent personalized letters with information on their patients. inefficient regimens and suggested dose consolidation options. Patients of prescribers in one intervention arm received a complementary, patient-oriented letter. Pharmacy claims for patients in all arms were examined at 180 days after the date of the letter mailing for conversion to an efficient (once-daily) regimen. Financial modeling analysis calculated net savings as changes in pharmacy expenditures minus administrative costs. A total of 2,614 inefficient regimens, representing 6.7% of claims for the targeted medications, were identified. The rate of consolidation to a suggested dosing option was lower for the Physician Letter arm (7.3%) than for the Physician/Member Letter arm (10.2%) (P = 0.046). Both intervention arms had higher consolidation rates than the Control arm (3.9%) (P = 0.018 and P = 0.000, respectively.). Approximately 30% of the regimens in each study arm were never refilled after being targeted. Financial modeling indicated that a dose consolidation intervention could save 0.03 dollars to 0.07 dollars per member per month (PMPM) in 2003 dollars with full medication compliance but only 0.02 dollars to 0.03 dollars PMPM when savings were calculated with realistic, partial compliance rates. Subanalyses performed at the drug therapy class level revealed few opportunities to justify implementing a dose consolidation program. After taking into consideration program administrative costs, high rates of refill discontinuation, and dose consolidation that occurs naturally without intervention, the results indicated that a letter-based dose consolidation program did not appreciably decrease pharmacy expenditures.

Comparison of the safety and efficacy of a fixed-dose combination regimen and separate formulations for pulmonary tuberculosis treatment.

PubMed

Wu, Jiun-Ting; Chiu, Chien-Tung; Wei, Yu-Feng; Lai, Yung-Fa

2015-06-01

Fixed-dose combination formulations, which simplify the administration of drugs and prevent the development of drug resistance, have been recommended as a standard anti-tuberculosis treatment regimen. However, the composition and dosage recommendations for fixed-dose combination formulations differ from those for separate formulations. Thus, questions about the effectiveness and side effects of combination formulations remain. The aim of this study was to compare the safety and efficacy of these two types of anti-tuberculosis regimens for pulmonary tuberculosis treatment. A prospective, randomized controlled study was conducted using the directly observed treatment short-course strategy. Patients were randomly allocated to one of two short-course regimens. One year after completing the treatment, these patients' outcomes were analyzed. ClinicalTrials.gov: NCT00979290. A total of 161 patients were enrolled, 142 of whom were evaluable for safety assessment. The two regimens had a similar incidence of adverse effects. In the per-protocol population, serum bilirubin concentrations at the peak level, at week 4, and at week 8 were significantly higher for the fixed-dose combination formulation than for the separate formulations. All patients had negative sputum cultures at the end of the treatment, and no relapse occurred after one year of follow-up. In this randomized study, transient higher serum bilirubin levels were noted for the fixed-dose combination regimen compared with the separate formulations during treatment. However, no significant difference in safety or efficacy was found between the groups when the directly observed treatment short-course strategy was used.

Rethinking the laryngopharyngeal reflux treatment algorithm: Evaluating an alternate empiric dosing regimen and considering up-front, pH-impedance, and manometry testing to minimize cost in treating suspect laryngopharyngeal reflux disease.

PubMed

Carroll, Thomas L; Werner, Astrid; Nahikian, Kael; Dezube, Aaron; Roth, Douglas F

2017-10-01

Empiric proton pump inhibitor (PPI) trials for laryngopharyngeal reflux (LPR) are common. A majority of the patients respond to acid suppression. This work intends to evaluate once-daily, 40 mg omeprazole and once-nightly, 300 mg ranitidine (QD/QHS) dosing as an alternative regimen, and use this study's cohort to evaluate empiric regimens prescribed for LPR as compared to up-front testing with pH impedance multichannel intraluminal impedance (MII) with dual pH probes and high-resolution manometry (HRM) for potential cost minimization. Retrospective cohort review and cost minimization study. A chart review identified patients diagnosed with LPR. All subjects were treated sequentially and outcomes recorded. Initial QD/QHS dosing increased after 3 months to BID if no improvement and ultimately prescribed MII and HRM if they failed BID dosing. Decision tree diagrams were constructed to determine costs of two empiric regimens and up-front MII and HRM. Ninety-seven subjects met the criteria. Responders and nonresponders to empiric therapy were identified. Seventy-two subjects (74%) responded. Forty-eight (67% of responders and 49% of all) improved with QD/QHS dosing. Forty-nine (51%) subjects escalated to BID dosing. Twenty-four subjects (33% of responders and 25% of all) improved on BID therapy. Twenty-five subjects (26%) did not respond to acid suppression. Average weighted cost was $1,897.00 per patient for up-front testing, $3,033.00 for initial BID, and $3,366.00 for initial QD/QHS. An alternate QD/QHS regimen improved the majority who presented with presumed LPR. Cost estimates demonstrate that the QD/QHS regimen was more expensive than the initial BID high-dose PPI for 6 months. Overall per-patient cost appears less with up-front MII and HRM. 4. Laryngoscope, 127:S1-S13, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013

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

Taylor, Carolyn W., E-mail: carolyn.taylor@ctsu.ox.ac.uk; Wang, Zhe; Macaulay, Elizabeth

Purpose: Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Methods and Materials: Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this “mean heart dose.” Results: In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28more » countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Conclusions: Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose.« less

Efficacy of alternate day versus daily dosing of rosuvastatin

PubMed Central

Dulay, Daisy; LaHaye, Stephen A; Lahey, Karen A; Day, Andrew G

2009-01-01

BACKGROUND: Compared with other statins, rosuvastatin has a relatively long half-life, which may allow for the administration of this medication on an alternate day basis. OBJECTIVE: To compare the efficacy of administering rosuvastatin on a daily basis versus on an alternate day basis for the treatment of dyslipidemia. METHODS: In the present crossover study, 45 patients with documented hypercholesterolemia requiring pharmacotherapy were administered either 20 mg of rosuvastatin on alternate days or 10 mg of rosuvastatin daily for six weeks. After a four-week washout period, patients were then switched to the other regimen for another six weeks. The primary end point was the percentage reduction of low-density lipoprotein cholesterol (LDL-C). RESULTS: LDL-C decreased by 48.5% versus 40.9% with daily and alternate day dosing, respectively. This represented an additional absolute reduction of LDL-C of 7.6% (95% CI 1.8% to 13.4%, P=0.012) with the daily dosing regimen. Both dosing regimens provided similar improvements in high-density lipoprotein cholesterol and triglycerides. CONCLUSIONS: Compared with alternate day dosing, daily dosing of rosuvastatin provides a statistically significant advantage in LDL-C reduction. However, the alternate day regimen may be a viable option for those patients in whom cost is a limitation to compliance. PMID:19214297

Delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen: a case report.

PubMed

Sokolova, Alexandra; Chan, Onyee; Ullah, Waqas; Hamdani, Auon Abbas; Anwer, Faiz

2017-04-11

High-dose chemotherapy with autologous stem cell rescue is commonly used for the treatment of relapsed germ cell tumors. We report the first case of delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen. We report a case of a 21-year-old African-American man diagnosed with relapsed non-seminomatous germ cell tumor who received high-dose chemotherapy with carboplatin and etoposide following TIGER trial arm B off-protocol. His course was complicated by muscle pain and rhabdomyolysis after cycle 4 on day +12 after infusion of autologous stem cells. To the best of our knowledge, this complication has not been reported with this regimen. A differential diagnosis of sepsis and neutropenic fever along with side effects of high-dose chemotherapy were considered, but based on the timing of events, it was concluded that the etiology of rhabdomyolysis is high-dose chemotherapy. Rhabdomyolysis was successfully treated with hydration and did not recur during subsequent cycle 5. Delayed rhabdomyolysis after high-dose chemotherapy with paclitaxel, ifosfamide, carboplatin, and etoposide regimen has not been previously reported and needs to be considered for preventive strategy and prompt diagnosis and treatment to avoid renal complications. Physicians should have a low threshold to check creatine kinase enzymes in patients with unexplained muscle pain or renal insufficiency after high-dose chemotherapy.

Comparative antimicrobial activity of levofloxacin and ciprofloxacin against Streptococcus pneumoniae.

PubMed

Garrison, Mark W

2003-09-01

Levofloxacin has good coverage against both Gram-positive and Gram-negative pathogens. Recent reports demonstrate enhanced activity associated with a higher 750 mg dosage of levofloxacin. The objective of this study was to comparatively evaluate the activity of common regimens of levofloxacin (500 mg) and ciprofloxacin (500 mg), and a higher 750 mg levofloxacin regimen against penicillin susceptible and non-susceptible strains of S. pneumoniae. An in vitro pharmacodynamic modelling apparatus (PDMA) characterized specific bacterial kill profiles for simulated regimens of levofloxacin and ciprofloxacin against four strains of S. pneumoniae. Total log reduction, time for 3-log reduction and AUC/MIC were determined. Ciprofloxacin was less effective than the levofloxacin regimens against all four study isolates. Ciprofloxacin produced 3-log reduction in only one isolate compared with all four isolates with the levofloxacin regimens. Bacterial regrowth did not occur over 12 h with levofloxacin; however, three of four isolates demonstrated bacterial regrowth with ciprofloxacin. None of the isolates were cleared from the PDMA by ciprofloxacin. The 500 mg levofloxacin regimen cleared two of four isolates and the 750 mg dose of levofloxacin cleared all study isolates. Respective AUC/MIC values for levofloxacin (500 and 750 mg) and ciprofloxacin were 44-89, 63-126 and < or =13, which correlated well with bacterial kill data. Both levofloxacin regimens were more effective than ciprofloxacin against the study isolates tested. The 750 mg levofloxacin regimen generated more favourable bacterial killing compared with the 500 mg levofloxacin regimen. In addition to using the 750 mg levofloxacin dose for nosocomial infections, this dose may also prove useful for the management of resistant pneumococcal infections.

Evaluation of language concordant, patient-centered drug label instructions.

PubMed

Bailey, Stacy Cooper; Sarkar, Urmimala; Chen, Alice Hm; Schillinger, Dean; Wolf, Michael S

2012-12-01

Despite federal laws requiring language access in healthcare settings, most US pharmacies are unable to provide prescription (Rx) medication instructions to limited English proficient (LEP) patients in their native language. To evaluate the efficacy of health literacy-informed, multilingual Rx instructions (the ConcordantRx instructions) to improve Rx understanding, regimen dosing and regimen consolidation in comparison to standard, language-concordant Rx instructions. Randomized, experimental evaluation. Two hundred and two LEP adults speaking five non-English languages (Chinese, Korean, Russian, Spanish, Vietnamese), recruited from nine clinics and community organizations in San Francisco and Chicago. Subjects were randomized to review Rx bottles with either ConcordantRx or standard instructions. Proper demonstration of common prescription label instructions for single and multi-drug medication regimens. Regimen consolidation was assessed by determining how many times per day subjects would take medicine for a multi-drug regimen. Subjects receiving the ConcordantRx instructions demonstrated significantly greater Rx understanding, regimen dosing and regimen consolidation in comparison to those receiving standard instructions (incidence rate ratio [IRR]: 1.25, 95 % confidence interval [CI]: 1.06-1.48; P= 0.007 for Rx understanding, IRR: 1.19, 95 % CI: 1.03-1.39; P= 0.02 for regimen dosing and IRR: 0.76, 95 % CI: 0.64-0.90; P= 0.001 for regimen consolidation). In most cases, instruction type was the sole, independent predictor of outcomes in multivariate models controlling for relevant covariates. There is a need for standardized, multilingual Rx instructions that can be implemented in pharmacy practices to promote safe medication use among LEP patients. The ConcordantRx instructions represent an important step towards achieving this goal.

Translational PK/PD of Anti-Infective Therapeutics

PubMed Central

Rathi, Chetan; Lee, Richard E.; Meibohm, Bernd

2016-01-01

Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses. With this tool set at hand, mechanism-based PK/PD modeling and simulation allows to develop optimal dosing regimens for novel and established antibiotics for maximum efficacy and minimal resistance development. PMID:27978987

Temporal changes in physiology and haematology in response to high- and micro-doses of recombinant human erythropoietin.

PubMed

Clark, Brad; Woolford, Sarah M; Eastwood, Annette; Sharpe, Ken; Barnes, Peter G; Gore, Christopher J

2017-10-01

There is evidence to suggest athletes have adopted recombinant human erythropoietin (rHuEPO) dosing regimens that diminish the likelihood of being caught by direct detection techniques. However, the temporal response in physiology, performance, and Athlete Biological Passport (ABP) parameters to such regimens is not clearly understood. Participants were assigned to a high-dose only group (HIGH, n = 8, six rHuEPO doses of 250 IU/kg over two weeks), a combined high micro-dose group (COMB, n = 8, high-dose plus nine rHuEPO micro-doses over a further three weeks), or one of two placebo control groups who received saline in the same pattern as the HIGH (HIGH-PLACEBO, n = 4) or COMB (COMB-PLACEBO, n = 4) groups. Temporal changes in physiology and performance were tracked by graded exercise test (GXT) and haemoglobin mass assessment at baseline, after high dose, after micro-dose (COMB and COMB-PLACEBO only) and after a four-week washout. Venous blood samples were collected throughout the baseline, rHuEPO administration, and washout periods to determine the haematological and ABP response to each dosing regimen. Physiological adaptations induced by a two-week rHuEPO high-dose were maintained by rHuEPO micro-dosing for at least three weeks. However, all participants administered rHuEPO registered at least one suspicious ABP value during the administration or washout periods. These results indicate there is sufficient sensitivity in the ABP to detect use of high rHuEPO doping regimens in athletic populations and they provide important empirical examples for use by anti-doping experts. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes.

PubMed

Mohamed, Tarek Mostafa; Ghaffar, Hamdy M Abdel; El Husseiny, Rabee M R

2015-12-01

The present study is an unsubstantiated qualitative assessment of the abused drugs-tramadol and clonazepam. The aim of this study is to evaluate whether the effects of tramadol, clonazepam, and their combination on mitochondrial electron transport chain (ETC) complexes were influential at therapeutic or at progressively increasing doses. The study comprised of a total of 70 healthy male rats, aged 3 months. According to the drug intake regimen, animals were divided into seven groups: control, tramadol therapeutic, clonazepam therapeutic, combination therapeutic, tramadol abuse, clonazepam abuse, and combination abuse group. At the end of the experiment, brain mitochondrial ETC complexes (I, II, III, and IV) were evaluated. Histopathological examinations were also performed on brain tissues. The results showed that groups that received tramadol (therapeutic and abuse) suffered from weight loss. Tramadol abuse group and combination abuse group showed significant decrease in the activities of I, III, and IV complexes but not in the activity of complex II. In conclusion, tramadol but not clonazepam has been found to partially inhibit the activities of respiratory chain complexes I, III, and IV but not the activity of complex II and such inhibition occurred only at doses that exceeded the maximum recommended adult human daily therapeutic doses. This result explains the clinical and histopathological effects of tramadol, such as seizures and red neurons (marker for apoptosis), respectively. © The Author(s) 2012.

The lowest-dose, extended-cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 μg/levonorgestrel 100 μg + ethinyl estradiol 10 μg.

PubMed

Krishnan, Sheila; Kiley, Jessica

2010-08-10

Extended-cycle oral contraceptives (OCs) are increasing in popularity in the United States. A new extended-cycle OC that contains the lowest doses of ethinyl estradiol (EE) and levonorgestrel (LNG) + continuous EE throughout the cycle is now available. It provides 84 days of a low-dose, combined active pill containing levonorgestrel 100 μg and ethinyl estradiol 20 μg. Instead of 7 days of placebo following the active pills, the regimen delivers 7 days of ethinyl estradiol 10 μg. Existing studies reveal a similar efficacy and adverse effect profile compared with other extended-regimen OCs. Specifically, the unscheduled bleeding profile is similar to other extended-cycle OCs and improves with the increase in the duration of use. Although lower daily doses of hormonal exposure have potential benefit, to our knowledge, there are no published studies indicating that this specific regimen offers a lower incidence of hormone-related side effects or adverse events. In summary, this new extended-cycle OC provides patients a low-dose, extended-regimen OC option without sacrificing efficacy or tolerability.

Toward a universal antiretroviral regimen: special considerations of pregnancy and breast feeding.

PubMed

Slogrove, Amy L; Clayden, Polly; Abrams, Elaine J

2017-07-01

As optimized antiretroviral therapy (ART) regimens are prepared for introduction in low-income and middle-income countries (LMIC), we consider the current evidence related to dosing, efficacy and safety during pregnancy and breastfeeding of next-generation first-line and second-line ART regimens proposed for imminent introduction in the global marketplace. Pregnancy pharmacokinetic considerations include potentially insufficient efavirenz exposure if dosed at 400 mg/day, the need for twice daily darunavir dosing and the paucity of data related to tenofovir alafenamide and dolutegravir dosing, safety and efficacy. Increasingly evidence suggests an association with adverse birth outcomes, particularly in women conceiving on ART, and with varying risk by drug and drug combination. Clinical trials and studies are in progress or planned that aim to determine dosing, safety and efficacy of several new antiretrovirals (ARVs). Having a universal, highly potent and safe ART regimen for all individuals living with HIV in LMIC including pregnant women is clearly the most beneficial strategy to keep mothers alive and healthy and to prevent transmission of HIV to their children. It will have to be determined whether the use of this next generation of optimized ARVs will also optimize health outcomes of pregnant women and their children.

Pharmacokinetics and pharmacodynamics of qinghaosu derivatives: how do they impact on the choice of drug and the dosage regimens?

PubMed

Kyle, D E; Teja-Isavadharm, P; Li, Q; Leo, K

1998-01-01

The critical decisions of which artemisinin derivative(s) to use and by which route(s) of administration for falciparum malaria are complex scientifically and politically. Despite the need for additional pharmacokinetic, pharmacodynamic and toxicokinetic data, these drugs are too important to delay concise, rational recommendations any longer. These types of decisions must be made now, implemented on a multinational level with WHO leadership, and revised as new findings emerge. For acute, uncomplicated disease, per os dosing of artesunate or artemether for three days is recommended, but only in combination with other antimalarial drugs like mefloquine. For severe falciparum malaria, intravenous administration is the preferred route, yet current formulations for intravenous dosing are not optimal and should be an area for future development emphasis. Clearly intramuscular administration of artemether has proven effective for severe disease, yet dosing regimens shouldn't be designed with ultimate parasitological cure as the aim and the problem of bioavailability of the sesame oil formulations must be examined further. Once the life-saving reduction in parasitemia and pathophysiological sequelae have been achieved, the patient can be given oral medication to affect radical cure. Much more data will be required to define the role of per rectum dosing for the treatment of severe malaria, yet this approach holds great promise as a life-saving intervention in rural areas where this disease has it most dramatic impact.

Induction of labor using prostaglandin E2 (PGE2) vaginal gel in triacetin base. An efficacy study comparing two dosage regimens.

PubMed

Seeras, R C; Olatunbosun, O A; Pierson, R A; Turnell, R W

1995-01-01

To compare two dosage regimens for the administration of vaginal prostaglandin gel in triacetin base for induction of labor. Seventy subjects planned for elective induction of labor at term were randomized to treatment with PGE2 vaginal gel every 6 or 12 hours. The 6-hourly group received an initial dose of 1 mg, followed by 2 mg at 6 hour intervals for a maximum of two additional doses if not in active labor. The 12-hourly group had an initial dose of 2 mg followed by two additional doses at 12 hour intervals if not in active labor. Successful induction rate was higher in the 12-hourly as compared to 6-hourly gel regimen (100% vs. 91%, P > 0.05). Twelve hours after the initial dose, delivery occurred in 34% delivery had occurred in 57% and 37% respectively (P < 0.01). We found no difference in the induction-active labor interval (P > 0.05), and the induction-delivery interval (P > 0.05) between the two groups. Active labor followed a single dose of gel in 66% of the 12-hourly group compared to 40% of the 6-hourly group (P < 0.01). Syntocinon augmentation was needed in 6% of subjects in the 12-hourly group as compared to 26% in the 6-hourly group (P < 0.01). The cesarean section rate was similar in both groups. Uterine hyperstimulation occurred less frequently in the 12-hourly group (P < 0.05). The perinatal outcome was similar in both groups. The 12-hourly regimen was more effective than the 6-hourly regimen in initiating labor. The majority of the subjects in the 12 hourly group achieved labor following a single dose of gel. Induction delivery interval, however, was similar in both groups.

Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens.

PubMed

Wu, Lan; Leng, Donglei; Cun, Dongmei; Foged, Camilla; Yang, Mingshi

2017-08-28

Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy using different pharmaceuticals has been proven highly effective due to the ability to affect multiple cellular pathways involved in the disease progression. However, the currently used drug combination designs are primarily based on empirical clinical studies, and little attention has been given to dosage regimens, i.e. how administration routes, onsets, and durations of the combinations influence the therapeutic outcome. This is partly because combination therapy is challenged by distinct physicochemical properties and in vivo pharmacokinetics/pharmacodynamics of the individual pharmaceuticals, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Treatment regimens of classical and newer taxanes.

PubMed

Joerger, Markus

2016-02-01

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. The taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and a substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Still, the optimal dosing regimen (weekly vs 3 weekly) and optimal dose of the taxanes are controversial, as is the value of pharmacological personalization of taxane dosing. In this article, an overview is given on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen, the recommended initial dose and the issue of therapeutic drug dosing.

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

DOE PAGES

Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.; ...

2015-11-14

Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data frommore » non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. In conclusion, our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.« less

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

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

Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.

Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data frommore » non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. In conclusion, our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.« less

Evaluation of the Pharmacokinetics and Efficacy of a Busulfan Test Dose in Adult Patients Undergoing Myeloablative Hematopoietic Cell Transplantation.

PubMed

Weil, Elizabeth; Zook, Felicia; Oxencis, Carolyn; Canadeo, Angela; Urmanski, Angela; Waggoner, Mindy; Eastwood, Daniel; Pasquini, Marcelo; Hamadani, Mehdi; Hari, Parameswaran

2017-06-01

Owing to interpatient variability in busulfan exposure, therapeutic monitoring of busulfan is often used in myeloablative allogeneic transplantation to ensure that patients are near the optimal steady-state goal of 900 ng/mL. One challenge in therapeutic monitoring of busulfan is the brief course of busulfan treatment, requiring prompt analysis and dose adjustments as needed. Pharmacokinetic evaluation of a busulfan test dose before the start of the conditioning regimen would allow for all conditioning regimen doses to be given at the calculated optimized dose. An observational study was completed to evaluate the effects of a busulfan test dose of 0.9 mg/kg administered before the start of a myeloablative intravenous busulfan-based conditioning regimen. Sixty adult patients who received a busulfan conditioning regimen were reviewed, including 30 patients prior to the implementation of the busulfan test dose (pretest dose group) and 30 patients who received the busulfan test dose (posttest dose group). The primary objective was a pharmacokinetic evaluation of the percentage of patients who achieved the desired steady-state goal using the test dose strategy. The safety and efficacy of the busulfan test dose were evaluated as well. The average busulfan steady-state level after the first dose of the conditioning regimen was significantly lower in the pre-test dose group compared with the post-test dose group (660 ng/mL versus 879.9 ng/mL; P < 0.001). Compared with the post-test dose group, significantly fewer patients in the pre-test dose group were within 10% of the busulfan steady-state goal (10% versus 73.3%; P < 0.001) or within 5% of the goal (0% versus 53%; P < 0.001). Requirements for parenteral nutrition and/or patient-controlled analgesia owing to mucositis and rates of veno-occlusive disease were not significantly different between the pre-test dose group and the post-test dose group. The rates of disease relapse, mortality, and acute graft-versus-host disease were similar in the two groups. A pretransplantation busulfan test dose of 0.9 mg/kg improved the patients' ability to reach therapeutic busulfan target levels after the first conditioning dose and resulted in fewer adjustments during conditioning. The use of a busulfan test dose did not significantly increase patients' risk of mucositis or other safety outcomes. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Influence of the number of daily pills and doses on adherence to antiretroviral treatment: a 7-year study.

PubMed

Hernández Arroyo, M J; Cabrera Figueroa, S E; Sepúlveda Correa, R; Valverde Merino, M P; Luna Rodrigo, G; Domínguez-Gil Hurlé, A

2016-02-01

Antiretroviral treatment (ART) is hampered by complicated regimens, high pill burden, drug-drug interactions, and frequent short- and long-term adverse effects, leading to decreased adherence. Over recent years, considerable effort has been directed at developing regimens that are less burdening. We undertook a 7-year retrospective study of the records of 264 HIV-infected subjects enrolled in a pharmaceutical care programme to document the progress made and to study the influence of the number of ART pills and doses on the level of treatment adherence. Antiretroviral dispensing records were analysed for the number of pills and doses administered and the ART adherence rate estimated. In 2005, the patients took a mean of 6·2 pills daily (CI 95%: 5·9-6·6), and 92·9% of them were on a twice-a-day (BID) dosage regimen. By 2012, the mean number of pills was reduced to 4·1 (CI 95%: 3·8-4·4), and only 50·9% were on a BID regimen. No statistically significant relation was observed between number of daily pills and doses and ART adherence reached by the patients in any of the analyses performed. There has been a continuous reduction in the number of pills and doses of antiretrovirals taken by individual patients over the last 7 years due largely to the introduction of improved treatments and regimens. More daily pills or doses was not associated with worse ART adherence in our pharmaceutical care programme. © 2015 John Wiley & Sons Ltd.

Decorporation Approach after Rat Lung Contamination with Plutonium: Evaluation of the Key Parameters Influencing the Efficacy of a Protracted Chelation Treatment.

PubMed

Grémy, Olivier; Coudert, Sylvie; Renault, Daniel; Miccoli, Laurent

2017-11-01

While the efficacy of a protracted zinc (Zn)- or calcium (Ca)-diethylenetriaminepentaacetic acid (DTPA) treatment in reducing transuranic body burden has already been demonstrated, questions about therapeutic variables remain. In response to this, we designed animal experiments primarily to assess both the effect of fractionation of a given dose and the effect of the frequency of dose fraction, with the same total dose. In our study, rats were contaminated intravenously with plutonium (Pu) then treated several days later with Ca-DTPA given at once or in various split-dose regimens cumulating to the same total dose and spread over several days. Similar efficacies were induced by the injection of the total dose or by splitting the dose in several smaller doses, independent of the number of doses and the dose level per injection. In a second study, rats were pulmonary contaminated, and three weeks later they received a Ca-DTPA dose 11-fold higher than the maximal daily recommended dose, administered either as a single bolus or as numerous multiple injections cumulating to the same dose, based on different injection frequency schedules. Independent of frequency schedule, the various split-dose regimens spread over weeks/months were as efficient as single delivery of the total dose in mobilizing lung plutonium, and had a therapeutic advantage for removal of retained hepatic and bone plutonium burdens. We concluded that cumulative dose level was a therapeutic variable of greater importance than the distribution of split doses for the success of a repeated treatment regimen on retained tissue plutonium. In addition, pulmonary administration of clodronate, which aims at killing alveolar macrophages and subsequently releasing their plutonium content, and which is associated with a continuous Ca-DTPA infusion regimen, suggested that the efficacy of injected Ca-DTPA in decorporating lung deposit is limited, due to its restricted penetration into alveolar macrophages and not because plutonium, as a physicochemical form, is unavailable for chelation.

Extended-interval Dosing of Gentamicin in Premature Neonates Born at <32 Weeks' Gestation and >7 Days of age.

PubMed

Sundaram, Arun; Alshaikh, Belal; Dersch-Mills, Deonne; Dobry, Jenna; Akierman, Albert R; Yusuf, Kamran

2017-06-01

Extended-interval dosing (EID) regimens of gentamicin have been validated for treating confirmed or suspected early- and late-onset sepsis in preterm infants in the first week of life. Despite the marked changes in volume of distribution and renal clearance in preterm infants after the first few days of life, few studies have validated EID regimens of gentamicin in this population. The objective of the study was to evaluate an EID regimen of gentamicin in infants born at <32 weeks' gestational age and aged >7 days. This observational study of an EID regimen was conducted in 39 infants. Dosing interval was based on the serum drug concentration at 22 hours after the administration of the first dose of 5 mg/kg. Gentamicin peak (5-12 µg/mL) and trough (<2 µg/mL) levels were compared to those in a historical control group of 39 infants who received traditional-interval dosing (TID) of 2.5 mg/kg of gentamicin with dosing intervals of 8, 12, or 24 hours. There were no differences in birthweight, gestational age at birth, postmenstrual age, weight at the start of gentamicin administration, postnatal age, small for gestational age status, antenatal corticosteroid use, or postnatal indomethacin exposure between the 2 groups. In the EID group, dosing intervals were 24 hours in 30 infants, 36 hours in 6 infants, and 48 hours in 3 infants. Compared with the TID group (n = 39), the EID group had a significantly higher peak level (median, 9.0 vs 4.7 µg/mL) and a significantly lower trough level (median, 0.7 vs 1.1 µg/mL) (both, P < 0.001). On regression analysis, the postmenstrual age was correlated significantly with trough levels in the EID group. There was no adverse effect on renal function in either group. On follow-up, 1 infant in the EID group and 2 infants in the TID group had evidence of sensorineural hearing loss. In infants born at <32 weeks' gestation and >7 days of age, an EID gentamicin regimen, with a dosing interval based on a single concentration measurement at 22 hours after the administration of the first dose, achieved therapeutic peak and trough levels and performed significantly better than did a TID regimen in reaching target peak and trough levels. Larger-scale trials are needed for assessing the clinical efficacy (treatment failure/success) of these regimens. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Cardiovascular effects of Phaleria macrocarpa extracts combined with mainstay FAC regimen for breast cancer.

PubMed

Anggadiredja, Kusnandar; Tjandrawinata, Raymond R

2015-01-01

DLBS1425 is a bioactive compound extracted from Phaleria macrocarpa, with anti-proliferative, anti-inflammatory and anti-angiogenic properties against cancer cells. The present study was aimed to assess cardiotoxicity of DLBS1425, compared to the mainstay regimen for breast cancer, 5-fluorouracil:doxorubicin:cyclophosphamide (FAC, given at 500/50/500 mg/m(2)). Treatment with FAC regimen at standard dose resulted in very severe toxicity, so mice had no chance to survive for more than 7 days following initial drug treatment. Furthermore, histological examination on the heart revealed severe muscular damage when mice were given the FAC regimen alone (severe toxicity). FAC as chemotherapeutic regimen exerted high toxicity profile to the cardiovascular cells in this experiment. Meanwhile, treatment with DLBS1425 alone up to a dose equivalent to as high as 300 mg three times daily in human had no hazardous consequences on the heart, hematological feature, as well as general safety. In the cardiovascular cells, DLBS1425 in the presence of FAC regimen (one-eight of the initial dose) gave protection to the cardiac muscle cells as well as other hematological features. Taken together, results of the present study suggest that DLBS1425 is safe when used as adjuvant therapy for breast cancer and may be even protective against cardiac cellular damage produced by chemotherapeutic regimen.

How to mathematically optimize drug regimens using optimal control.

PubMed

Moore, Helen

2018-02-01

This article gives an overview of a technique called optimal control, which is used to optimize real-world quantities represented by mathematical models. I include background information about the historical development of the technique and applications in a variety of fields. The main focus here is the application to diseases and therapies, particularly the optimization of combination therapies, and I highlight several such examples. I also describe the basic theory of optimal control, and illustrate each of the steps with an example that optimizes the doses in a combination regimen for leukemia. References are provided for more complex cases. The article is aimed at modelers working in drug development, who have not used optimal control previously. My goal is to make this technique more accessible in the biopharma community.

Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers.

PubMed

Polepally, Akshanth R; King, Jennifer R; Ding, Bifeng; Shuster, Diana L; Dumas, Emily O; Khatri, Amit; Chiu, Yi-Lin; Podsadecki, Thomas J; Menon, Rajeev M

2016-08-01

The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments. Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC). Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP. Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose adjustment is necessary for the 3D regimen.

Dose-dependent effects of prenatal ethanol exposure in the guinea pig.

PubMed

Catlin, M C; Abdollah, S; Brien, J F

1993-01-01

The guinea pig is an appropriate animal for studying ethanol central nervous system (CNS) teratogenesis due to its extensive prenatal CNS development. In order to establish an ethanol dosage regimen that produces CNS teratogenesis, the objective of this study was to characterize the dose-dependent effects of chronic ethanol administration on pregnancy outcome and locomotor activity of the offspring. Pregnant guinea pigs received one of the following oral treatments, via intubation into the oral cavity, throughout gestation: 3, 4, 5 or 6 g ethanol/kg maternal body weight/day; isocaloric sucrose and pair feeding; or water. The 5 and 6 g ethanol/kg/day regimens produced maternal death, spontaneous abortion, and perinatal death with at least 75% incidence; the 3 and 4 g ethanol/kg/day regimens produced little or no maternal, embryonic/fetal, or perinatal lethality. The 3 and 4 g ethanol/kg/day regimens did not affect other indices of pregnancy outcome compared with the respective isocaloric-sucrose pair-fed control animals and water-treated animals. The 3, 4, and 5 g ethanol/kg/day regimens increased spontaneous locomotor activity in the offspring, and there was a direct relationship between the magnitude of hyperactivity at days 10 and 60 of age and each of the ethanol dosage regimens and the maternal blood ethanol concentration on day 56 of gestation. The data demonstrate that, in the guinea pig, chronic oral administration of ethanol produces: (a) dose-dependent effects on pregnancy outcome, (b) hyperactivity in the offspring that is dose- (and maternal blood ethanol concentration-) and age-related, and (c) persistent hyperactivity into adulthood with minimal toxicity on pregnancy outcome for the 4 g ethanol/kg/day regimen.

Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: the PASSPORT Program-Asia-Pacific Region.

PubMed

Roberts, Jason A; Kwa, Andrea; Montakantikul, Preecha; Gomersall, Charles; Kuti, Joseph L; Nicolau, David P

2011-03-01

Due to escalating antimicrobial resistance amongst Gram-negative organisms, the choice of effective empirical antimicrobial regimens has become challenging. Monte Carlo simulations were conducted for conventional and prolonged infusion regimens of doripenem, imipenem and meropenem using pharmacokinetic data from adult patients with conserved renal function. Minimum inhibitory concentration data against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii were incorporated from the COMPACT surveillance programme in the Asia-Pacific region of the world. The cumulative fraction of response (CFR) was determined for each regimen against each bacterial population. All simulated carbapenem regimens achieved an optimal CFR against E. coli and K. pneumoniae (94.5-100% CFR). Against P. aeruginosa, doripenem achieved 78.7-92.6% CFR, imipenem achieved 60.4-79.0% CFR and meropenem achieved 73.0-85.1% CFR. The only dosing regimen to achieve ≥ 90% CFR against P. aeruginosa was doripenem 1000 mg and 2000 mg every 8 h (4-h infusion). Carbapenem CFRs against A. baumannii were much lower (29.2-54.4% CFR). CFRs for non-fermenting isolates were ca. 10% lower for isolates collected in the Intensive Care Unit. Carbapenem resistance amongst Enterobacteriaceae remains low in the Asia-Pacific region and thus standard carbapenem dosing regimens had a high likelihood of achieving pharmacodynamic exposures. However, larger doses combined with prolonged infusion will be required to increase the CFR for these carbapenems against resistant non-fermenting Gram-negatives that are common in these countries. The safety and efficacy of these high dosing regimens will need to be confirmed in the clinical setting. Copyright © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Duration of treatment for asymptomatic bacteriuria during pregnancy.

PubMed

Widmer, Mariana; Gülmezoglu, A Metin; Mignini, Luciano; Roganti, Ariel

2011-12-07

A Cochrane systematic review has shown that drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis and reduces the risk of preterm delivery. However, it is not clear whether single-dose therapy is as effective as longer conventional antibiotic treatment. To assess the effects of different durations of treatment for asymptomatic bacteriuria in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2011) and reference lists of identified articles. Randomized and quasi-randomized trials comparing antimicrobial therapeutic regimens that differed in duration (particularly comparing single dose with longer duration regimens) in pregnant women diagnosed with asymptomatic bacteriuria. We assessed trial quality and extracted data independently. We included 13 studies, involving 1622 women. All were comparisons of single-dose treatment with four- to seven-day treatments. The trials were generally of limited quality. The 'no cure rate' for asymptomatic bacteriuria in pregnant women was slightly higher for the single-dose than for the short-course treatment; however, these results were not statistically significant and showed heterogeneity. When comparing the trials that used the same antibiotic in both treatment and control groups with the trials that used different antibiotics in both groups, the 'no cure rate' risk ratio was similar. There was no statistically significant difference in the recurrence of asymptomatic bacteriuria rate between treatment and control groups. Slight differences were detected for preterm births and pyelonephritis although, apart from one trial, the sample size of the trials was inadequate. Single-dose treatment was associated with a decrease in reports of 'any side-effects' . Single-dose regimen of antibiotics may be less effective than the seven-day regimen. Women with asymptomatic bacteriuria in pregnancy should be treated by the standard regimen of antibiotics until more data become available testing seven-day compared with three- or five-day regimens.

The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer's disease: a preliminary investigation.

PubMed

Nathan, Pradeep J; Boardley, Rebecca; Scott, Nicola; Berges, Alienor; Maruff, Paul; Sivananthan, Tharani; Upton, Neil; Lowy, Martin T; Nestor, Peter J; Lai, Robert

2013-03-01

The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer's disease using ascending dose titration regimens. The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients. Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37. GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.

Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning.

PubMed

Wong, Anselm; Landersdorfer, Cornelia; Graudins, Andis

2017-09-01

Paracetamol overdose is common and is treated with acetylcysteine to prevent the development of hepatotoxicity. N-acetyl-p-benzoquinone imine (NAPQI) is the toxic metabolite of paracetamol overdose. We aimed to assess the expected acetylcysteine concentration time profiles following delivery of modified acetylcysteine regimens proposed for those at high and low risk of hepatotoxicity. In addition, we will determine acetylcysteine concentrations post-cessation of abbreviated infusions. We performed pharmacokinetic simulations using Berkeley Madonna (version 8.3.23.0) comparing the time course of acetylcysteine concentration during and after the cessation of an abbreviated 12-h regimen (250 mg/kg) using a two-bag infusion and compared this to the standard 21-h three-bag (300 mg/kg) regimen. We also simulated extended duration acetylcysteine regimens and other increased dosing strategies that have been recommended in specific paracetamol poisoning scenarios. A more sustained serum concentration is achieved when the acetylcysteine loading dose is delivered over 4 h using the two-bag compared to the 1-h loading dose of the three-bag regimen. When administering an abbreviated 12-h acetylcysteine regimen, circulating acetylcysteine is detectable for 8 h after cessation of the infusion. This may provide a continued hepatoprotective effect if NAPQI is still being generated after the infusion is ceased. This pharmacokinetic simulation study is an important step in determining plasma acetylcysteine concentrations that are likely to be achieved using various modified treatment regimens. Importantly, for patients at low risk of liver injury after acute overdose, acetylcysteine is likely to be detectable many hours post-cessation of a 12-h regimen. This should provide a safety factor against development of hepatotoxicity for any ongoing paracetamol metabolism after cessation of the acetylcysteine infusion.

Comparison of current recommended regimens of atropinization in organophosphate poisoning.

PubMed

Connors, Nicholas J; Harnett, Zachary H; Hoffman, Robert S

2014-06-01

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.'s work, texts of Internal and Emergency Medicine, and electronic resources were reviewed for atropine dosing recommendations. For comparison, recommendations were assessed using the same mean dose (23.4 mg) and the highest dose (75 mg) of atropine as used in the original paper. Recommendations were also compared with the dosing regimen from the World Health Organization (WHO). Thirteen of the original recommendations were updated and 15 additional references were added giving a convenience sample of 28. Sufficient information to calculate time to targeted dose was provided by 24 of these samples. Compared to 2004, current recommendations have greatly increased the speed of atropinization with 13/24 able to reach the mean and high atropine dose within 30 min compared to 1/36 in 2004. In 2004, there were 13 regimens where the maximum time to reach 75 mg was over 18 h, whereas now, there are 2. While only one recommendation called for doubling the dose for faster escalation in 2004, 15 of the 24 current works include dose doubling. In 2004, Eddleston et al. called for an evidence-based guideline for the treatment of OP poisoning that could be disseminated worldwide. Many current recommendations can adequately treat patients within 1 h. While the WHO recommendations remain slow to treat patients with OP poisoning, other authorities are close to a consensus on rapid atropinization.

Integrative population pharmacokinetic and pharmacodynamic dose finding approach of the new camptothecin compound namitecan (ST1968)

PubMed Central

Joerger, M; Hess, D; Delmonte, A; Gallerani, E; Fasolo, A; Gianni, L; Cresta, S; Barbieri, P; Pace, S; Sessa, C

2015-01-01

Aims Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development. Methods Plasma concentration–time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1–3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations. Results Clearance was estimated to be 0.15 l h–1, with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration–time curve (AUC) and the percentage drop of neutrophils (r2 = 0.51, P < 10−4) or thrombocytes (r2 = 0.49, P < 10−4). With a target for haematological dose-limiting toxicity of <20%, the recommended dose was defined as 12.5 mg for the D1,8 regimen, 23 mg for the once every 3 week regimen and 7 mg for the D1–3 regimen. Conclusion This is the first integrated population PK–PD analysis of the new hydrophilic topoisomerase I inhibitor namitecan, that is currently undergoing early clinical development. A distinct relationship was found between drug exposure and haematological toxicity, supporting flat-dosing once every 3 weeks as the most adequate dosing regimen. PMID:25580946

Pharmacodynamic evaluation of intragastric pH and implications for famotidine dosing in the prophylaxis of non-steroidal anti-inflammatory drug induced gastropathy-a proof of concept analysis.

PubMed

Kent, Jeffery D; Holt, Robert J; Jung, Donald; Tidmarsh, George F; Grahn, Amy Y; Ball, Julie; Peura, David A

2014-01-01

Famotidine given at a dose of 80 mg/day is effective in preventing NSAID-induced gastropathy. The aim of this proof of concept study was to compare twice a day (BID) vs 3-times a day (TID) administration of this total dose of famotidine on intragastric pH in healthy volunteers. Two analyses were undertaken: (1) a 13 subject controlled cross-over 24-h intragastric pH evaluation of the BID and TID administration of 80 mg/day of famotidine, as well as measures for drug accumulation over 5 days (EudraCT, number 2006-002930-39); and (2) a pharmacokinetic (PK)/pharmacodynamic (PD) model which predicted steady-state famotidine plasma concentrations and pH of the two regimens. For the cross-over study, gastric pH was above 3.5 for a mean of 20 min longer for TID dosing compared to BID dosing on Day 1. On Day 5, the mean time above this threshold was higher with the BID regimen by ∼25 min. For pH 4, subjects' gastric pH was above this pH value for a mean of 25 min longer for TID dosing compared to BID dosing on Day 1. For Day 5, the pH was above 4 for ∼45 min longer with the TID regimen as compared with the BID regimen. The mean 24-h gastric pH values when taken in the upright position trended higher for the TID dosing period compared to the BID regimen on Day 1. The steady-state simulation model indicated that, following TID dosing, intragastric pH will be above 3 for 24 h vs 16 h for the BID regimen. There was no evidence for plasma accumulation of famotidine with TID dosing as compared to BID dosing from either analysis. The data indicate that overall more time is spent above the acidic threshold pH values when 80 mg/day of famotidine is administered TID vs BID. Key limitations included small study size with a short duration and lack of a baseline examination, but was compensated for by the cross-over and PK/PD modeling design. Although most of the comparisons in this proof of concept study were not statistically significant these results have important implications for future research on gastric acid lowering agents used for the prevention of NSAID-induced gastropathy.

Effect of antiretroviral therapy use and adherence on the risk of hyperlipidemia among HIV-infected patients, in the highly active antiretroviral therapy era

PubMed Central

Tsai, Fuu-Jen; Cheng, Chi-Fung; Lai, Chih-Ho; Wu, Yang-Chang; Ho, Mao-Wang; Wang, Jen-Hsien; Tien, Ni; Liu, Xiang; Tsang, Hsinyi; Lin, Ting-Hsu; Liao, Chiu-Chu; Huang, Shao-Mei; Li, Ju-Pi; Lin, Jung-Chun; Lin, Chih-Chien; Chen, Jin-Hua; Liang, Wen-Miin; Lin, Ying-Ju

2017-01-01

HIV-infected patients exposed to antiretroviral therapy (ART) have an increased risk for hyperlipidemia and cardiovascular disease. We performed a longitudinal, comprehensive, and population-based study to investigate the cumulative effect of different types of ART regimens on hyperlipidemia risk in the Taiwanese HIV/ART cohort. A total of 13,370 HIV-infected patients (2,674 hyperlipidemia and 10,696 non-hyperlipidemia patients) were recruited after matching for age, gender, and the first diagnosis date of HIV infection by using the National Health Insurance Research Database in Taiwan. Hyperlipidemia risk associated with cumulative ART use, ART adherence, and their combination was assessed. The matched hyperlipidemia group had a larger number of patients using ART and a higher incidence of comorbidities, specifically, respiratory disease and diabetes. Patients with high ART dosage and dose-dependent manner adherence, respectively, demonstrated an increased risk of hyperlipidemia. For single ART regimens, patients receiving nucleoside reverse-transcriptase inhibitors (NRTI/NRTI)- containing regimen had the highest hyperlipidemia risk, followed by protease inhibitor (PI)- containing and non-NRTI- containing regimens. For combination ART regimens, patients receiving a NRTI/NRTI + PI regimen had the highest hyperlipidemia risk. An increased cumulative drug dose was observed in patients who received the PI, NRTI/NRTI, NRTI, and NNRTI regimens in the hyperlipidemia group, when compared to the non-hyperlipidemia group. In conclusion, ART cumulative use, adherence, and regimen may affect hyperlipidemia risk among HIV-infected patients in a dose-dependent manner. PMID:29290955

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers▿

PubMed Central

Di Stefano, A. F. D.; Rusca, A.; Loprete, L.; Dröge, M. J.; Moro, L.; Assandri, A.

2011-01-01

The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ± 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed. PMID:21402860

Pharmacokinetics of Epsilon-Aminocaproic Acid in Neonates

PubMed Central

Eaton, Michael P.; Alfieris, George M; Sweeney, Dawn M; Angona, Ronald E; Cholette, Jill M; Venuto, Charles; Anderson, Brian

2016-01-01

Background Antifibrinolytic medications such as epsilon-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. We sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. Methods Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70 kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/L). Results Pharmacokinetics were described using a two compartment model plus an additional compartment for the cardiopulmonary bypass pump. First order elimination was described with a clearance of 5.07 L/h*(WT/70) 0.75. Simulation showed a dosing regimen with a loading dose of 40 mg/kg, and an infusion of 30 mg/kg/h, with a pump prime concentration of 100 mg/L maintained plasma concentrations above 50 mg/L in 90% of neonates during cardiopulmonary bypass surgery. Conclusions EACA clearance, expressed using allometry, is reduced in neonates compared to older children and adults. Loading dose and infusion dose are approximately half those required in children and adults. PMID:25723765

Pharmacokinetics of ε-Aminocaproic Acid in Neonates Undergoing Cardiac Surgery with Cardiopulmonary Bypass.

PubMed

Eaton, Michael P; Alfieris, George M; Sweeney, Dawn M; Angona, Ronald E; Cholette, Jill M; Venuto, Charles; Anderson, Brian

2015-05-01

Antifibrinolytic medications such as ε-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h × (WT/70). Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg · kg · h, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults.

Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer

NASA Astrophysics Data System (ADS)

Anderle, Kristjan; Stroom, Joep; Vieira, Sandra; Pimentel, Nuno; Greco, Carlo; Durante, Marco; Graeff, Christian

2018-01-01

Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

Lean body mass as an independent determinant of dose-limiting toxicity and neuropathy in patients with colon cancer treated with FOLFOX regimens.

PubMed

Ali, Raafi; Baracos, Vickie E; Sawyer, Michael B; Bianchi, Laurent; Roberts, Sarah; Assenat, Eric; Mollevi, Caroline; Senesse, Pierre

2016-04-01

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France (n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients (n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center.

PubMed

Dodd, C; Watts, R G

2012-07-01

Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non-compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up. © 2012 Blackwell Publishing Ltd.

Quantifying the medication burden of kidney transplant recipients in the first year post-transplantation.

PubMed

Low, Jac Kee; Crawford, Kimberley; Manias, Elizabeth; Williams, Allison

2018-06-28

Background Kidney transplantation is an effective treatment, but it is not a cure. Since the risk of graft rejection and the presence of comorbid conditions remain for a lifetime, medications are necessary. Objective To examine the prescription medication burden of adult kidney transplant recipients from 3- to 12-months post-transplantation. Setting All five adult kidney transplant units in Victoria, Australia. Method As part of a larger intervention study, we conducet a retrospective review of prescription refill records and medical records containing the history of medication changes of 64 participants who completed the study was undertaken. The complexity of the medication management was studied, and we looked at the burden of maintaining the medications supply. Outcome measures Pill burden, administration frequency, dose changes frequency, immunosuppressive medication changes, the estimated out-of-pocket costs of medications and frequency of pharmacy visits. Results At 3 months, the average daily pill burden was 22 (SD = 9) whilst at 12 months, it was 23 (SD = 10). Some participants required long-term prophylaxis of fungal infections up to 4 times a day whilst those with diabetes had to manage up to 4 insulin doses a day. The average out-of-pocket cost per person and the frequency of pharmacy visits at 6, 9 and 12 months post-transplantation remained relatively unchanged. Conclusion The medication regimen prescribed for kidney transplant recipients is complex and for most patients, it did not simplify over time post transplantation. Strategies are needed to support patients in managing the complexity of their medication regimen following kidney transplantation.

Renal dysfunction after total body irradiation: Dose-effect relationship

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

Kal, Henk B.; Kempen-Harteveld, M. Loes van

2006-07-15

Purpose: Late complications related to total body irradiation (TBI) as part of the conditioning regimen for hematopoietic stem cell transplantation have been increasingly noted. We reviewed and compared the results of treatments with various TBI regimens and tried to derive a dose-effect relationship for the endpoint of late renal dysfunction. The aim was to find the tolerance dose for the kidney when TBI is performed. Methods and Materials: A literature search was performed using PubMed for articles reporting late renal dysfunction. For intercomparison, the various TBI regimens were normalized using the linear-quadratic model, and biologically effective doses (BEDs) were calculated.more » Results: Eleven reports were found describing the frequency of renal dysfunction after TBI. The frequency of renal dysfunction as a function of the BED was obtained. For BED >16 Gy an increase in the frequency of dysfunction was observed. Conclusions: The tolerance BED for kidney tissue undergoing TBI is about 16 Gy. This BED can be realized with highly fractionated TBI (e.g., 6 x 1.7 Gy or 9 x 1.2 Gy at dose rates >5 cGy/min). To prevent late renal dysfunction, the TBI regimens with BED values >16 Gy (almost all found in published reports) should be applied with appropriate shielding of the kidneys.« less

Time of day of prednisolone administration in rheumatoid arthritis.

PubMed Central

Kowanko, I C; Pownall, R; Knapp, M S; Swannell, A J; Mahoney, P G

1982-01-01

Twelve patients with rheumatoid arthritis took low dosage prednisolone, mean 5.6 mg daily, at either 0800 h, 1300 h or 2300 h in a double-blind within-patient controlled trial. Each patient was studied on each of the 3 regimens to assess control of symptoms and side effects and also to examine circadian rhythms in signs and symptoms. For several days during each drug regimen patients collected urine at each micturition and self-assessed their signs and symptoms. Circadian rhythms of finger joint swelling and of grip strength were determined, and were similar on all regimens, with morning peaks of symptoms and signs. Subjective and objective assessments showed no differences in effectiveness between the 3 times of administration of prednisolone. Urinary excretion patterns were similar to those observed in untreated people. The quantity and circadian pattern of 11-hydroxycorticosteroids excreted were similar to those in healthy patients, providing no evidence of adrenal cortical suppression at the dose levels studied, even when this dose was taken in the evening. A single morning dose of prednisolone appears in many patients to be as effective as a single evening dose or divided doses. It is therefore reasonable to initiate therapy with a morning-only regimen, because adrenopituitary suppression should be minimised. PMID:6751242

Assessment of serum magnesium levels and its outcome in neonates of eclamptic mothers treated with low-dose magnesium sulfate regimen

PubMed Central

Das, Monalisa; Chaudhuri, Patralekha Ray; Mondal, Badal C.; Mitra, Sukumar; Bandyopadhyay, Debasmita; Pramanik, Sushobhan

2015-01-01

Objectives: Magnesium historically has been used for treatment and/or prevention of eclampsia. Considering the low body mass index of Indian women, a low-dose magnesium sulfate regime has been introduced by some authors. Increased blood levels of magnesium in neonates is associated with increased still birth, early neonatal death, birth asphyxia, bradycardia, hypotonia, gastrointestinal hypomotility. The objective of this study was to assess safety of low-dose magnesium sulfate regimen in neonates of eclamptic mothers treated with this regimen. Materials and Methods: This was a cross-sectional observational study of 100 eclampsia patients and their neonates. Loading dose and maintenance doses of magnesium sulfate were administered to patients by combination of intravenous and intramuscular routes. Maternal serum and cord blood magnesium levels were estimated. Neonatal outcome was assessed. Results: Bradycardia was observed in 18 (19.15%) of the neonates, 16 (17.02%) of the neonates were diagnosed with hypotonia. Pearson Correlation Coefficient showed Apgar scores decreased with increase in cord blood magnesium levels. Unpaired t-test showed lower Apgar scores with increasing dose of magnesium sulfate. The Chi-square/Fisher's exact test showed significant increase in hypotonia, birth asphyxia, intubation in delivery room, Neonatal Intensive Care Unit (NICU) care requirement, with increasing dose of magnesium sulfate. (P ≤ 0.05). Conclusion: Several neonatal complications are significantly related to increasing serum magnesium levels. Overall, the low-dose magnesium sulfate regimen was safe in the management of eclamptic mothers, without toxicity to their neonates. PMID:26600638

Ibandronate treatment for osteoporosis: rationale, preclinical, and clinical development of extended dosing regimens.

PubMed

Epstein, Solomon

2006-03-01

Ibandronate is a potent nitrogen-containing bisphosphonate available as a once-monthly oral formulation for the treatment and prevention of osteoporosis. Preclinical experiments with estrogen-depleted rats, dogs, and monkeys demonstrated the efficacy of daily and intermittent ibandronate dosing. Initial clinical trials explored the optimal dosing regimens for oral administration in humans. The Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) and Monthly Oral Ibandronate in Ladies (MOBILE) trials demonstrated that long-term daily and intermittent administration of ibandronate was efficacious for increasing bone mineral density, reducing markers of bone turnover, and preventing fractures, while maintaining bone quality. These preclinical and clinical ibandronate trials provided progressive evidence that a simple, long interval dosing regimen could offer efficacy and safety comparable with currently available bisphosphonates. It is anticipated that once-monthly ibandronate may have a positive impact on patient adherence, and ultimately, on fracture protection in osteoporotic women.

Clinical experience in the use of clavulanic acid/penicillin regimens in the treatment of uncomplicated gonorrhoea.

PubMed

Lim, K B; Thirumoorthy, T; Lee, C T; Sng, E H; Tan, T

1986-04-01

In an attempt to investigate the possibility of re-establishing the use of penicillins in the treatment of gonorrhoea in Singapore, a series of studies were conducted between 1981 and 1984, to evaluate the efficacy of a variety of penicillin-clavulanic acid combinations. A total of 6 different regimens were evaluated, and we concluded that 3 regimens consisting of 2 doses of Augmentin 3.25 g P.O., 4 hours apart (regimen C), aqueous procaine penicillin G (APPG) 4.5 mega units I.M. + Augmentin 375 mg + probenecid 1g P.O. (regimen E), and APPG 4.5 mega units I.M. + Augmentin 750 mg + probenecid 1g P.O. (regimen F) were very efficacious against infection due to PPNG and non PPNG. The cure rates obtained were 96.6% (regimens C and E), and 95% (regimen F) for infection due to PPNG and 95.6% (regimen C), and 100% (regimens E and F) for those due to non PPNG. Regimen E consisting of aqueous procaine penicillin G 4.5 meg units I.M. + Augmentin 375 mg + probenecid 1g P.O. was felt to be economical as well as effective against PPNG and non PPNG, and had the potential advantage of being effective against incubating syphillis. Regimen consisting 2 oral doses of Augmentin 3.25 g, 4 hours apart was an effective therapy for patients who preferred oral medication alone. However, this therapy was most costly. No serious side effects of treatment were observed with any of the regimens used.

Aspirin administered to women at 100 mg every other day produces less platelet inhibition than aspirin administered at 81 mg per day: implications for interpreting the women's health study.

PubMed

Swaim, Lisa; Hillman, Robert S

2009-07-01

We aimed to determine the relative level of platelet inhibition achieved with low-dose aspirin (81 mg daily) compared with a very low-dose (100 mg every other day). The Womens Health Study (WHS) found that a dose of 100 mg every other day of aspirin provided protection against stroke as primary prophylaxis, but not myocardial infarction. In the United States, the most commonly prescribed dose of aspirin for primary prophylaxis is 81 mg per day. As a result, it is important to know whether these doses are equivalent before extrapolating the results of the WHS to women in the U.S. To achieve this goal, we have studied the effects of these two dosing regimens on platelet function in healthy women meeting the WHS inclusion criteria using a randomized design. We enrolled 49 healthy female volunteers and used a sequential, crossover design to compare the two regimens. The participants received a 17-day course of each aspirin-dosing regimen separated by a 7-day washout period. The degree of platelet inhibition was measured on days 14-17 of each dosing regimen using a point-of-care platelet function assay utilizing arachidonic acid to activate platelets (VerifyNow-Aspirin). Participants platelet response, expressed as Aspirin Response Unit (ARU) attained a significantly greater level of platelet inhibition on days 14-17 while taking aspirin 81 mg daily compared to aspirin 100 mg every other day (31.3% vs. 12.7%, P < 0.0001) with mean +/- SD ARU values of 445 +/- 50 and 570 +/- 68, P < 0.0001. Significantly more daily readings in participants were >or=550 ARU, a value correlated with clinical outcomes in several studies, with the 100 mg every other day regimen (72.0% vs. 6.4% with 81 mg daily, P < 0.0001), and this alternate-day regimen also resulted in more day-to-day variability in platelet function (P = 0.0002). We found significantly less inhibition of platelet function with the dose used in the WHS than the usual U.S. dose. We observed that the degree of platelet inhibition was significantly less with aspirin 100 mg every other day compared with aspirin 81 mg daily, suggesting that results of the Women's Health Study may have underestimated both the efficacy and toxicity of aspirin as it is commonly administered. These data need to be considered when developing recommendations about the use of aspirin in the primary prevention of cardiovascular disease in women.

A rational quantitative approach to determine the best dosing regimen for a target therapeutic effect: a unified formalism for antibiotic evaluation.

PubMed

Li, Jun; Nekka, Fahima

2013-02-21

The determination of an optimal dosing regimen is a critical step to enhance the drug efficacy and avoid toxicity. Rational dosing recommendations based on mathematical considerations are increasingly being adopted in the process of drug development and use. In this paper, we propose a quantitative approach to evaluate the efficacy of antibiotic agents. By integrating both pharmacokinetic (PK) and pharmacodynamic (PD) information, this approach gives rise to a unified formalism able to measure the cause-effect of dosing regimens. This new pharmaco-metric allows to cover a whole range of antibiotics, including the two well known concentration and time dependent classes, through the introduction of the Hill-dependency concept. As a direct fallout, our formalism opens a new path toward the bioequivalence evaluation in terms of PK and PD, which associates the in vivo drug concentration and the in vitro drug effect. Using this new approach, we succeeded to reveal unexpected, but relevant behaviors of drug performance when different drug regimens and drug classes are considered. Of particular notice, we found that the doses required to reach the same therapeutic effect, when scheduled differently, exhibit completely different tendencies for concentration and time dependent drugs. Moreover, we theoretically confirmed the previous experimental results of the superiority of the once daily regimen of aminoglycosides. The proposed methodology is appealing for its computational features and can easily be applicable to design fair clinical protocols or rationalize prescription decisions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Drug Interactions Between Hepatoprotective Agents Ursodeoxycholic Acid or Glycyrrhizin and Ombitasvir/Paritaprevir/Ritonavir in Healthy Japanese Subjects.

PubMed

Zha, Jiuhong; Badri, Prajakta S; Ding, Bifeng; Uchiyama, Naotaka; Alves, Katia; Rodrigues, Lino; Redman, Rebecca; Dutta, Sandeep; Menon, Rajeev M

2015-11-01

The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for the treatment of chronic hepatitis C virus infection in Japan. Ursodeoxycholic acid (UDCA) and glycyrrhizin (GCR) are hepatoprotective agents widely used in Japan. A drug-drug interaction (DDI) study was conducted to guide dosing recommendations for UDCA and GCR when coadministered with the 2D regimen. DDIs between the 2D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg orally once daily) and UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) were evaluated in a 2-arm, multiple-dose study in 24 Japanese healthy subjects under fed conditions. Pharmacokinetic and safety evaluations were performed when UDCA or GCR and the 2D regimen were administered alone and during coadministration. Exposures from coadministration of the 2D regimen plus UDCA or GCR versus the 2D regimen, UDCA, or GCR alone were compared using repeated-measures analyses of natural logarithms of the maximum plasma concentration (Cmax) and area under the curve (AUC). After coadministration of the 2D regimen and UDCA, steady-state exposures (Cmax and AUC) of ombitasvir, paritaprevir, and ritonavir showed a ≤9% change, and UDCA exposures showed a ≤20% change compared with administration alone. When the 2D regimen and GCR were coadministered, steady-state exposures of ombitasvir, paritaprevir, and ritonavir were not affected (≤9% change), GCR AUC increased by 49%, and GCR Cmax was unaffected (<1% change). No dose adjustment is needed for UDCA, GCR, or the 2D regimen when UDCA or GCR is coadministered with the 2D regimen in hepatitis C virus-infected patients under fed conditions. Clinical monitoring of patients using GCR is recommended due to an approximately 50% increase in GCR AUC when coadministered with the 2D regimen. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Retrospective Comparison of Fludarabine in Combination With Intermediate-Dose Cytarabine Versus High-Dose Cytarabine As Consolidation Therapies for Acute Myeloid Leukemia

PubMed Central

Zhang, Wenjun; Ding, Yi; Wu, Hao; Chen, Yuhua; Lu, Huina; Chen, Chunying; Fu, Jianfei; Wang, Weiguang; Liang, Aibin; Zou, Shanhua

2014-01-01

Abstract This retrospective study compared efficacy and safety of fludarabine combined with intermediate-dose cytarabine (FA regimen) versus high-dose cytarabine (HiDAC regimen) as consolidation therapy in acute myeloid leukemia (AML) patients who achieved complete remission. Disease-free survival (DFS) and overall survival (OS) based on age (≥60, <60 years) and cytogenetics were evaluated from data between January 2005 and March 2013. Total 82 patients (FA, n = 45; HiDAC, n = 37; 14–65 years) were evaluated. Five-year DFS was 32.0% and 36.2% for FA and HiDAC groups, respectively (P = 0.729), and 5-year OS was 39.5% and 47.8% (P = 0.568), respectively. Among older patients (≥60 years), 3-year DFS was 26.0% for FA group and 12.5% for HiDAC group (P = 0.032), and 3-year OS was 34.6% and 12.5%, respectively (P = 0.026). In FA group, hematological toxicities were significantly lower. FA regimen was as effective as HiDAC regimen in patients with good/intermediate cytogenetics and significantly improved DFS and OS in older patients. PMID:25501050

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.

PubMed

Madelain, Vincent; Guedj, Jérémie; Mentré, France; Nguyen, Thi Huyen Tram; Jacquot, Frédéric; Oestereich, Lisa; Kadota, Takumi; Yamada, Koichi; Taburet, Anne-Marie; de Lamballerie, Xavier; Raoul, Hervé

2017-01-01

Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC 50 ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC 50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses. Copyright © 2016 American Society for Microbiology.

A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex.

PubMed

Cignarelli, M; Picca, G; Campo, M; Margaglione, M; Marino, A; Logoluso, F; Giorgino, F

2005-01-01

A low-dose mitotane (MT) regimen was evaluated as a pharmacological approach for correcting the severe hypercortisolism in a young woman affected by Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD). In the first 12 week period, the MT daily dose was progressively increased from 0.5 to 4.0 g/day. This dosage was maintained for an additional 16 weeks (cumulative dose 602 g, plasma MT maximum level 12 microg/ml), and then stopped because of sustained signs of hypoadrenalism requiring prednisone replacement. Complete regression of seborrhea, acne, and plethora was observed after 8 weeks of treatment (cumulative dose 95 g). Regular menses returned after 13 weeks (cumulative dose 197 g, plasma MT 8 microg/ml). Profound decrease of both serum cortisol (from 615 to 220 nmol/l) and urinary free cortisol (UFC) values (from 1498 to 477 nmol/day) was noted after 16 weeks of treatment (cumulative dose 314 g, plasma MT 8 microg/ml). MT treatment was associated with mild gastric discomfort and reversible increase of cholesterol plasma levels. Low serum cortisol and UFC were still observed 41 weeks after MT was discontinued (plasma MT 0.2 microg/ml). Our report demonstrates that low dose MT treatment may be a safe and effective modality for a sustained correction of hypercortisolism by PPNAD in subjects with CNC waiting for surgery.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

PubMed

Dow, Geoffrey S; Gettayacamin, Montip; Hansukjariya, Pranee; Imerbsin, Rawiwan; Komcharoen, Srawuth; Sattabongkot, Jetsumon; Kyle, Dennis; Milhous, Wilbur; Cozens, Simon; Kenworthy, David; Miller, Anne; Veazey, Jim; Ohrt, Colin

2011-07-29

Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

PubMed Central

2011-01-01

Background Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. Methods In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. Results The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Conclusions Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs. PMID:21801400

Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

PubMed

Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-23

The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa

PubMed Central

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-01-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation. PMID:26038704

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa.

PubMed

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-03-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (I sc). Subsequent I sc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. I sc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.

Inactivated H9N2 avian influenza virus vaccine with gel-primed and mineral oil-boosted regimen could produce improved immune response in broiler breeders.

PubMed

Lee, D-H; Kwon, J-S; Lee, H-J; Lee, Y-N; Hur, W; Hong, Y-H; Lee, J-B; Park, S-Y; Choi, I-S; Song, C-S

2011-05-01

The frequent economic losses incurred with H9N2 low pathogenic avian influenza viruses (LPAI) infection have raised serious concerns for the poultry industry. A 1-dose regimen with inactivated H9N2 LPAI vaccine could not prevent vaccinated poultry from becoming infected and from shedding wild viruses. A study was conducted to determine whether a 2-dose regimen of inactivated H9N2 LPAI vaccine could enhance the immunologic response in chickens. Such gel-primed and mineral oil-boosted regimen has produced encouraging results associated with improved immune responses to an H9N2 LPAI. This strategy could be cost effective and helpful for preventing avian influenza virus in the poultry industry.

A randomized controlled trial of increased dose and frequency of albendazole with standard dose DEC for treatment of Wuchereria bancrofti microfilaremics in Odisha, India.

PubMed

Kar, Shantanu Kumar; Dwibedi, Bhagirathi; Kerketa, Anna Salomi; Maharana, Antaryami; Panda, Sudanshu S; Mohanty, Prafulla Chandra; Horton, John; Ramachandran, Cherubala P

2015-03-01

Although current programmes to eliminate lymphatic filariasis have made significant progress it may be necessary to use different approaches to achieve the global goal, especially where compliance has been poor and 'hot spots' of continued infection exist. In the absence of alternative drugs, the use of higher or more frequent dosing with the existing drugs needs to be explored. We examined the effect of higher and/or more frequent dosing with albendazole with a fixed 300 mg dose of diethylcarbamazine in a Wuchereria bancrofti endemic area in Odisha, India. Following screening, 104 consenting adults were randomly assigned to treatment with the standard regimen annually for 24 months (S1), or annually with increased dose (800 mg albendazole)(H1) or with increased frequency (6 monthly) with either standard (S2) or increased (H2) dose. Pre-treatment microfilaria counts (GM) ranged from 348 to 459 mf/ml. Subjects were followed using microfilaria counts, OG4C3 antigen levels and ultrasound scanning for adult worm nests. Microfilarial counts tended to decrease more rapidly with higher or more frequent dosing at all time points. At 12 months, Mf clearance was marginally greater with the high dose regimens, while by 24 months, there was a trend to higher Mf clearance in the arm with increased frequency and 800 mg of albendazole (76.9%) compared to other arms, (S1:64%, S2:69.2% & H1:73.1%). Although higher and/or more frequent dosing showed a trend towards a greater decline in antigenemia and clearance of "nests", all regimens demonstrated the potential macrofilaricidal effect of the combination. The higher doses of albendazole did not result in a greater number or more severe side effects. The alternative regimens could be useful in the later stages of existing elimination programmes or achieving elimination more rapidly in areas where programmes have yet to start.

Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study.

PubMed

Regules, Jason A; Cicatelli, Susan B; Bennett, Jason W; Paolino, Kristopher M; Twomey, Patrick S; Moon, James E; Kathcart, April K; Hauns, Kevin D; Komisar, Jack L; Qabar, Aziz N; Davidson, Silas A; Dutta, Sheetij; Griffith, Matthew E; Magee, Charles D; Wojnarski, Mariusz; Livezey, Jeffrey R; Kress, Adrian T; Waterman, Paige E; Jongert, Erik; Wille-Reece, Ulrike; Volkmuth, Wayne; Emerling, Daniel; Robinson, William H; Lievens, Marc; Morelle, Danielle; Lee, Cynthia K; Yassin-Rajkumar, Bebi; Weltzin, Richard; Cohen, Joe; Paris, Robert M; Waters, Norman C; Birkett, Ashley J; Kaslow, David C; Ballou, W Ripley; Ockenhouse, Christian F; Vekemans, Johan

2016-09-01

Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. NCT01857869. Published by Oxford University Press on behalf of the Infectious Diseases Society of America, 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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

The prednisone dosage in the CHOP chemotherapy regimen for non-Hodgkin's lymphomas (NHL): is there a standard?

PubMed

Moreno, A; Colon-Otero, G; Solberg, L A

2000-01-01

Discrepancies in the quoted prednisone dosages in the regimens reported as the only standard CHOP regimen stimulated our interest in reviewing the medical literature regarding this issue and to assess whether practicing hematologists and oncologists in the U.S. are aware of the different dose schedules of prednisone in the published CHOP programs. Sixteen textbooks and chemotherapy reference books were reviewed. A MEDLINE search of English-language articles published between January 1970 and December 1998 was performed. An eight-point questionnaire was sent via e-mail with responses obtained from 421 hematology/oncology physicians in the U.S. Sixteen textbooks and chemotherapy reference books reviewed quoted only one prednisone dosage as part of the standard CHOP regimen; the prednisone dosages quoted as standard varied between publications. More than 4,000 eligible non-Hodgkin's lymphoma patients have been treated with the CHOP chemotherapy as part of 43 different clinical trials reviewed. The dosages of prednisone and prednisolone used varied among six different levels. Thirty percent (127/421) of practicing U.S. physicians were not aware of the existence of more than one prednisone dose schedule as part of the CHOP regimen. The three most frequently used dosages are 100 mg/days 1-5 (67%), 100 mg/m(2)/days 1-5 (17%), and 60 mg/m(2)/days 1-5 (13%). Discrepancies in steroid dosages used as part of the reported standard CHOP regimens are common and not well recognized in the medical literature nor by practicing U.S. hematologists/oncologists. Based on this study, a prednisone dose of 100 mg/day for five days should be considered the standard dose.

A randomized comparative trial of two low-dose oral isotretinoin regimens in moderate to severe acne vulgaris

PubMed Central

Dhaked, Daulat Ram; Meena, Ram Singh; Maheshwari, Anshul; Agarwal, Uma Shankar; Purohit, Saroj

2016-01-01

Background: Oral isotretinoin is highly effective in all forms and grades of acne, even in lower dosages (<0.5 mg/kg/day). There is a paucity of comparative data on the various low-dose regimens of oral isotretinoin in the Indian literature. Objectives: To assess and compare the efficacy and tolerability of two low-dose oral isotretinoin treatment regimens (20 mg daily and 20 mg alternate days) in moderate to severe acne vulgaris. Materials and Methods: A total of 240 patients with moderate to severe acne vulgaris were selected and randomized into two groups and treated with a fixed dose of 20 mg of isotretinoin (Group A - daily and Group B - alternate days) for 24 weeks and followed up for 12 weeks post therapy. Results: A total of 234 patients completed the study. At the end of therapy, decrease in the total acne loads up to 98.99% (Group A) and 97.69% (Group B) was achieved from the baseline (P < 0.01), excellent response was observed in 98.3% (Group A) and 93.96% (Group B) patients (P = 0.166). In the severe acne, Group A performed significantly better than Group B until the end of 36 weeks. While in the moderate acne, significant difference in the response between both groups was observed only up to 12 weeks. No serious side effect was observed. Conclusion: Both isotretinoin regimens were well tolerated and found to be an effective treatment for moderate to severe acne vulgaris. However, in moderate acne 20 mg alternate day regimen may be preferred. A 20 mg daily regimen is a better choice for severe acne in terms of response. Limitation: Small sample size and short follow-up period. PMID:27730033

Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects

PubMed Central

Legangneux, Eric; Gardin, Anne; Johns, Donald

2013-01-01

Aim Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1‐phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects. Methods Fifty‐six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25–10 mg over 9–10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. Results Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1–12 vs. the non‐titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non‐titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non‐titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3–7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min−1; P ≤ 0.0001). From days 9–12, HRs in both titration regimens were comparable with placebo. Conclusion Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg. PMID:22845008

Cost analytic model to determine the least costly inpatient erythropoiesis stimulating therapy regimen.

PubMed

Sikand, Harminder; Decter, Adam; Greco, Tina; Watson, Sue H; Kang, Yoon Jun; Mody, Samir H; Piech, Catherine Tak; Duh, Mei Sheng; Naeem, Ayesha

2008-01-01

Unlike in outpatient settings, the comparative costs of epoetin alpha (EPO) and darbepoetin alpha (DARB) have not been evaluated broadly from the inpatient hospital perspective. To develop a cost analytic model comparing hospital inpatient costs for erythropoiesis stimulating therapies within the nephrology and oncology settings. A cost analytic model incorporating erythropoietic drug, pharmacy, and nursing costs was developed from the inpatient hospital perspective to evaluate comparative costs of EPO and DARB. Erythropoietic drug costs were calculated using unit wholesale acquisition cost multiplied by the number of units or micrograms while comparing the following dosing regimens: EPO 3 times weekly, EPO once weekly, and DARB once weekly. Pharmacy costs included dispensing and delivery costs, while nursing costs incorporated administration time costs; all were calculated by estimated fractional hours per activity multiplied by hourly wages. The total frequency of erythropoiesis stimulating therapy administrations was determined based on the average hospital length of stay. The first erythropoiesis stimulating therapy dose was assumed to occur on day 3 of hospitalization. For total inpatient costs, a weighted average was calculated across disease states. One-way sensitivity analyses were conducted by varying length of stay, day of initial erythropoiesis stimulating therapy dose, pharmacy and nursing costs, and once-weekly DARB dose. EPO 3 times weekly was the least costly regimen across all disease states evaluated. Threshold analysis indicated that the cost of once-weekly DARB regimens would have to be reduced by 37% to equal the cost of EPO 3 times weekly for an average length of stay. Sensitivity analyses did not considerably affect the results. EPO 3 times weekly was found to be the least costly erythropoiesis stimulating therapy regimen for nephrology and oncology inpatients for the average length of stay as well as most other lengths of stay considered. Once-weekly EPO was the least costly erythropoiesis stimulating therapy regimen for several other lengths of stay, while once-weekly DARB was never found to be the least costly regimen.

Optimizing the Anti-VEGF Treatment Strategy for Neovascular Age-Related Macular Degeneration: From Clinical Trials to Real-Life Requirements.

PubMed

Mantel, Irmela

2015-06-01

This Perspective discusses the pertinence of variable dosing regimens with anti-vascular endothelial growth factor (VEGF) for neovascular age-related macular degeneration (nAMD) with regard to real-life requirements. After the initial pivotal trials of anti-VEGF therapy, the variable dosing regimens pro re nata (PRN), Treat-and-Extend, and Observe-and-Plan, a recently introduced regimen, aimed to optimize the anti-VEGF treatment strategy for nAMD. The PRN regimen showed good visual results but requires monthly monitoring visits and can therefore be difficult to implement. Moreover, application of the PRN regimen revealed inferior results in real-life circumstances due to problems with resource allocation. The Treat-and-Extend regimen uses an interval based approach and has become widely accepted for its ease of preplanning and the reduced number of office visits required. The parallel development of the Observe-and-Plan regimen demonstrated that the future need for retreatment (interval) could be reliably predicted. Studies investigating the observe-and-plan regimen also showed that this could be used in individualized fixed treatment plans, allowing for dramatically reduced clinical burden and good outcomes, thus meeting the real life requirements. This progressive development of variable dosing regimens is a response to the real-life circumstances of limited human, technical, and financial resources. This includes an individualized treatment approach, optimization of the number of retreatments, a minimal number of monitoring visits, and ease of planning ahead. The Observe-and-Plan regimen achieves this goal with good functional results. Translational Relevance: This perspective reviews the process from the pivotal clinical trials to the development of treatment regimens which are adjusted to real life requirements. The article discusses this translational process which- although not the classical interpretation of translation from fundamental to clinical research, but a subsequent process after the pivotal clinical trials - represents an important translational step from the clinical proof of efficacy to optimization in terms of patients' and clinics' needs. The related scientific procedure includes the exploration of the concept, evaluation of security, and finally proof of efficacy.

High-dose rifapentine with moxifloxacin for pulmonary tuberculosis.

PubMed

Jindani, Amina; Harrison, Thomas S; Nunn, Andrew J; Phillips, Patrick P J; Churchyard, Gavin J; Charalambous, Salome; Hatherill, Mark; Geldenhuys, Hennie; McIlleron, Helen M; Zvada, Simbarashe P; Mungofa, Stanley; Shah, Nasir A; Zizhou, Simukai; Magweta, Lloyd; Shepherd, James; Nyirenda, Sambayawo; van Dijk, Janneke H; Clouting, Heather E; Coleman, David; Bateson, Anna L E; McHugh, Timothy D; Butcher, Philip D; Mitchison, Denny A

2014-10-23

Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals. We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4). The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

The efficacy and safety of a low-dose, 91-day, extended-regimen oral contraceptive with continuous ethinyl estradiol.

PubMed

Kroll, Robin; Reape, Kathleen Z; Margolis, Marya

2010-01-01

This clinical trial was conducted to demonstrate the efficacy and safety of a 91-day extended-regimen, low-dose combination oral contraceptive (OC) consisting of 84 days of ethinyl estradiol (EE) 20 mcg/levonorgestrel (LNG) 100 mcg, followed by 7 days of 10 mcg EE in place of placebo. A multicenter open-label, single-treatment, Phase 3 study evaluated women aged 18 through 40 years over a treatment period of up to 1 year (four 91-day extended cycles). All subjects completed daily paper diaries to monitor compliance, bleeding and additional forms of contraception used during the course of the study. A total of 1249 subjects completed the study. The Pearl Index was 2.74 (95% confidence interval, 1.92-3.78), based on 36 pregnancies that occurred after the onset of treatment and within 14 days after the last combination tablet in women aged 18-35 years. Among compliant-use subjects 18-35 years old, the Pearl Index was 1.73 based on 22 on-treatment pregnancies. The life table pregnancy rate for subjects 18-35 years of age was 2.39%. Cycle control and adverse events reported with this regimen were similar to those reported with other low-dose OCs. This study demonstrated effective prevention of pregnancy with a 20-mcg EE, 91-day extended-regimen OC. In addition, the regimen was well tolerated and incidence of adverse events were consistent with what has been reported with other low-dose OCs.

Development of symptomatic brain metastases after chemoradiotherapy for stage III non-small cell lung cancer: Does the type of chemotherapy regimen matter?

PubMed

Hendriks, Lizza E L; Brouns, Anita J W M; Amini, Mohammad; Uyterlinde, Wilma; Wijsman, Robin; Bussink, Jan; Biesma, Bonne; Oei, S Bing; Stigt, Jos A; Bootsma, Gerben P; Belderbos, José S A; De Ruysscher, Dirk K M; Van den Heuvel, Michel M; Dingemans, Anne-Marie C

2016-11-01

Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development. Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of ≥50 patients. Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60)). approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass.

PubMed

Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-01

The purpose of this study was to investigate the population pharmacokinetics (PK) of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix (version 4.4) software. Pharmacokinetic-pharmacodynamic (PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples from 78 patients were analyzed. The PK for cefuroxime were best described by a two-compartment model with between-subject variability on clearance, the volume of distribution of the central compartment, and the volume of distribution of the peripheral compartment. The clearance of cefuroxime was related to creatinine clearance (CL CR ). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of the percentage of the time that the free concentration is maintained above the MIC during a dosing interval ( fT MIC ) of 65% for an MIC of 8 mg/liter in patients with a CL CR of 30, 60, or 90 ml/min, whereas this dosing regimen failed to achieve the PK-PD target in patients with a CL CR of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CL CR values required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CL CR values (≤30 ml/min). Copyright © 2018 American Society for Microbiology.

Retinoid metabolism and transplacental pharmacokinetics in the cynomolgus monkey following a nonteratogenic dosing regimen with all-trans-retinoic acid.

PubMed

Tzimas, G; Nau, H; Hendrickx, A G; Peterson, P E; Hummler, H

1996-11-01

Retinoids often exhibit a complex metabolic pattern and differential transplacental kinetics, which make it difficult to pinpoint the proximate compound responsible for the observed teratogenic effect. We have therefore studied the pharmacokinetics and metabolism of all-trans-retinoic acid (all-trans-RA) in cynomolgus monkeys following application of a nonteratogenic dosing regimen and compared the results with corresponding data from a previous study with a teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. All-trans-RA was administered to pregnant cynomolgus monkeys (Macaca fascicularis) by nasogastric intubation at a dose of 5 mg/kg body wt once daily from gestational day (GD) 16 to 26 and twice daily at 8-h intervals from GD 27 to 31. Examination of the fetuses of four dams on GD 100 +/- 2 showed no embryotoxic or teratogenic effects of the applied dosing regimen (Experiment 1). Maternal plasma retinoid pharmacokinetics on GD 16, 26, and 31 as well as embryonic retinoid profiles after the last drug administration on GD 31 were determined in thirteen further dams (Experiment 2). All-trans-RA reached much lower plasma concentrations after the last two treatments on GD 31 than after the first one on GD 16 and the eleventh one on GD 26 (0-24-h area-under-the-concentration-time-curve (AUC) values: 104 +/- 59 ng x h/ml (after the last treatment on GD 31), 189 +/- 110 (GD 16) and 393 +/- 305 ng x h/ml (GD 26). The predominant plasma metabolites of all-trans-RA were its beta-glucuronide and the beta-glucuronide of all-trans-4-oxo-RA. Both of these retinoids accumulated in the plasma during the period of treatment and displayed AUC values 5- to 30-fold higher than those of all-trans-RA. Embryonic concentrations of all-trans-RA were not increased over endogenous levels after the last administration on GD 31 when plasma concentrations were low. To evaluate the placental transport of all-trans-RA in the presence of high plasma concentrations, a further experiment was performed, in which a single dose of all-trans-RA (10 mg/kg body wt) was given to four pregnant monkeys on GD 31, and plasma pharmacokinetics as well as embryonic concentrations of retinoids at 4 h post-treatment were determined (Experiment 3). This dosing schedule yielded high plasma concentrations of all-trans-RA, while embryonic concentrations were about 40% of plasma levels. Based on the plasma AUC values on GDs 16 and 26 obtained in Experiment 2 and the degree of placental transfer, as determined on GD 31 in the presence of high plasma levels in Experiment 3, we estimated embryonic AUC values for the 24-h period following the nonteratogenic doses on GDs 16 and 26 in Experiment 2. These AUC values were similarly high to the embryonic AUC value of all-trans-RA obtained after application of the teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. In addition, plasma AUC values of all-trans-RA were 2- to 7-fold higher after all-trans-RA administration (present study) than after dosing with the teratogenic dose of 13-cis-RA. These results strengthen our recent suggestion that the teratogenic effects induced in cynomolgus monkeys by 13-cis-RA treatment cannot solely result from the action of all-trans-RA, but may involve 13-cis-RA and 13-cis-4-oxo-RA, which could act directly or function as transport vehicle.

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.

PubMed

Niesvizky, Ruben; Martínez-Baños, Déborah; Jalbrzikowski, Jessica; Christos, Paul; Furst, Jessica; De Sancho, Maria; Mark, Tomer; Pearse, Roger; Mazumdar, Madhu; Zafar, Faiza; Pekle, Karen; Leonard, John; Jayabalan, David; Coleman, Morton

2007-12-01

Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment with thalidomide/dexamethasone or lenalidomide/dexamethasone increases this risk. This report describes the use of low-dose aspirin (81 mg) as primary thromboprophylaxis in three series of MM patients receiving thalidomide or lenalidomide with other drugs. In the first regimen (clarithromycin, thalidomide, dexamethasone), initiation of low-dose aspirin negated the occurrence of any further TE. In a second study, prophylactic aspirin given with thalidomide/dexamethasone resulted in a rate of TE similar to that seen with dexamethasone alone (without aspirin). A third study (n = 72) evaluated thrombosis rates with aspirin and a lenalidomide-containing regimen (clarithromycin, lenalidomide, dexamethasone). Of nine occurrences of thromboembolism, five were associated with aspirin interruption or poor compliance. Low-dose aspirin appears to reduce the incidence of thrombosis with these regimens. Routine use of aspirin as antithrombotic prophylaxis in MM patients receiving immunomodulatory drugs with corticosteroids is warranted.

Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery.

PubMed

Coppola, Antonio; Windyga, Jerzy; Tufano, Antonella; Yeung, Cindy; Di Minno, Matteo Nicola Dario

2015-02-09

In people with haemophilia or other congenital bleeding disorders undergoing surgical interventions, haemostatic treatment is needed in order to correct the underlying coagulation abnormalities and minimise the bleeding risk. This treatment varies according to the specific haemostatic defect, its severity and the type of surgical procedure. The aim of treatment is to ensure adequate haemostatic coverage for as long as the bleeding risk persists and until wound healing is complete. To assess the effectiveness and safety of different haemostatic regimens (type, dose and duration, modality of administration and target haemostatic levels) administered in people with haemophilia or other congenital bleeding disorders for preventing bleeding complications during and after surgical procedures. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of the last search: 20 November 2014. Randomised and quasi-randomised controlled trials comparing any hemostatic treatment regimen to no treatment or to another active regimen in children and adults with haemophilia or other congenital bleeding disorders undergoing any surgical intervention. Two authors independently assessed trials (eligibility and risks of bias) and extracted data. Meta-analyses were performed on available and relevant data. Of the 16 identified trials, four (112 participants) were eligible for inclusion.Two trials evaluated 59 people with haemophilia A and B undergoing 63 dental extractions. Trials compared the use of a different type (tranexamic acid or epsilon-aminocaproic acid) and regimen of antifibrinolytic agents as haemostatic support to the initial replacement treatment. Neither trial specifically addressed mortality (one of this review's primary outcomes); however, in the frame of safety assessments, no fatal adverse events were reported. The second primary outcome of blood loss was assessed after surgery and these trials showed the reduction of blood loss and requirement of post-operative replacement treatment in people receiving antifibrinolytic agents compared with placebo. The remaining primary outcome of need for re-intervention was not reported by either trial.Two trials reported on 53 people with haemophilia A and B with inhibitors treated with different regimens of recombinant activated factor VII (rFVIIa) for haemostatic coverage of 33 major and 20 minor surgical interventions. Neither of the included trials specifically addressed any of the review's primary outcomes (mortality, blood loss and need for re-intervention). In one trial a high-dose rFVIIa regimen (90 μg/kg) was compared with a low-dose regimen (35 μg/kg); the higher dose showed increased haemostatic efficacy, in particular in major surgery, with shorter duration of treatment, similar total dose of rFVIIa administered and similar safety levels. In the second trial, bolus infusion and continuous infusion of rFVIIa were compared, showing similar haemostatic efficacy, duration of treatment and safety. There is insufficient evidence from randomised controlled trials to assess the most effective and safe haemostatic treatment to prevent bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgical procedures. Ideally large, adequately powered, and well-designed randomised controlled trials would be needed, in particular to address the cost-effectiveness of such demanding treatments in the light of the increasing present economic constraints, and to explore the new challenge of ageing patients with haemophilia or other congenital bleeding disorders. However, performing such trials is always a complex task in this setting and presently does not appear to be a clinical and research priority. Indeed, major and minor surgeries are effectively and safely performed in these individuals in clinical practice, with the numerous national and international recommendations and guidelines providing regimens for treatment in this setting mainly based on data from observational, uncontrolled studies.

Fewer Doses of HPV Vaccine Result in Immune Response Similar to Three-Dose Regimen

MedlinePlus

... Releases NCI News Note Fewer doses of HPV vaccine result in immune response similar to three-dose ... that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody ...

Total Body Irradiation: Guidelines from the International Lymphoma Radiation Oncology Group (ILROG).

PubMed

Wong, Jeffrey Y C; Filippi, Andrea Riccardo; Dabaja, Bouthaina Shbib; Yahalom, Joachim; Specht, Lena

2018-07-01

Total body irradiation (TBI) remains an effective myeloablative treatment in regimens used for preparation and conditioning before allogeneic stem cell transplantation for leukemia. The regimens used vary across institutions in terms of dose, dose rate, fractionation, and technique. The objective of this document is to provide comprehensive guidelines for the current practice of delivering total body irradiation. Copyright © 2018 Elsevier Inc. All rights reserved.

Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

PubMed

de Velde, Femke; de Winter, Brenda C M; Koch, Birgit C P; van Gelder, Teun; Mouton, Johan W

2016-10-01

To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens. Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens. AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily). The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial

PubMed Central

Chapman, Arlene B.; Torres, Vicente E.; Ouyang, John; Czerwiec, Frank S.

2017-01-01

Abstract In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2‐receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient‐reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split‐dose regimen: a single ascending‐dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split‐dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8‐week open‐label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to <300 mOsm/kg for 24 hours. The 45/15‐mg regimen was well tolerated and effective in suppressing Uosm in >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30‐mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate. PMID:28218410

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

Optimal antimalarial dose regimens for chloroquine in pregnancy based on population pharmacokinetic modelling.

PubMed

Salman, Sam; Baiwog, Francesca; Page-Sharp, Madhu; Kose, Kay; Karunajeewa, Harin A; Mueller, Ivo; Rogerson, Stephen J; Siba, Peter M; Ilett, Kenneth F; Davis, Timothy M E

2017-10-01

Despite extensive use and accumulated evidence of safety, there have been few pharmacokinetic studies from which appropriate chloroquine (CQ) dosing regimens could be developed specifically for pregnant women. Such optimised CQ-based regimens, used as treatment for acute malaria or as intermittent preventive treatment in pregnancy (IPTp), may have a valuable role if parasite CQ sensitivity returns following reduced drug pressure. In this study, population pharmacokinetic/pharmacodynamic modelling was used to simultaneously analyse plasma concentration-time data for CQ and its active metabolite desethylchloroquine (DCQ) in 44 non-pregnant and 45 pregnant Papua New Guinean women treated with CQ and sulfadoxine/pyrimethamine or azithromycin (AZM). Pregnancy was associated with 16% and 49% increases in CQ and DCQ clearance, respectively, as well as a 24% reduction in CQ relative bioavailability. Clearance of DCQ was 22% lower in those who received AZM in both groups. Simulations based on the final multicompartmental model demonstrated that a 33% CQ dose increase may be suitable for acute treatment for malaria in pregnancy as it resulted in equivalent exposure to that in non-pregnant women receiving recommended doses, whilst a double dose would likely be required for an effective duration of post-treatment prophylaxis when used as IPTp especially in areas of CQ resistance. The impact of co-administered AZM was clinically insignificant in simulations. The results of past/ongoing trials employing recommended adult doses of CQ-based regimens in pregnant women should be interpreted in light of these findings, and consideration should be given to using increased doses in future trials. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Comparison of once-daily versus twice-daily combination of ropinirole prolonged release in Parkinson's disease.

PubMed

Yun, Ji Young; Kim, Han-Joon; Lee, Jee-Young; Kim, Young Eun; Kim, Ji Seon; Kim, Jong-Min; Jeon, Beom S

2013-09-02

Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson's disease. This study was an open-label crossover study. We enrolled Parkinson's disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson's Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI). A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen. RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.

Evaluation of pharmacotherapy complexity in residents of long-term care facilities: a cross-sectional descriptive study.

PubMed

Alves-Conceição, Vanessa; Silva, Daniel Tenório da; Santana, Vanessa Lima de; Santos, Edileide Guimarães Dos; Santos, Lincoln Marques Cavalcante; Lyra, Divaldo Pereira de

2017-07-25

Polypharmacy is a reality in long-term care facilities. However, number of medications used by the patient should not be the only predictor of a complex pharmacotherapy. Although the level of complexity of pharmacotherapy is considered an important factor that may lead to side effects, there are few studies in this field. The aim of this study was to evaluate the complexity of pharmacotherapy in residents of three long-term care facilities. A cross-sectional study was performed to evaluate the complexity of pharmacotherapy using the protocols laid out in the Medication Regimen Complexity Index instrument in three long-term care facilities in northeastern Brazil. As a secondary result, potential drug interactions, potentially inappropriate medications, medication duplication, and polypharmacy were evaluated. After the assessment, the association among these variables and the Medication Regimen Complexity Index was performed. In this study, there was a higher prevalence of women (64.4%) with a high mean age among the study population of 81.8 (±9.7) years. The complexity of pharmacotherapy obtained a mean of 15.1 points (±9.8), with a minimum of 2 and a maximum of 59. The highest levels of complexity were associated with dose frequency, with a mean of 5.5 (±3.6), followed by additional instructions of use averaging 4.9 (±3.7) and by the dosage forms averaging 4.6 (±3.0). The present study evaluated some factors that complicate the pharmacotherapy of geriatric patients. Although polypharmacy was implicated as a factor directly related to complexity, other indicators such as drug interactions, potentially inappropriate medications, and therapeutic duplication can also make the use of pharmacotherapy in such patients more difficult.

Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term.

PubMed

de Zegher, Francis; Hokken-Koelega, Anita

2005-04-01

Approximately 3% of children are born small for gestational age (SGA), and approximately 10% of SGA children maintain a small body size throughout childhood and often into adult life. Among short SGA children, growth hormone (GH) therapy increases short-term growth in a dose-dependent manner; experience with long-term therapy is limited. To delineate the dose dependency of long-term height gain among short SGA children receiving GH therapy. We performed an epianalysis of the first adult height data for SGA children (n = 28) enrolled in 3 randomized trials comparing the growth-promoting efficacy of 2 continuous GH regimens (33 or 67 microg/kg per day for approximately 10 years, starting at approximately 5 years of age); in addition, we performed a meta-analysis of the adult height results published previously and those presented here. Epianalysis outcomes (n = 28) suggested that adult height increased more with a higher-dose regimen than with a lower-dose regimen. In the meta-analysis (n = 82), the higher-dose regimen was found to elicit a long-term height gain superior to that achieved with the lower-dose regimen by a mean of 0.4 SD (approximately 1 inch). Children who were shorter at the start of therapy experienced more long-term height gain. These findings confirm GH therapy as an effective and safe approach to reduce the adult height deficit that short SGA children otherwise face. In addition, the first meta-analysis indicated that height gain is less dose dependent over the long term than over the short term, at least within the dose range explored to date. For SGA children whose stature is not extremely short, current data support the use of a GH dose of approximately 33 microg/kg per day from start to adult height, particularly if treatment starts at a young age; shorter children (for example, height below -3 SD) might benefit from an approach in which short-term catch-up growth is achieved with a higher dose (> or =50 microg/kg per day) and long-term growth to adult height is ensured with a GH dose of approximately 33 mug/kg per day. Because GH-induced accelerations of height and weight gain evolve in parallel, the dose tapering from > or =50 microg/kg to approximately 33 microg/kg can be accomplished by simply maintaining the absolute GH dose (in micrograms) while the child gains weight (in kilograms). With this algorithm, more growth-responsive children taper their GH dose down to approximately 33 microg/kg per day more quickly.

Adverse drug reactions and outcome of short course anti-tuberculosis drugs between single daily dose and split drug dose (BID) in pulmonary tuberculosis.

PubMed

Chuchottaworn, Charoen; Saipan, Benjawan; Kittisup, Chomnapa; Cheewakul, Krisana

2012-08-01

Standard six months short course regimen for treatment of pulmonary tuberculosis is very effective and is recommended as standard treatment. But this regimen composes of many drugs and causes high adverse drug reactions especially gastrointestinal irritation. Spitted administration of drugs to two times a day may reduce adverse drug reactions. To study adverse drug reactions and outcome of single daily versus split drug (two times a day) administration of standard six month short course regimen in newly diagnosed pulmonary tuberculosis. Newly diagnosed pulmonary tuberculosis patients of the Central Chest Institute of Thailand were randomized to receive standard six months regimen once daily or two times a day (split drug). Patients were followed-up every two weeks and a questionnaire was used to detect adverse drug reactions. Outcome of treatment was evaluated according to national tuberculosis treatment guideline. 122 pulmonary tuberculosis were eligible for the present study and 61 patients were enrolled to each group of once daily or split drug regimen. Pulmonary tuberculosis patients who received split drug regimen had a higher cure rate but not statistical significance because of lower transfer out rate. Adverse drug reactions were similar in both groups of patients who received once daily and split drug regimen. Although split drug group had lower gastrointestinal adverse drug reactions. Split drug regimen has the same cure rate of treatment as single daily regimen and same adverse drug reactions.

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

Sugano, Yasutaka; Mizuta, Masahiro; Takao, Seishin

Purpose: Radiotherapy of solid tumors has been performed with various fractionation regimens such as multi- and hypofractionations. However, the ability to optimize the fractionation regimen considering the physical dose distribution remains insufficient. This study aims to optimize the fractionation regimen, in which the authors propose a graphical method for selecting the optimal number of fractions (n) and dose per fraction (d) based on dose–volume histograms for tumor and normal tissues of organs around the tumor. Methods: Modified linear-quadratic models were employed to estimate the radiation effects on the tumor and an organ at risk (OAR), where the repopulation of themore » tumor cells and the linearity of the dose-response curve in the high dose range of the surviving fraction were considered. The minimization problem for the damage effect on the OAR was solved under the constraint that the radiation effect on the tumor is fixed by a graphical method. Here, the damage effect on the OAR was estimated based on the dose–volume histogram. Results: It was found that the optimization of fractionation scheme incorporating the dose–volume histogram is possible by employing appropriate cell surviving models. The graphical method considering the repopulation of tumor cells and a rectilinear response in the high dose range enables them to derive the optimal number of fractions and dose per fraction. For example, in the treatment of prostate cancer, the optimal fractionation was suggested to lie in the range of 8–32 fractions with a daily dose of 2.2–6.3 Gy. Conclusions: It is possible to optimize the number of fractions and dose per fraction based on the physical dose distribution (i.e., dose–volume histogram) by the graphical method considering the effects on tumor and OARs around the tumor. This method may stipulate a new guideline to optimize the fractionation regimen for physics-guided fractionation.« less

LDR vs. HDR brachytherapy for localized prostate cancer: the view from radiobiological models.

PubMed

King, Christopher R

2002-01-01

Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated (192)Ir HDR brachytherapy, and (125)I and (103)Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses (<70 Gy), but similar to results from dose escalation series. LDR brachytherapy as boost achieves superior tumor control than when used as monotherapy. Stage for stage, both LDR and current HDR regimens achieve similar tumor control rates, in agreement with current clinical data. HDR monotherapy with large-dose fraction sizes might achieve superior tumor control compared with LDR, especially if prostate cancer possesses a high sensitivity to dose fractionation (i.e., if the alpha/beta ratio is low). Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. However, HDR brachytherapy dose escalation regimens might be able to achieve higher biologically effective doses of irradiation in comparison to LDR, and hence improved outcomes. This advantage over LDR would be amplified should prostate cancer possess a high sensitivity to dose fractionation (i.e., a low alpha/beta ratio) as the current evidence suggests.

The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases.

PubMed

Salmonson, Heléne; Sjöberg, Gunilla; Brogren, Jacob

2018-01-01

The use of the standard procedure for managing overdoses with immediate release (IR) paracetamol is questionable when applied to overdoses with modified release (MR) formulations. This study describes the pharmacokinetics of paracetamol and the clinical outcomes following overdoses with a MR formulation. Medical records including laboratory analyses concerning overdoses of MR paracetamol from 2009 to 2015 were collected retrospectively. Inclusion criteria were ingestion of a toxic dose, known time of intake and documented measurements of serum paracetamol and liver function tests. Graphical analysis, descriptive statistics and population pharmacokinetic modelling were used to describe data. Fifty-three cases were identified. Median age was 26 years (range 13-68), median dose was 20 g (range 10-166) and 74% were females. The pharmacokinetic analysis showed a complex, dose dependent serum versus time profile with prolonged absorption and delayed serum peak concentrations with increasing dose. Ten patients had persistently high serum levels for 24 h or more, six of them had a second peak 8-19 h after ingestion. Seven of 34 patients receiving N-acetylcysteine (NAC) within 8 h had alanine aminotransferase (ALT) above reference range. Three of them developed hepatotoxicity (ALT >1000 IU/l). The pharmacokinetic and clinical analysis showed that the standard treatment protocol, including risk assessment and NAC regimen, used for IR paracetamol poisoning not appear suitable for MR formulation. Individual and tailored treatment may be valuable but further studies are warranted to determine optimal regimen of overdoses with MR formulation.

Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.

PubMed

Shiber, Shachaf; Stiebel-Kalish, Hadas; Shimon, Ilan; Grossman, Alon; Robenshtok, Eyal

2014-10-01

Glucocorticoid (GC) therapy has been shown to prevent Graves' ophthalmopathy (GO) progression following radioactive iodine (RAI) treatment. However, the optimal regimen is controversial, with studies from recent years suggesting the use of lower doses and shorter GC treatment courses. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective controlled trials comparing GC regimens versus placebo, no treatment, or other GC regimens. Eight trials evaluating 850 patients fulfilled inclusion criteria. In patients with preexisting GO, standard dose prednisone (0.4-0.5 mg/kg tapered over 3 months) was very effective for prevention of GO progression (OR 0.14 [CI 0.06-0.35], p<0.01) in patients with mild to moderate GO. Two studies evaluated low-dose prednisone (0.2-0.3 mg/kg for 4-6 weeks) in patients with mild GO or risk factors, but were limited by not including patients with preexisting GO in the control groups. Therefore, the two low-dose groups were evaluated using indirect comparisons with control groups matched for age and clinical activity score, showing excellent efficacy versus no treatment or placebo (OR 0.20 [CI 0.07-0.60], p=0.004) and no significant difference compared with standard dose (OR 1.7 [CI 0.52-5.52], p=0.47). In patients without preexisting GO, steroid prophylaxis had no beneficial effect (OR 1.87 [CI 0.81-4.3]), though there were insufficient data regarding patients with risk factors for GO development. GC prophylaxis had no impact on hyperthyroidism resolution (OR 1.05 [CI 0.69-1.58]), and GC side effects were common but mild. Current evidence supports a three-tier approach for prevention of GO progression following RAI. Standard dose prednisone is the best validated regimen and should be used in patients with mild to moderate GO who have high risk of progression, while low dose prednisone can be used in patients with mild GO, and in patients without preexisting GO who have risk factors and are selected for GC prophylaxis. Patients without preexisting GO and without risk factors should not be treated with GC prophylaxis.

Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

PubMed Central

Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

2015-01-01

Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

Levofloxacin : a review of its use as a high-dose, short-course treatment for bacterial infection.

PubMed

Anderson, Vanessa R; Perry, Caroline M

2008-01-01

Levofloxacin (Levaquin) is a fluoroquinolone antibacterial that is the L-isomer of ofloxacin. A high-dose (750 mg) short-course (5 days) of once-daily levofloxacin is approved for use in the US in the treatment of community-acquired pneumonia (CAP), acute bacterial sinusitis (ABS), complicated urinary tract infections (UTI) and acute pyelonephritis (AP). The broad spectrum antibacterial profile of levofloxacin means that monotherapy is often a possibility in patients with CAP at times when other agents may require combination therapy, although levofloxacin can be used in combination therapy when necessary. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent bactericidal activity and may reduce the potential for resistance to emerge. In addition, this regimen lends itself to better compliance because of the shorter duration of treatment and the convenient once-daily administration schedule. Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation; importantly, patients can transition between the formulations, which results in more options in regards to the treatment regimen and the potential for patients with varying degrees of illness to be treated. Levofloxacin has good tissue penetration and an adequate concentration can be maintained in the urinary tract to treat uropathogens. Levofloxacin is generally well tolerated and has good efficacy in the treatment of patients with CAP, ABS, complicated UTI and AP. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP, ABS and UTIs is well established, and the high-dose, short-course levofloxacin regimen has been shown to be noninferior to the 10-day regimen in CAP and ABS, and to have a similar tolerability profile. Similarly, the high-dose, short-course levofloxacin regimen is noninferior to ciprofloxacin in patients with complicated UTI or AP. Thus, levofloxacin is a valuable antimicrobial agent that has activity against a wide range of bacterial pathogens; however, its use should be considered carefully so that the potential for resistance selection can be minimized and its usefulness in severe infections and against a range of penicillin- and macrolide-resistant pathogens can be maintained.

Chemoprophylaxis of infective endocarditis.

PubMed

Finch, R

1990-01-01

Infective endocarditis is a serious disease with a continuing mortality of approximately 20%. Risk factors include a variety of congenital and acquired heart diseases. Infection follows an episode of bacteraemia which is most commonly due to oral bacteria, notably streptococci. Less commonly bacteraemia may arise from surgical procedures or diseases of the gastrointestinal and genitourinary tracts or from sepsis at other body sites, including intravenous drug abuse. Several societies and associations have published recommendations for the prevention of bacteraemia in those at risk from endocarditis through the use of perioperative antibiotic chemoprophylaxis. The recommendations are targetted at patients with defined cardiovascular lesions undergoing dental and other procedures known to predictably produce bacteraemia. The major recommendations for standard risk patients undergoing dental procedures without general anaesthesia is high-dose oral penicillin or amoxycillin. Alternative agents include erythromycin and clindamycin. For those requiring general anaesthesia, parenteral regimens are generally recommended although the British Society for Antimicrobial Chemotherapy permits an oral amoxycillin regimen 4 hours preoperatively. For specified gastrointestinal and genitourinary procedures a 2-drug regimen of ampicillin/amoxycillin (or vancomycin for penicillin-allergic patients) plus an aminoglycoside is generally recommended. The emphasis has been to simplify the earlier regimens without compromising the antimicrobial protection with a view to encouraging maximum compliance. The latter continues to be a problem where drug recommendations are either complex or include multiple drug or dosage recommendations. The emphasis on maintaining good dental health is endorsed by all authorities.

Pharmacokinetic and pharmacodynamic model for analysis of adalimumab administered for Crohn's disease.

PubMed

Kimura, Koji; Yoshida, Atsushi; Takayanagi, Risa; Yamada, Yasuhiko

2018-05-23

Adalimumab (ADA) is used as a therapeutic agent for Crohn's disease (CD). Although that dosage regimen has been established through clinical trial experience, it has not been analyzed theoretically. In the present study, we analyzed of sequential changes of the Crohn's disease activity index (CDAI) after repeated administrations of ADA using a pharmacokinetic and pharmacodynamic model. In addition, we analyzed the validity of the dosage regimen, and potential efficacy gained by increasing the dose and reducing the interval of administration. The sequential changes in CDAI values obtained with our model were in good agreement with observed CDAI values, which was considered to show the validity of our analysis. We considered that our results showed the importance of the loading dose of ADA to obtain remission in an early stage of active CD. In addition, we showed that patients who have an incomplete response to ADA can obtain similar efficacy from increasing the dose and reducing the dose interval. In conclusion, our results showed that the present model may be applied to predict the CDAI values of ADA for CD. They indicated the validity of the dosage regimen, as well as the efficacy of increasing the dose and reducing the dose interval. This article is protected by copyright. All rights reserved.

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling.

PubMed

Mori, Takehiko; Koh, Hideo; Onishi, Yasushi; Kako, Shinichi; Onizuka, Makoto; Kanamori, Heiwa; Ozawa, Yukiyasu; Kato, Chiaki; Iida, Hiroatsu; Suzuki, Ritsuro; Ichinohe, Tatsuo; Kanda, Yoshinobu; Maeda, Tetsuo; Nakao, Shinji; Yamazaki, Hirohito

2016-04-01

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

PubMed

Hendrix, James A; Bateman, Randall J; Brashear, H Robert; Duggan, Cynthia; Carrillo, Maria C; Bain, Lisa J; DeMattos, Ronald; Katz, Russell G; Ostrowitzki, Susanne; Siemers, Eric; Sperling, Reisa; Vitolo, Ottavio V

2016-05-01

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders. Copyright © 2016 Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil *

PubMed Central

Ferreira, Anna Carolina Galvão; da Silva, José Laerte Rodrigues; Conde, Marcus Barreto; Rabahi, Marcelo Fouad

2013-01-01

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health-rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months-involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (≥ 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous basic regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%). PMID:23503489

Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil.

PubMed

Ferreira, Anna Carolina Galvão; Silva Júnior, José Laerte Rodrigues da; Conde, Marcus Barreto; Rabahi, Marcelo Fouad

2013-01-01

To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer.

PubMed

Masters, G A; Mauer, A M; Hoffman, P C; Wyka, D; Samuels, B L; Krauss, S A; Watson, S; Golomb, H; Vokes, E E

1998-06-01

We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Modification of Enrofloxacin Treatment Regimens for Poultry Experimentally Infected with Salmonella enterica Serovar Typhimurium DT104 To Minimize Selection of Resistance▿

PubMed Central

Randall, Luke P.; Cooles, Sue W.; Coldham, Nick C.; Stapleton, Ken S.; Piddock, Laura J. V.; Woodward, Martin J.

2006-01-01

We hypothesized that higher doses of fluoroquinolones for a shorter duration could maintain efficacy (as measured by reduction in bacterial count) while reducing selection in chickens of bacteria with reduced susceptibility. Chicks were infected with Salmonella enterica serovar Typhimurium DT104 and treated 1 week later with enrofloxacin at the recommended dose for 5 days (water dose adjusted to give 10 mg/kg of body weight of birds or equivalence, i.e., water at 50 ppm) or at 2.5 or 5 times the recommended dose for 2 days or 1 day, respectively. The dose was delivered continuously (ppm) or pulsed in the water (mg/kg) or by gavage (mg/kg). In vitro in sera, increasing concentrations of 0.5 to 8 μg/ml enrofloxacin correlated with increased activity. In vivo, the efficacy of the 1-day treatment was significantly less than that of the 2- and 5-day treatments. The 2-day treatments showed efficacy similar to that of the 5-day treatment in all but one repeat treatment group and significantly (P < 0.01) reduced the Salmonella counts. Dosing at 2.5× the recommended dose and pulsed dosing both increased the peak antibiotic concentrations in cecal contents, liver, lung, and sera as determined by high-pressure liquid chromatography. There was limited evidence that shorter treatment regimens (in particular the 1-day regimen) selected for fewer strains with reduced susceptibility. In conclusion, the 2-day treatment would overall require a shorter withholding time than the 5-day treatment and, in view of the increased peak antibiotic concentrations, may give rise to improved efficacy, in particular for treating respiratory and systemic infections. However, it would be necessary to validate the 2-day regimen in a field situation and in particular against respiratory and systemic infections to validate or refute this hypothesis. PMID:17030564

Oral oxybutynin for the treatment of hyperhidrosis: outcomes after one-year follow-up.

PubMed

Millán-Cayetano, José Francisco; Del Boz, Javier; Rivas-Ruiz, Francisco; Blázquez-Sánchez, Nuria; Hernández Ibáñez, Carlos; de Troya-Martín, Magdalena

2017-05-01

Although many treatments are available to address hyperhidrosis, the results are not always satisfactory. The aim of the study was to assess the effectiveness, optimal dosage regimen and long-term safety of oral oxybutynin in the treatment of hyperhidrosis. A retrospective review was performed on 110 patients who underwent treatment for hyperhidrosis between February 2007 and December 2013. Their response to treatment was evaluated using the hyperhidrosis disease severity scale at baseline, 3 and 12 months. Additionally, the safety and effectiveness of different up-dosing and fixed-dose regimens were compared. After 3 months of treatment, 87 of the 110 patients (79%) had responded (63%), which was considered excellent. After 12 months, 63 patients (62%) continued to respond, and the response was considered excellent in 50%. Nine patients were lost to follow up between month 3 and 12. In total, 77 and 70% of the patients who responded at 3 and 12 months, respectively, reported mild adverse events. No serious adverse events were observed. Treatment adherence was significantly higher among patients following the individualised up-dosing regimen. Oral oxybutynin may be an effective and safe option for the long-term treatment of hyperhidrosis. To improve treatment adherence, oxybutynin dosing regimens should be individualised on the basis of the patient's tolerance and response. © 2016 The Australasian College of Dermatologists.

Estimating age-based antiretroviral therapy costs for HIV-infected children in resource-limited settings based on World Health Organization weight-based dosing recommendations.

PubMed

Doherty, Kathleen; Essajee, Shaffiq; Penazzato, Martina; Holmes, Charles; Resch, Stephen; Ciaranello, Andrea

2014-05-02

Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0-13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments.

The effect of single dose versus two doses of praziquantel on Schistosoma haematobium infection and pathology among school-aged children in Mali.

PubMed

Sacko, M; Magnussen, P; Traoré, M; Landouré, A; Doucouré, A; Reimert, C M; Vennervald, B J

2009-11-01

The aim of this study was to assess the effect of two doses of 40 mg/kg praziquantel with 2 weeks interval versus a standard single dose of 40 mg/kg on cure rates, egg reduction, intensity of infection, and micro-haematuria in Schistosoma haematobium infections. A randomised controlled intervention study was carried out among school-aged children in two different endemic settings with follow-up at 3, 6 and 18 months following drug administration. Differences in cure rates between the two treatment regimens were not significant. However, in high transmission areas, the double treatment regimen was more effective in egg reduction than single treatment regimen and the difference in egg reduction between the two treatments was significant at 3 months (P<0.005), 6 months (P<0.0001) and 18 months (P<0.003) after treatment. There was a significant difference in the effect of the two treatments on prevalence of micro-haematuria at 18-month follow-up in both Koulikoro (P<0.001) and Selingue (P<0.003). The study shows that although no significant difference could be observed in the overall cure-rates between the two treatment regimens, the effect of double treatment was a significant reduction in infection intensity as well as micro-haematuria which may have a great impact in reducing subtle morbidity.

Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine.

PubMed

Sampson, Joshua N; Hildesheim, Allan; Herrero, Rolando; Gonzalez, Paula; Kreimer, Aimee R; Gail, Mitchell H

2018-05-01

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. Copyright © 2018. Published by Elsevier Inc.

Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects.

PubMed

Legangneux, Eric; Gardin, Anne; Johns, Donald

2013-03-01

Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects. Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25-10 mg over 9-10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1-12 vs. the non-titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non-titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non-titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3-7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min⁻¹; P ≤ 0.0001). From days 9-12, HRs in both titration regimens were comparable with placebo. Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg. © 2012 Novartis Institutes for BioMedical Research (NIBIR). British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

PubMed Central

Paradisis, Mary; Jiang, Xuemin; McLachlan, Andrew J; Evans, Nick; Kluckow, Martin; Osborn, David

2007-01-01

Aims To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. Methods A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). Results Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. Conclusion Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology. PMID:16690639

The treat-and-extend injection regimen versus alternate dosing strategies in age-related macular degeneration: a systematic review and meta-analysis.

PubMed

Okada, Mali; Kandasamy, Rathika; Chong, Elaine W; McGuiness, Myra; Guymer, Robyn H

2018-06-06

To assess outcomes of the treat-and-extend (T&E) injection regimen for neovascular age related macular degeneration (AMD) as compared to either a monthly or a pro-re-nata (PRN) treatment strategy. Systematic review and meta-analysis METHODS: Studies that compared the T&E regimen with either monthly or PRN dosing for treatment-naïve AMD were included. Trial eligibility, data extraction and risk of bias were assessed according to Cochrane review methods. Estimates were pooled using random effects meta-analysis. Four eligible studies were identified, all using ranibizumab (total n=940 eyes), including two randomized controlled trials comparing T&E to monthly and two retrospective reviews comparing T&E to PRN. No studies evaluating aflibercept were identified. Improvements in vision and central retinal thickness were similar between T&E and monthly at 12 months, with a mean difference of -1.79 letters (95% CI: 3.70, 0.13) and 3.76μm (95% CI: -13.78, 21.30) in favour of monthly injections. In contrast, visual gains were higher in the T&E compared to PRN group (difference of +6.18 letters, 95% CI: 3.28, 9.08). Fewer injections were required using the T&E regimen when compared to monthly (mean of -1.6 and -6.9 injections less at 12 and 24 months respectively). A mean of 1.44 more injections was required for the T&E compared to PRN regimen at 12 months, however this was achieved with fewer visits. Despite the growing preference for the T&E regimen, there is limited head-to-head evidence comparing dosing strategies. The evidence available however, suggests that at 12 months, T&E is comparable to monthly and superior to PRN dosing for both efficacy and safety outcomes when using ranibizumab. Copyright © 2018 Elsevier Inc. All rights reserved.

Comparison of evening and morning dosing of travoprost 0.004%/timolol 0.5% fixed combination in 6 month period.

PubMed

Suić, Smiljka Popović; Laus, Katia Novak; Dosen, Vukosava Maricic; Ekert, Miroslav; Mandić, Zdravko; Bojić, Lovro

2010-09-01

An open label, multi-center, 6 months observational study of new fixed combination (travoprost 0.004%/timolol 0.5%), in order to evaluate both efficacy (intraocular pressure lowering) and tolerability (patient and investigator satisfaction) of two dosing regimens--evening (PM) and morning (AM). After screening for enrollment, to 40 patients (79 eyes with primary open angle glaucoma or ocular hypertension), new fixed combination travoprost 0.004%/timolol 0.5% was prescribed once a day in the evening (PM). Patients were enrolled according to each investigator decision on indication for travoprost 0.004%/timolol 0.5% fixed combination once a day, without washout period after previous medication. Intraocular pressure was measured at 9 AM at all time control points: at baseline, after 1 month, after 3 months and after 6 month. After 1 month, screening for nonresponders (criteria: 20% intraocular pressure lowering) and subjects with major side effects was performed. At second control visit, after 3 months PM dosing, intraocular pressure was measured and patients were instructed to continue once a day the same medication, but in the morning (AM) for consequent 3 months. After 1 month, reduction in mean intraocular pressure value was 21.66%. At the visit after 3 month, the mean intraocular pressure was 15.67 +/- 2.17 mm Hg (reduction 21.14%). 3 month after dosing regimen changed to AM (6 month after beginning of travoprost 0.004%/timolol 0.5% combination therapy), reduction in intraocular pressure value was 19.86%. The differences (mean +/- standard deviation) in intraocular pressure values after 1, 3 and 6 month were all highly statistically significant compared to baseline values. The tolerability was evaluated in five steps (Likert scale) ranging from unsatisfactory to excellent by both patient and investigator--taken at 3 and 6 month control visit. 95% of patients and 100% of investigators were satisfied with the possibility of choosing dosing regimen for travoprost 0.004%/timolol 0.5% fixed combination. Travoprost 0.004%/timolol 0.5% fixed combination proved sufficient intraocular pressure control dosed either PM or AM with no statistically significant difference between two dosing regimens. Possibility to choose between two dosing regimens gives each practitioner additional reassurance that glaucoma therapy will be individualised to needs of each patient.

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours

PubMed Central

2013-01-01

Background Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Methods Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5–12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Results Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m2, which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in Cmax and AUC0–t were dose proportional for the 6–12 mg/m2 doses. Conclusion The MTD of weekly cabazitaxel was 12 mg/m2 and the recommended weekly dose was 10 mg/m2. The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. Trial registration The study was registered with ClinicalTrials.gov as NCT01755390. PMID:24099585

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

PubMed

Iversen, Ole-Erik; Miranda, Maria Jose; Ulied, Angels; Soerdal, Terje; Lazarus, Erica; Chokephaibulkit, Kulkanya; Block, Stan L; Skrivanek, Ales; Nur Azurah, Abdul Ghani; Fong, Siew Moy; Dvorak, Vladimir; Kim, Kyung-Hyo; Cestero, Ramon M; Berkovitch, Matitiahu; Ceyhan, Mehmet; Ellison, Misoo C; Ritter, Michael A; Yuan, Shuai S; DiNubile, Mark J; Saah, Alfred J; Luxembourg, Alain

2016-12-13

Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. clinicaltrials.gov Identifier: NCT01984697.

Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen).

PubMed

Mahendra, B J; Narayana, Dh Ashwath; Agarkhedkar, Sharad; Ravish, H S; Harish, B R; Agarkhedkar, Shalaka; Madhusudana, S N; Belludi, Ashwin; Ahmed, Khaleel; Jonnalagedda, Rekha; Vakil, Hoshang; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2015-01-01

Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857.

Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen)

PubMed Central

Mahendra, BJ; Narayana, DH Ashwath; Agarkhedkar, Sharad; Ravish, HS; Harish, BR; Agarkhedkar, Shalaka; Madhusudana, SN; Belludi, Ashwin; Ahmed, Khaleel; Jonnalagedda, Rekha; Vakil, Hoshang; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2015-01-01

Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857 PMID:25692792

The use of granulocyte colony stimulating factor (G-CSF) and management of chemotherapy delivery during adjuvant treatment for early-stage breast cancer--further observations from the IMPACT solid study.

PubMed

Mäenpää, Johanna; Varthalitis, Ioannis; Erdkamp, Frans; Trojan, Andreas; Krzemieniecki, Krzysztof; Lindman, Henrik; Bendall, Kate; Vogl, Florian D; Verma, Shailendra

2016-02-01

To investigate the use and impact of granulocyte colony-stimulating factors (G-CSF) on chemotherapy delivery and neutropenia management in breast cancer in a clinical practice setting. IMPACT Solid was an international, prospective observational study in patients with a physician-assessed febrile neutropenia (FN) risk of ≥20%. This analysis focused on stages I-III breast cancer patients who received a standard chemotherapy regimen for which the FN risk was published. Chemotherapy delivery and neutropenia-related outcomes were reported according to the FN risk of the regimen and intent of G-CSF use. 690 patients received a standard chemotherapy regimen; 483 received the textbook dose/schedule with a majority of these regimens (84%) having a FN risk ≥10%. Patients receiving a regimen with a FN risk ≥10% were younger with better performance status than those receiving a regimen with a FN risk <10%. Patients who received higher-risk regimens were more likely to receive G-CSF primary prophylaxis (48% vs 22%), complete their planned chemotherapy (97% vs 88%) and achieve relative dose intensity ≥85% (93% vs 86%) than those receiving lower-risk regimens. Most first FN events (56%) occurred in cycles not supported with G-CSF primary prophylaxis. Physicians generally recommend standard adjuvant chemotherapy regimens and were more likely to follow G-CSF guidelines for younger, good performance status patients in the curative setting, and often modify standard regimens in more compromised patients. However, G-CSF support is not optimal, indicated by G-CSF primary prophylaxis use in <50% of high-risk patients and observation of FN without G-CSF support. Copyright © 2015 Elsevier Ltd. All rights reserved.

High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial.

PubMed

Pearson, Andrew D J; Pinkerton, C Ross; Lewis, Ian J; Imeson, John; Ellershaw, Caroline; Machin, David

2008-03-01

The current standard treatment for patients with high-risk neuroblastoma includes initial induction chemotherapy with a 21-day interval between induction treatments. We aimed to assess whether an intensive chemotherapy protocol that had a 10-day interval between treatments would improve event-free survival (EFS) in patients aged 1 year or over with high-risk neuroblastoma. Between Oct 30, 1990, and March 18, 1999, patients with stage 4 neuroblastoma who had not received previous chemotherapy were enrolled from 29 centres in Europe. Patients were randomly assigned to rapid treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC) or standard treatment (vincristine [O], cisplatin [P], etoposide [E], and cyclophosphamide [C], ie, OPEC, alternated with vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], ie, OJEC). Both regimens used the same total cumulative doses of each drug (except vincristine), but the dose intensity of the rapid regimen was 1.8-times higher than that of the standard regimen. The standard regimen was given every 21 days if patients showed haematological recovery, whereas the rapid regimen was given every 10 days irrespective of haematological recovery. Response to chemotherapy was assessed according to the conventional International Neuroblastoma Response Criteria (INRC). In responders, surgical excision of the primary tumour was attempted, followed by myeloablation (with 200 mg/m2 of melphalan) and haemopoietic stem-cell rescue. Primary endpoints were 3-year, 5-year, and 10-year EFS. Data were analysed by intention to treat. This trial is registered on the clinical trials site of the US National Cancer Institute website, number NCT00365755, and also as EU-20592 and CCLG-NB-1990-11. 262 patients, of median age 2.95 years (range 1.03-20.97), were randomly assigned-132 patients to standard and 130 patients to rapid treatment. 111 patients in the standard group and 109 patients in the rapid group completed chemotherapy. Chemotherapy doses were recorded for 123 patients in the standard group and 126 patients in the rapid group. 97 of 123 (79%) patients in the standard group and 84 of 126 (67%) patients in the rapid group received at least 90% of the scheduled chemotherapy, and the relative dose intensity was 1.94 compared with the standard regimen. 3-year EFS was 24.2% for patients in the standard group and 31.0% for those in the rapid group (hazard ratio [HR] 0.86 [95% CI 0.66-1.14], p=0.30. 5-year EFS was 18.2% in the standard group and 30.2% in the rapid group, representing a difference of 12.0% (1.8 to 22.3), p=0.022. 10-year EFS was 18.2% in the standard group and 27.1% in the rapid group, representing a difference of 8.9% (-1.2 to 19.0), p=0.085. Myeloablation was given a median of 55 days earlier in patients assigned rapid treatment than those assigned standard treatment. Infective complications (numbers of patients with febrile neutropenia and septicaemia, and if given, time on antibiotic and antifungal treatment) and time in hospital were greater with rapid treatment. Occurrence of fungal infection was the same in both regimens. Dose intensity can be increased with a rapid induction regimen in patients with high-risk neuroblastoma. There was no significant difference in OS between the rapid and standard regimens at 5 years and 10 years. However, an increasing difference in EFS after 3 years suggests that the efficacy of the rapid regimen is better than the standard regimen. A rapid induction regimen enables myeloablation to be given much earlier, which might contribute to a better outcome.

Induction chemotherapy in metastatic neuroblastoma--does dose influence response? A critical review of published data standards, options and recommendations (SOR) project of the National Federation of French Cancer Centres (FNCLCC).

PubMed

Pinkerton, C R; Blanc Vincent, M P; Bergeron, C; Fervers, B; Philip, T

2000-09-01

The purpose of this study was to determine, from a review of published data, whether in stage 4 neuroblastoma in children over 1 year of age, the dose or scheduling of induction chemotherapy influenced the response rate in distant metastases. Publications relating to induction chemotherapy since the introduction of cisplatin/epipodophyllotoxin combinations were identified using Medline, Current Contents and personal reference lists. Thirteen publications were identified which described 17 regimens involving 948 children. The doses and the scheduling of the various regimens were compared with a standard regimen OPEC (vincristine, cisplatin, teniposide, cyclophosphamide). These were correlated with the reported response rates in the bone marrow. Due to a lack of standardisation in the nature of restaging investigations, timing of restaging and definitions of response it was difficult to compare all studies. The complete response rate at distant metastases ranged from less than 40% to over 90%. For individual drugs; the comparative doses given in each course ranged up to 4.2 g/m(2) for cyclophosphamide, 280 mg/m(2) for cisplatin, 600 mg/m(2) for etoposide and 4.5 mg/m(2) for vincristine. There was no evidence of any positive correlation between response rate in the marrow and either the dose of any individual drug or the schedule used. In contrast to a previous study which included a number of older studies where disease assessment was even more variable, this analysis has failed to show any justification for the routine use of very intensive induction regimens in this disease. Such an approach should only be taken in the context of randomised trials in which timing and methods of reassessment can be standardised. Until such studies demonstrate superiority either in terms of response rate or progression-free survival lower morbidity regimens should remain the standard therapy.

Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention: A Randomized Trial.

PubMed

Baden, Lindsey R; Karita, Etienne; Mutua, Gaudensia; Bekker, Linda-Gail; Gray, Glenda; Page-Shipp, Liesl; Walsh, Stephen R; Nyombayire, Julien; Anzala, Omu; Roux, Surita; Laher, Fatima; Innes, Craig; Seaman, Michael S; Cohen, Yehuda Z; Peter, Lauren; Frahm, Nicole; McElrath, M Juliana; Hayes, Peter; Swann, Edith; Grunenberg, Nicole; Grazia-Pau, Maria; Weijtens, Mo; Sadoff, Jerry; Dally, Len; Lombardo, Angela; Gilmour, Jill; Cox, Josephine; Dolin, Raphael; Fast, Patricia; Barouch, Dan H; Laufer, Dagna S

2016-03-01

A prophylactic HIV-1 vaccine is a global health priority. To assess a novel vaccine platform as a prophylactic HIV-1 regimen. Randomized, double-blind, placebo-controlled trial. Both participants and study personnel were blinded to treatment allocation. (ClinicalTrials.gov: NCT01215149). United States, East Africa, and South Africa. Healthy adults without HIV infection. 2 HIV-1 vaccines (adenovirus serotype 26 with an HIV-1 envelope A insert [Ad26.EnvA] and adenovirus serotype 35 with an HIV-1 envelope A insert [Ad35.Env], both administered at a dose of 5 × 1010 viral particles) in homologous and heterologous combinations. Safety and immunogenicity and the effect of baseline vector immunity. 217 participants received at least 1 vaccination, and 210 (>96%) completed follow-up. No vaccine-associated serious adverse events occurred. All regimens were generally well-tolerated. All regimens elicited humoral and cellular immune responses in nearly all participants. Preexisting Ad26- or Ad35-neutralizing antibody titers had no effect on vaccine safety and little effect on immunogenicity. In both homologous and heterologous regimens, the second vaccination significantly increased EnvA antibody titers (approximately 20-fold from the median enzyme-linked immunosorbent assay titers of 30-300 to 3000). The heterologous regimen of Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States. Because the 2 envelope inserts were not identical, the boosting responses were complex to interpret. Durability of the immune responses elicited beyond 1 year is unknown. Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not significantly affect responses. Second vaccinations in all regimens significantly boosted EnvA antibody titers, although vaccine order in the heterologous regimen had a modest effect on the immune response. International AIDS Vaccine Initiative, National Institutes of Health, Ragon Institute, Crucell Holland.

A meta-analysis of phase III randomized controlled trials with novel oral anticoagulants in atrial fibrillation: comparisons between direct thrombin inhibitors vs. factor Xa inhibitors and different dosing regimens.

PubMed

Providência, Rui; Grove, Erik Lerkevang; Husted, Steen; Barra, Sérgio; Boveda, Serge; Morais, João

2014-12-01

Previous studies evaluating the ability of novel oral anticoagulants (NOAC) to prevent thromboembolism in patients with non-valvular atrial fibrillation (AF) have identified differences between the efficacy and safety of the drugs tested. Whether these differences reflect differences in direct thrombin or Xa inhibition, different dosing regimens or specific aspects of each agent or trial has not yet been explored. A search was performed on MEDLINE, EMBASE and COCHRANE, and ongoing studies were tracked on clinicaltrials.gov. Phase III randomized controlled trials of direct thrombin inhibitors (DTI) and factor Xa inhibitors (FXaI) vs. warfarin in patients with AF were eligible. Data were pooled using random-effects, according to the Mantel-Haenszel model. Sensitivity analyses were performed on DTI, FXaI, once-daily and twice-daily regimens. Seven studies were pooled, including a total of 80,290 patients. Both DTI and FXaI outperformed warfarin regarding stroke or systemic embolism, intracranial bleeding, total and cardiovascular mortality. No significant differences were found between DTI and FXaI or between once-daily and twice-daily regimens. Some drugs performed worse than warfarin regarding some secondary endpoints, including: edoxaban 30 mg bid on ischaemic stroke, dabigatran on acute myocardial infarction, dabigatran 150 mg bid and rivaroxaban 20mgod on gastrointestinal bleeding. Our pooled data do not support the hypothesis of a significant class-effect of DTI or FXaI, nor the benefit of once-daily vs. twice-daily dosing in the setting of AF, reinforcing that the choice of NOAC should be adapted to the specific patient and focused on the agent itself, rather than the pharmacological class or dosing regimen.

Comparison of two dose regimens of growth hormone (GH) with different target IGF-1 levels on glucose metabolism, lipid profile, cardiovascular function and anthropometric parameters in gh-deficient adults.

PubMed

Cenci, Maria Claudia Peixoto; Soares, Débora Vieira; Spina, Luciana Diniz Carneiro; Brasil, Rosane Resende de Lima Oliveira; Lobo, Priscila Marise; Michmacher, Eduardo; Vaisman, Mario; Boguszewski, Cesar Luiz; Conceição, Flávia Lúcia

2012-01-01

To compare the effects of two regimens of GH therapy with different target IGF-1 levels on anthropometric parameters, glucose metabolism, lipid profile and cardiac function in adults with GH deficiency (GHD). Retrospective analysis of 14 GHD adults from Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil, who were treated with a GH regimen aimed at maintaining serum IGF-1 levels between the median and upper reference limit (high dose group - HDGH) and 18 GHD adults from Federal University Hospital, Curitiba, Brazil, who received a fixed GH dose of 0.2mg/day in the first year of treatment, followed by titration to maintain serum IGF-1 levels between the median and lower reference limit (low dose group - LDGH). All patients were followed for 2 years with analysis of anthropometric parameters, serum levels of IGF-1, glucose, insulin, HOMA-IR, lipid profile, and transthoracic echocardiography. Changes on weight, BMI and waist circumference were similar between the two groups. Insulin levels increased and HOMA-IR worsened in the LDGH group at 1year and improved thereafter. Total cholesterol and triglycerides did not change with therapy. LDL cholesterol reduced in both groups, while HDL-cholesterol significantly increased only in the HDGH group (p=0.007 vs LDGH). No significant variations on echocardiographic parameters were observed. The HDGH and LDGH regimens resulted in similar changes on anthropometric, echocardiographic, glucose and lipid parameters in GHD adults, except for increase in HDL cholesterol that was only observed in the HDGH regimen. Copyright © 2012 Elsevier Ltd. All rights reserved.

Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticle-encapsulated aspirin and curcumin in combination with free sulforaphane in BALB/c mice

PubMed Central

Thakkar, Arvind; Chenreddy, Sushma; Thio, Astrid; Khamas, Wael; Wang, Jeffrey; Prabhu, Sunil

2016-01-01

Our previous studies have established the efficacy of chemopreventive regimens of aspirin and curcumin (CUR) encapsulated within solid lipid nanoparticles (SLNs) in combination with free sulforaphane (ACS combination) to prevent or delay the initiation and progression of pancreatic cancer, classified as one of the deadliest diseases with very low chances of survival upon diagnosis. Although toxicity of individual drugs and SLN has been studied previously, there are no studies in current literature that evaluate the potential toxicity of a combined regimen of ACS, especially when encapsulated within chitosan-SLNs (c-SLNs). Hence, objective of the current study was to investigate the potential toxic effects of ACS c-SLN combined chemopreventive regimens following acute (3 days), subacute (28 days), and subchronic (90 days) administrations by oral gavage in BALB/c mice. Mice were administered the following regimens: saline, blank c-SLN, low-dose ACS c-SLN (2+4.5+0.16 mg/kg), medium-dose ACS c-SLN (20+45+1.6 mg/kg), and high-dose ACS c-SLN (60+135+4.8 mg/kg). The potential toxicity was evaluated based on animal survival, body weight, hematology, blood chemistry, and organ histopathology. During 3-day, 28-day, and 90-day study periods, no animal deaths were observed. Treatment with ACS c-SLNs did not cause alteration in complete blood counts and blood chemistry data. Histopathological examination of various organ sections (pancreas, heart, liver, kidney, and brain) appeared normal. Based on the results of this study, no signs of toxicity in acute, subacute, and subchronic studies following oral administration of ACS c-SLNs were found indicating that the oral dosing regimens were safe at the levels tested for long-term administration to prevent the onset of pancreatic cancer. PMID:27499621

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

PubMed

Shiue, Harn J; Taylor, Maria; Sands, Kara A

2017-10-01

Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1

PubMed Central

Ziegler, David S.; Cohn, Richard J.; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

2006-01-01

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children’s Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen. PMID:16443948

Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

PubMed

Lehmann-Che, Jacqueline; André, Fabrice; Desmedt, Christine; Mazouni, Chafika; Giacchetti, Sylvie; Turpin, Elisabeth; Espié, Marc; Plassa, Louis-François; Marty, Michel; Bertheau, Philippe; Sotiriou, Christos; Piccart, Martine; Symmans, W Fraser; Pusztai, Lajos; de Thé, Hugues

2010-01-01

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

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.

Assessment of micafungin regimens by pharmacokinetic-pharmacodynamic analysis: a dosing strategy for Aspergillus infections.

PubMed

Ikawa, Kazuro; Nomura, Kenichi; Morikawa, Norifumi; Ikeda, Kayo; Taniwaki, Masafumi

2009-10-01

A pharmacokinetic (PK)-pharmacodynamic (PD) analysis was conducted to assess various micafungin regimens for Candida and Aspergillus infections, as appropriate regimens have not been established, especially for Aspergillus infections. Plasma drug concentrations (48 samples from 10 adult patients with haematological malignancies) were determined chromatographically, and used for population PK modelling and Monte Carlo simulation to evaluate the ability of regimens (1 h infusions) to attain genus-dependent PK-PD targets, namely fungistatic and fungicidal targets against Candida spp. [area under the plasma unbound (1%) drug concentration-time curve over 24 h/MIC (fAUC/MIC) = 10 and 20] and an effective concentration target against Aspergillus spp. (plasma unbound drug concentration = 0.05 mg/L). Mean (variance) values for two-compartment PK model parameters were: clearance, 0.762 L/h (15.4%); volume of central compartment, 9.25 L (24.6%); intercompartmental clearance, 7.02 L/h (fixed); and volume of peripheral compartment, 8.86 L (71.8%). The Monte Carlo simulation demonstrated that 50 mg once daily and 100 mg once daily for the fungistatic and fungicidal targets achieved a >95% probability of target attainment against Candida spp. To achieve such probability against Aspergillus spp., 250 mg once daily or 100 mg twice daily was required. These results rationalize the approved micafungin dosages for Candida infections (50 mg once daily for prophylaxis and 100-150 mg once daily for treatment), and on the basis of these results we propose a PK-PD-based dosing strategy for Aspergillus infections. A regimen of 200-250 mg/day should be initiated to ensure the likelihood of a favourable outcome. The regimen can be optimized by decreasing the dosing interval.

RESULTS OF THE MEGAVERTEBRATE ANALGESIA SURVEY: ELEPHANTS AND RHINO.

PubMed

Kottwitz, Jack; Boothe, Matthew; Harmon, Roy; Citino, Scott B; Zuba, Jeffery R; Boothe, Dawn M

2016-03-01

An online survey utilizing Survey Monkey linked through the American Association of Zoo Veterinarians listserve examined current practices in megavertebrate analgesia. Data collected included drugs administered, dosing regimens, ease of administration, efficacy, and adverse events. Fifty-nine facilities (38 housing elephants, 33 housing rhinoceroses) responded. All facilities administered nonsteroidal anti-inflammatory drugs (NSAIDs), with phenylbutazone (0.25-10 mg/kg) and flunixin meglumine (0.2-4 mg/kg) being most common. Efficacy was reported as "good" to "excellent" for these medications. Opioids were administered to elephants (11 of 38) and rhinoceroses (7 of 33), with tramadol (0.5-3.0 mg/kg) and butorphanol (0.05-1.0 mg/kg) being most common. Tramadol efficacy scores were highly variable in both elephants and rhinoceroses. While drug choices were similar among institutions, substantial variability in dosing regimens and reported efficacy between and within facilities indicates the need for pharmacokinetic studies and standardized methods of analyzing response to treatment to establish dosing regimens and clinical trials to establish efficacy and safety.

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.

PubMed

Smith, S D; Bolwell, B J; Rybicki, L A; Brown, S; Dean, R; Kalaycio, M; Sobecks, R; Andresen, S; Hsi, E D; Pohlman, B; Sweetenham, J W

2007-08-01

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Rapid promotion and progression of fibrovascular polyps by inflammation and/or hyperplasia in hamster check pouch: implications for carcinogenesis assay.

PubMed

McGaughey, C; Jensen, J L

1983-03-01

Tumor initiation by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) in dimethyl sulfoxide (DMSO) followed by topical application of retinyl acetate (RA), ethylphenylpropiolate, or acetic acid in DMSO at inflammatory and hyperplasiogenic dose regimens caused the rapid promotion of fibrovascular polyps with dysplastic epithelium in hamster cheek pouch. Such lesions did not occur in control animals initiated with DMBA followed by application of DMSO only, where inflammation was also minimal. At the dose regimen employed, RA caused obvious cytotoxicity and tissue destruction. With EPP and AA, there was no histological evidence of tissue destruction. At dose regimens resulting in minimal inflammation and no apparent cytotoxicity, RA promoted almost no polyps, but a higher yield of other tumor types. Thus, inflammation and/or hyperplasia apparently exerted a strong polyp-promoting and progressive influence. This and other differences between the tumorigenic responses of hamster-pouch mucosa and mouse skin suggest that the former supplement the latter in carcinogenic risk assessment.

Exploration of optimal dosing regimens of haloperidol, a D2 Antagonist, via modeling and simulation analysis in a D2 receptor occupancy study.

PubMed

Lim, Hyeong-Seok; Kim, Su Jin; Noh, Yook-Hwan; Lee, Byung Chul; Jin, Seok-Joon; Park, Hyun Soo; Kim, Soohyeon; Jang, In-Jin; Kim, Sang Eun

2013-03-01

To evaluate the potential usage of D(2) receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development. In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n = 3), 1 (n = 2), or 3 mg (n = 3) of haloperidol once daily for 7 days. PET's were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D(2) receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens. One compartment model with a saturable binding compartment, and inhibitory E(max) model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650 ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2 mg every 12 h is near the optimal dose. This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D(2) antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.

Improved speed and stability of ST-segment recovery with reduced-dose tenecteplase and eptifibatide compared with full-dose tenecteplase for acute ST-segment elevation myocardial infarction.

PubMed

Roe, Matthew T; Green, Cynthia L; Giugliano, Robert P; Gibson, C Michael; Baran, Kenneth; Greenberg, Mark; Palmeri, Sebastian T; Crater, Suzanne; Trollinger, Kathleen; Hannan, Karen; Harrington, Robert A; Krucoff, Mitchell W

2004-02-18

This sub-study of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial evaluated of the impact of combination reperfusion therapy with reduced-dose tenecteplase plus eptifibatide on continuous ST-segment recovery and angiographic results. Combination therapy with reduced-dose fibrinolytics and glycoprotein IIb/IIIa inhibitors for ST-segment elevation myocardial infarction improves biomarkers of reperfusion success but has not reduced mortality when compared with full-dose fibrinolytics. We evaluated 140 patients enrolled in the INTEGRITI trial with 24-h continuous 12-lead ST-segment monitoring and angiography at 60 min. The dose-combination regimen of 50% of standard-dose tenecteplase (0.27 microg/kg) plus high-dose eptifibatide (2 boluses of 180 microg/kg separated by 10 min, 2.0 microg/kg/min infusion) was compared with full-dose tenecteplase (0.53 microg/kg). The dose-confirmation regimen of reduced-dose tenecteplase plus high-dose eptifibatide was associated with a faster median time to stable ST-segment recovery (55 vs. 98 min, p = 0.06), improved stable ST-segment recovery by 2 h (89.6% vs. 67.7%, p = 0.02), and less recurrent ischemia (34.0% vs. 57.1%, p = 0.05) when compared with full-dose tenecteplase. Continuously updated ST-segment recovery analyses demonstrated a modest trend toward greater ST-segment recovery at 30 min (57.7% vs. 40.6%, p = 0.13) and 60 min (82.7% vs. 65.6%, p = 0.08) with this regimen. These findings correlated with improved angiographic results at 60 min. Combination therapy with reduced-dose tenecteplase and eptifibatide leads to faster, more stable ST-segment recovery and improved angiographic flow patterns, compared with full-dose tenecteplase. These findings question the relationship between biomarkers of reperfusion success and clinical outcomes.

Life-saving rectal artesunate for complicated malaria in children.

PubMed

Pengsaa, Krisana; Sirivichayakul, Chukiat; Na-Bangchang, Kesara; Thaiarporn, Itthipon; Chaivisuth, Anong; Wongsuwan, Amnaj; Attanath, Phanorsri; Pojjaroen-Anant, Chanathep; Wisetsing, Pataraporn; Chanthavanich, Pornthep; Sabchareon, Arunee

2005-05-01

We report the effectiveness of two regimens of rectal artesunate formulation in treating 13 Thai children with cerebral/complicated falciparum malaria. The drug was given at an initial dose of 40 mg/kg bodyweight, in 3 or 4 divided doses in the first 24 hours, followed by 10 mg/kg bodyweight once daily for three consecutive days. Mefloquine, at a dose of 15 mg/kg bodyweight was given orally at 72 hours after the initial dose of artesunate, followed by 10 mg/kg bodyweight 6 hours later. Three cases with cerebral malaria gained consciousness within 20 hours of artesunate administration. The median time required for reduction of parasitemia by 90% of the initial value (P90) in 13 children was 11.2 hours. No recrudescence was observed in any of the patients during the 28-day follow-up period. Plasma concentrations of artesunate and dihydroartemisinin (active plasma metabolite of artesunate) measured in two patients who received the high initial dose regimen (20 mg/ kg bodyweight) suggested rapid absorption and adequate plasma concentrations of both compounds following the administration of artesunate via the rectal route. Further studies for the optimized regimen of rectal artesunate in the treatment of cerebral/complicated childhood falciparum malaria in areas of multidrug resistance are warranted.

Minor oral surgery without stopping daily low-dose aspirin therapy: a study of 51 patients.

PubMed

Madan, Gautam A; Madan, Sonal G; Madan, Gauri; Madan, A D

2005-09-01

The risk of excessive bleeding prompts physicians to stop low-dose long-term aspirin regimens before surgery, which puts the patient at risk from adverse thrombotic events. We hypothesize that most minor oral surgical procedures can be carried out safely without stopping low-dose aspirin. All minor oral surgery patients at our hospital (Madan Dental Hospital, Ahmedabad, India) from May 2002 to May 2003, who were also on long-term low-dose aspirin therapy regimens (acetylsalicylic acid 75 mg to 100 mg/day), were included. Investigation of bleeding time and platelet count was performed. If within normal limits, aspirin was not stopped before surgery. Patients were operated under local anesthesia on an outpatient basis. All wounds were sutured and followed up at 24, 48, and 72 hours, 1 week, and 2 weeks after the procedure. The study included 51 patients (32 males, 19 females), ranging in age from 45 to 70 years. Preoperative values were within normal limits for all patients. Aspirin was not stopped for a single patient. There was no excessive intraoperative bleeding in all cases except 1; there was no postoperative bleeding in all cases. We conclude that most minor oral surgery procedures can be carried out safely without stopping long-term low-dose aspirin regimen.

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship.

PubMed

Liu, Tao; Ivaturi, Vijay; Sabato, Philip; Gobburu, Jogarao V S; Greer, Jacqueline M; Wright, John J; Smith, B Douglas; Pratz, Keith W; Rudek, Michelle A

2018-04-27

Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E max ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC 50 of 69.3 ng/mL and ERK activity by 84% with an IC 50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

A survey of the utilization of anti-pseudomonal beta-lactam therapy in cystic fibrosis patients.

PubMed

Zobell, Jeffery T; Young, David C; Waters, C Dustin; Ampofo, Krow; Cash, Jared; Marshall, Bruce C; Olson, Jared; Chatfield, Barbara A

2011-10-01

The purpose of this study was to characterize the utilization of anti-pseudomonal beta-lactam antibiotics in the treatment of acute pulmonary exacerbations (APE) among Cystic Fibrosis Foundation (CFF)-accredited care centers. An anonymous national cross-sectional survey of CFF-accredited care centers was performed using an electronic survey tool (SurveyMonkey.com®). One hundred and twenty-one of 261 centers completed the survey (46%) representing 56% (14,856/26,740) of patients in the CFF Patient Registry. One hundred and nineteen of 121 (98%) respondents reported using beta-lactams for the treatment of APE. Intermittent dosing regimens constituted 155/167 (93%) reported regimens, while extended infusions were 12/167 (7%). Ceftazidime was the most commonly utilized beta-lactam comprising 74/167 (44%) of all infusions (intermittent and extended) of which 70/74 (95%) were intermittent infusions. The majority of intermittent ceftazidime regimens (56/70; 80%) were at doses lower than CFF and European guidelines recommended doses. In conclusion, a great majority of respondents use intermittent anti-pseudomonal beta-lactam antibiotics, with over half of respondents utilizing lower than guidelines recommended doses. While this is of concern, it is not known if optimization of dosing strategies according to guidelines recommendations will result in clinical benefit. Copyright © 2011 Wiley-Liss, Inc.

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way

PubMed Central

Deshpande, Devyani; Srivastava, Shashikant; Nuermberger, Eric; Pasipanodya, Jotam G.; Swaminathan, Soumya; Gumbo, Tawanda

2016-01-01

Background. The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination. Methods. We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (TMIC) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression. Results. TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem TMIC > 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem TMIC > 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment. Conclusions. We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children. PMID:27742640

Assessment of the effects of ISIS 2302, an anti-sense inhibitor of human ICAM-1, on cellular and humoral immunity in mice.

PubMed

Henry, Scott P; Levin, Arthur A; White, Kimber; Mennear, John H

2006-12-01

ISIS 2302 is a phosphorothioate oligonucleotide designed to inhibit human ICAM-1 and is intended for treatment of inflammatory diseases. Molecules of this class are known to elicit pro-inflammatory effects, and immunotoxicity studies were performed in mice to elucidate the nature of effects of ISIS 2302 on mammalian immune function. ISIS 2302 (1, 5, 20, or 50 mg/kg/dose) was administered intravenously every other day for 27 days. The pro-inflammatory properties of the drug were observed at doses > or = 20 mg/kg. A dose-dependent increase in spleen weight was associated with increased absolute splenocyte and B-lymphocyte counts after the 50 mg/kg/dose regimen. The mitogenic response of B-lymphocytes to bacterial lipopolysaccharide was increased after the 20 and 50 mg/kg/doses but antibody-forming cell activities remained unchanged. Total serum IgG concentration was decreased after the 20 and 50 mg/kg/dose regimens but IgM titers were unchanged. Increases in IL-6, IL-12, and MCP-1 as well as NK cell activity were observed after administration of 20 and 50 mg/kg/dose. Cytotoxic T-lymphocyte activity was decreased by the 50 mg/kg/dose regimen. Other changes in immune function were not observed in ISIS 2302-dosed mice. ISIS 3082, a murine active ICAM-1 inhibitor, was used to demonstrate the anti-inflammatory activity of ICAM-1 inhibition in the 2,4-dinitrofluorobenzene-induced contact sensitization model. Intravenous administration of 1 mg/kg of ISIS 3082 every other day for 27 days was unequivocally anti-inflammatory in the contact sensitization test. The results of these experiments support the conclusion that the prophlogistic effects of ISIS 2302 in mice are observed only at suprapharmacologic doses.

Estimating age-based antiretroviral therapy costs for HIV-infected children in resource-limited settings based on World Health Organization weight-based dosing recommendations

PubMed Central

2014-01-01

Background Pediatric antiretroviral therapy (ART) has been shown to substantially reduce morbidity and mortality in HIV-infected infants and children. To accurately project program costs, analysts need accurate estimations of antiretroviral drug (ARV) costs for children. However, the costing of pediatric antiretroviral therapy is complicated by weight-based dosing recommendations which change as children grow. Methods We developed a step-by-step methodology for estimating the cost of pediatric ARV regimens for children ages 0–13 years old. The costing approach incorporates weight-based dosing recommendations to provide estimated ARV doses throughout childhood development. Published unit drug costs are then used to calculate average monthly drug costs. We compared our derived monthly ARV costs to published estimates to assess the accuracy of our methodology. Results The estimates of monthly ARV costs are provided for six commonly used first-line pediatric ARV regimens, considering three possible care scenarios. The costs derived in our analysis for children were fairly comparable to or slightly higher than available published ARV drug or regimen estimates. Conclusions The methodology described here can be used to provide an accurate estimation of pediatric ARV regimen costs for cost-effectiveness analysts to project the optimum packages of care for HIV-infected children, as well as for program administrators and budget analysts who wish to assess the feasibility of increasing pediatric ART availability in constrained budget environments. PMID:24885453

Efficacy of Three-Week Oxytetracycline or Rifampin Monotherapy Compared with a Combination Regimen against the Filarial Nematode Onchocerca ochengi

PubMed Central

Bah, Germanus S.; Ward, Emma L.; Srivastava, Abhishek; Trees, Alexander J.; Tanya, Vincent N.

2014-01-01

Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a major cause of visual impairment and dermatitis in sub-Saharan Africa. As O. volvulus contains an obligatory bacterial symbiont (Wolbachia), it is susceptible to antibiotic chemotherapy, although current regimens are considered too prolonged for community-level control programs. The aim of this study was to compare the efficacies of oxytetracycline and rifampin, administered separately or in combination, against a close relative of O. volvulus (Onchocerca ochengi) in cattle. Six animals per group were treated with continuous or intermittent oxytetracycline regimens, and effects on adult worm viability, dermal microfilarial loads, and Wolbachia density in worm tissues were assessed. Subsequently, the efficacies of 3-week regimens of oxytetracycline and rifampin alone and a combination regimen were compared, and rifampin levels in plasma and skin were quantified. A 6-month regimen of oxytetracycline with monthly dosing was strongly adulticidal, while 3-week and 6-week regimens exhibited weaker adulticidal effects. However, all three regimens achieved >2-log reductions in microfilarial load. In contrast, rifampin monotherapy and oxytetracycline-rifampin duotherapy failed to induce substantive reductions in either adult worm burden or microfilarial load, although a borderline effect on Wolbachia density was observed following duotherapy. Dermal rifampin levels were maintained above the MIC for >24 h after a single intravenous dose. We conclude that oxytetracycline-rifampin duotherapy is less efficacious against O. ochengi than oxytetracycline alone. Further studies will be required to determine whether rifampin reduces oxytetracycline bioavailability in this system, as suggested by human studies using other tetracycline-rifampin combinations. PMID:24247133

Efficacy of three-week oxytetracycline or rifampin monotherapy compared with a combination regimen against the filarial nematode Onchocerca ochengi.

PubMed

Bah, Germanus S; Ward, Emma L; Srivastava, Abhishek; Trees, Alexander J; Tanya, Vincent N; Makepeace, Benjamin L

2014-01-01

Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a major cause of visual impairment and dermatitis in sub-Saharan Africa. As O. volvulus contains an obligatory bacterial symbiont (Wolbachia), it is susceptible to antibiotic chemotherapy, although current regimens are considered too prolonged for community-level control programs. The aim of this study was to compare the efficacies of oxytetracycline and rifampin, administered separately or in combination, against a close relative of O. volvulus (Onchocerca ochengi) in cattle. Six animals per group were treated with continuous or intermittent oxytetracycline regimens, and effects on adult worm viability, dermal microfilarial loads, and Wolbachia density in worm tissues were assessed. Subsequently, the efficacies of 3-week regimens of oxytetracycline and rifampin alone and a combination regimen were compared, and rifampin levels in plasma and skin were quantified. A 6-month regimen of oxytetracycline with monthly dosing was strongly adulticidal, while 3-week and 6-week regimens exhibited weaker adulticidal effects. However, all three regimens achieved >2-log reductions in microfilarial load. In contrast, rifampin monotherapy and oxytetracycline-rifampin duotherapy failed to induce substantive reductions in either adult worm burden or microfilarial load, although a borderline effect on Wolbachia density was observed following duotherapy. Dermal rifampin levels were maintained above the MIC for >24 h after a single intravenous dose. We conclude that oxytetracycline-rifampin duotherapy is less efficacious against O. ochengi than oxytetracycline alone. Further studies will be required to determine whether rifampin reduces oxytetracycline bioavailability in this system, as suggested by human studies using other tetracycline-rifampin combinations.

Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer.

PubMed

Bruera, Gemma; Massacese, Silvia; Galvano, Antonio; Mas, Antonella Dal; Guadagni, Stefano; Calvisi, Giuseppe; Ciacco, Eugenio; Russo, Antonio; Ricevuto, Enrico

2018-04-17

Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m 2 /d 1-2, 8-9, 15-16, 22-23, with 100 mg/m 2 /d increase for dose level; DTX 50 mg/m 2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m 2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m 2 /d and 80 mg/m 2 , respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.

Clinical Pharmacokinetics of Levornidazole in Elderly Subjects and Dosing Regimen Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis.

PubMed

Guo, Beining; He, Gaoli; Wu, Xiaojie; Yu, Jicheng; Cao, Guoying; Li, Yi; Fan, Yaxin; Chen, Yuancheng; Shi, Yaoguo; Zhang, Yingyuan; Zhang, Jing

2017-07-01

Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years). The PK profiles of levornidazole and its metabolites in elderly subjects were evaluated and compared with those in the young group. WinNonlin software was used for simulating the PK profile of levornidazole in the elderly population following the dosing regimens of 500 mg BID and 750 mg once daily for 7 days. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment of both dosing regimens against Bacteroides spp. The C max , AUC 0-24, and AUC 0-∞ values of levornidazole in the elderly group were 11.98 μg/mL, 131.36 μg·h/mL, and 173.61 μg·h/mL, respectively. The t 1/2 , CL t , and mean residence time from time 0 to infinity were 12.21 hours, 2.91 L/h, and 16.46 hours. The metabolic ratios of metabolites (M) 1, 2, 4, and 6 were <3.0%, and that of M16 was 17.70%. The urinary excretion values of levornidazole, M1, M2, M4, M6, and M16 over 96 hours were 10.21%, 0.92%, ~0%, 2.69%, 0.54%, and 41.98%. The PK properties of levornidazole and the urinary excretion of all metabolites were not statistically different between the 2 groups. The cumulative fraction of response was >90% against B fragilis and other Bacteroides spp, and the probability of target attainment was >90% when the minimum inhibitory concentration was ≤1 μg/mL, in both groups. No dosing regimen adjustment is suggested when levornidazole is used in elderly patients with normal hepatic functioning and mild renal dysfunction. The findings from the PK/PD analysis imply that both regimens may achieve satisfactory clinical and microbiological efficacy against anaerobic infections in elderly patients. Chinese Clinical Trial Registry (http://www.chictr.org.cn) identifier: ChiCTR-OPC-16007938. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

High-Dose Infusional Gemcitabine Combined with Busulfan and Melphalan with Autologous Stem-Cell Transplant in Patients with Refractory Lymphoid Malignancies

PubMed Central

Nieto, Y; Thall, P; Valdez, B; Andersson, B; Popat, U; Anderlini, P; Shpall, EJ; Bassett, R; Alousi, A; Hosing, C; Kebriaei, P; Qazilbash, M; Gulbis, A; Chancoco, C; Bashir, Q; Ciurea, S; Khouri, I; Parmar, S; Shah, N; Worth, L; Rondon, G; Champlin, R; Jones, RB

2014-01-01

We developed a new high-dose combination of infusional gemcitabine with busulfan/melphalan for lymphoid tumors. Gemcitabine dose was escalated by extending infusions at a fixed rate of 10 mg/m2/min in sequential cohorts, in daily, 3-dose or 2-dose schedules. Each dose immediately preceded busulfan (adjusted targeting AUC 4,000 μM.min−1/day × 4 days) or melphalan (60 mg/m2/day × 2 days). We enrolled 133 patients (80 Hodgkin’s lymphoma (HL), 46 non-Hodgkin’s lymphoma (NHL), 7 myeloma), median 3 prior regimens; primary refractory disease in 63% HL/45% NHL and PET-positive tumors at transplant in 50% patients. Two patients died from early posttransplant infections. The major toxicity was mucositis. The daily and 3-dose schedules caused substantial cutaneous toxicity. In contrast, the 2-dose schedule was better tolerated, which allowed us to extend the infusions from 15 to 270 minutes. Pretransplant values of C-reactive protein, b-type natriuretic peptide, ferritin or haptoglobin did not correlate with toxicity. Overall response and complete response rates were 87%/62% (HL), 100%/69% (B-LCL), 66%/66% (T-NHL), and 71%/57% (myeloma). At median follow-up of 24 months (3–63), the event-free/overall survival rates are 54%/72% (HL), 60%/89% (B-LCL), 70%/70% (T-NHL) and 43%/43% (myeloma). In conclusion, gemcitabine/busulfan/melphalan is a feasible regimen with substantial activity against a range of lymphoid malignancies. This regimen merits further evaluation in phase II and III trials. PMID:22643322

Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial.

PubMed

Seidman, Larry; Kroll, Robin; Howard, Brandon; Ricciotti, Nancy; Hsieh, Jennifer; Weiss, Herman

2015-06-01

This study describes ovarian activity suppression of a 21/7-active low-dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17β-estradiol, follicle-stimulating hormone and luteinizing hormone levels. The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens. Copyright © 2015 Elsevier Inc. All rights reserved.

Differences in Reporting Pearl Indices in the United States and Europe: Focus on a 91-Day Extended-Regimen Combined Oral Contraceptive with Low-Dose Ethinyl Estradiol Supplementation

PubMed Central

Abascal, Paloma Lobo; Luzar-Stiffler, Vesna; Giljanovic, Silvana; Howard, Brandon; Weiss, Herman; Trussell, James

2017-01-01

Background Regulatory agencies in the United States (US) and Europe differ in requirements for defining pregnancies after the last dose of oral contraceptive, sometimes resulting in discrepant Pearl Indices (PIs) for the same product despite identical clinical data. This brief report highlights one such example, a 91-day extended-regimen combined oral contraceptive (COC). Methods The US- and European-based PI methodologies were compared for a 91-day extended-regimen COC consisting of 84 days of active levonorgestrel/EE 150 μg/30 μg tablets, followed by 7 days of EE 10 μg tablets in place of placebo. Conclusions At the times of approval of the 91-day extended-regimen COC in the US and Europe, the requirements for defining ‘on-treatment’ pregnancies differed (14-day vs. 2-day rule, respectively). This difference resulted in a higher PI in the US- vs. European-based calculation (1.34 and 0.76, respectively). The differences in the PI should not be interpreted as the extended-regimen COC being less effective in preventing pregnancy in the US compared with Europe. PMID:26115381

Differences in reporting Pearl Indices in the United States and Europe: Focus on a 91-day extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation.

PubMed

Lobo Abascal, Paloma; Luzar-Stiffler, Vesna; Giljanovic, Silvana; Howard, Brandon; Weiss, Herman; Trussell, James

2016-01-01

Regulatory agencies in the United States (US) and Europe differ in requirements for defining pregnancies after the last dose of oral contraceptive, sometimes resulting in discrepant Pearl Indices (PIs) for the same product despite identical clinical data. This brief report highlights one such example, a 91-day extended-regimen combined oral contraceptive (COC). The US- and European-based PI methodologies were compared for a 91-day extended-regimen COC consisting of 84 days of active levonorgestrel/EE 150 μg/30 μg tablets, followed by seven days of EE 10 μg tablets in place of placebo. At the times of approval of the 91-day extended-regimen COC in the US and Europe, the requirements for defining 'on-treatment' pregnancies differed (14-day vs. 2-day rule, respectively). This difference resulted in a higher PI in the US- vs. European-based calculation (1.34 and 0.76, respectively). The differences in the PI should not be interpreted as the extended-regimen COC being less effective in preventing pregnancy in the US compared with Europe.

Application of mathematical models to metronomic chemotherapy: What can be inferred from minimal parameterized models?

PubMed

Ledzewicz, Urszula; Schättler, Heinz

2017-08-10

Metronomic chemotherapy refers to the frequent administration of chemotherapy at relatively low, minimally toxic doses without prolonged treatment interruptions. Different from conventional or maximum-tolerated-dose chemotherapy which aims at an eradication of all malignant cells, in a metronomic dosing the goal often lies in the long-term management of the disease when eradication proves elusive. Mathematical modeling and subsequent analysis (theoretical as well as numerical) have become an increasingly more valuable tool (in silico) both for determining conditions under which specific treatment strategies should be preferred and for numerically optimizing treatment regimens. While elaborate, computationally-driven patient specific schemes that would optimize the timing and drug dose levels are still a part of the future, such procedures may become instrumental in making chemotherapy effective in situations where it currently fails. Ideally, mathematical modeling and analysis will develop into an additional decision making tool in the complicated process that is the determination of efficient chemotherapy regimens. In this article, we review some of the results that have been obtained about metronomic chemotherapy from mathematical models and what they infer about the structure of optimal treatment regimens. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

PubMed

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

PubMed Central

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

Outcome of Children With Metastatic Medulloblastoma Treated With Carboplatin During Craniospinal Radiotherapy: A Children's Oncology Group Phase I/II Study

PubMed Central

Jakacki, Regina I.; Burger, Peter C.; Zhou, Tianni; Holmes, Emiko J.; Kocak, Mehmet; Onar, Arzu; Goldwein, Joel; Mehta, Minesh; Packer, Roger J.; Tarbell, Nancy; Fitz, Charles; Vezina, Gilbert; Hilden, Joanne; Pollack, Ian F.

2012-01-01

Purpose We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB. Patients and Methods After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m2/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B). Results In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m2/dose × 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ± 11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome. Conclusion The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy. PMID:22665539

The roles of safety and compliance in determining effectiveness of topical therapy for psoriasis.

PubMed

Stein Gold, Linda; Corvari, Linda

2007-01-01

Topical therapies are the mainstays of treatment for most patients with psoriasis because they relieve symptoms and reduce the size and severity of lesions. The effectiveness of a therapeutic intervention is a function of drug efficacy (determined by randomized clinical trial results) and patient safety and compliance. Alterations in any parameter can have a substantial influence on clinical outcomes. However, topical agents can be associated with unwanted and potentially toxic side effects that make physicians reluctant to prescribe them, and patients intentionally discontinue treatment with these topical agents. To maximize effectiveness and improve patient safety, physicians may prescribe medications in combination, sequential, or rotational therapeutic regimens. This treatment strategy has the potential to improve the overall efficacy and safety of topical therapy; however, the effectiveness of this method may be compromised because the complexity of the therapeutic regimen may decrease patient compliance. Newer topical therapies that have a convenient once-daily dosing schedule are needed and will have important implications for patient compliance.

A Randomized Controlled Trial of Low-Dose Tranexamic Acid versus Placebo to Reduce Red Blood Cell Transfusion During Complex Multilevel Spine Fusion Surgery.

PubMed

Carabini, Louanne M; Moreland, Natalie C; Vealey, Ryan J; Bebawy, John F; Koski, Tyler R; Koht, Antoun; Gupta, Dhanesh K; Avram, Michael J

2018-02-01

Multilevel spine fusion surgery for adult deformity correction is associated with significant blood loss and coagulopathy. Tranexamic acid reduces blood loss in high-risk surgery, but the efficacy of a low-dose regimen is unknown. Sixty-one patients undergoing multilevel complex spinal fusion with and without osteotomies were randomly assigned to receive low-dose tranexamic acid (10 mg/kg loading dose, then 1 mg·kg -1 ·hr -1 throughout surgery) or placebo. The primary outcome was the total volume of red blood cells transfused intraoperatively. Thirty-one patients received tranexamic acid, and 30 patients received placebo. Patient demographics, risk of major transfusion, preoperative hemoglobin, and surgical risk of the 2 groups were similar. There was a significant decrease in total volume of red blood cells transfused (placebo group median 1460 mL vs. tranexamic acid group 1140 mL; median difference 463 mL, 95% confidence interval 15 to 914 mL, P = 0.034), with a decrease in cell saver transfusion (placebo group median 490 mL vs. tranexamic acid group 256 mL; median difference 166 mL, 95% confidence interval 0 to 368 mL, P = 0.042). The decrease in packed red blood cell transfusion did not reach statistical significance (placebo group median 1050 mL vs. tranexamic acid group 600 mL; median difference 300 mL, 95% confidence interval 0 to 600 mL, P = 0.097). Our results support the use of low-dose tranexamic acid during complex multilevel spine fusion surgery to decrease total red blood cell transfusion. Copyright © 2017 Elsevier Inc. All rights reserved.

Increased anxiety 3 months after brief exposure to MDMA ("Ecstasy") in rats: association with altered 5-HT transporter and receptor density.

PubMed

McGregor, Iain S; Clemens, Kelly J; Van der Plasse, Geoffrey; Li, Kong M; Hunt, Glenn E; Chen, Feng; Lawrence, Andrew J

2003-08-01

Male Wistar rats were treated with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") using either a high dose (4 x 5 mg/kg over 4 h) or low dose (1 x 5 mg/kg over 4 h) regimen on each of 2 consecutive days. After 10 weeks, rats were tested in the social interaction and emergence tests of anxiety. Rats previously given either of the MDMA dose regimens were significantly more anxious on both tests. After behavioral testing, and 3 months after the MDMA treatment, the rats were killed and their brains examined. Rats given the high-, but not the low-, dose MDMA treatment regimen exhibited significant loss of 5-hydroxytryptamine (5-HT) and 5-HIAA in the amygdala, hippocampus, striatum, and cortex. Quantitative autoradiography showed loss of SERT binding in cortical, hippocampal, thalamic, and hypothalamic sites with the high-dose MDMA regime, while low-dose MDMA only produced significant loss in the medial hypothalamus. Neither high- nor low-dose MDMA affected 5HT(1A) receptor density. High-dose MDMA increased 5HT(1B) receptor density in the nucleus accumbens and lateral septum but decreased binding in the globus pallidus, insular cortex and medial thalamus. Low-dose MDMA decreased 5HT(1B) receptor density in the hippocampus, globus pallidus, and medial thalamus. High-dose MDMA caused dramatic decreases in cortical, striatal, thalamic, and hypothalamic 5HT(2A)/(2C) receptor density, while low-dose MDMA tended to produce similar effects but only significantly in the piriform cortex. These data suggest that even brief, relatively low-dose MDMA exposure can produce significant, long-term changes in 5-HT receptor and transporter function and associated emotional behavior. Interestingly, long-term 5-HT depletion may not be necessary to produce lasting effects on anxiety-like behavior after low-dose MDMA.

Simulation-Based Sodium Thiosulfate Dosing Strategies for the Treatment of Calciphylaxis

PubMed Central

Singh, Rajendra Pratap; Derendorf, Hartmut

2011-01-01

Summary Background and objectives Calciphylaxis remains a poorly understood life-threatening disorder with limited therapeutic options. Sodium thiosulfate (STS) has reported efficacy, thought to be because solubilizing calcium deposits promote clearance by hemodialysis (HD). Lack of rigorous pharmacokinetic studies makes it problematic for determining proper STS dosing given the expanding range of dialysis prescriptions and intensities. Design, setting, participants, & measurements The purpose of this study was to determine the dosing strategies for STS during different dialysis regimens. Given reported successes using an empiric 25 g, intravenous, 3 times per week after HD, simulations were performed to predict dosing guidelines for alternative, more or less intense dialysis to produce equivalent area under the curve drug exposure. The modeled prescriptions varied HD time from 12 to 40 h/wk over three to six sessions (Qb 200 to 400 ml/min, Qd 500 to 800 ml/min), and continuous venovenous hemodialysis at low flow rates (Qb 100 to 200 ml/min, Qd 35 to 50 ml/min), using high-flux polysulfone hemofilters. Results Simulations showed a marked variation in STS doses depending on HD frequency and duration. Blood and dialysate flows have a less prominent effect. Assuming no residual renal function, HD prescription permutations caused the dose to vary from 72 to 245 g/wk (70-kg adult), and the simulations provide specific guidelines for clinicians. Conclusions Based on the success reported for one STS dosing regimen and assuming area under the curve exposure of STS is proportional to its effect, pharmacokinetic simulations can be used to calculate the dose for alternative, higher or lower intensity dialysis regimens. These strategies are imperative to assure adequate treatment for this mortal disease, as well as to avoid toxicity from excess dosing. PMID:21441129

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.

PubMed

Yoneyama, Koichiro; Schmitt, Christophe; Kotani, Naoki; Levy, Gallia G; Kasai, Ryu; Iida, Satofumi; Shima, Midori; Kawanishi, Takehiko

2017-12-06

Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide.

PubMed

Schmitz, Ole; Lund, Sten; Andersen, Per Heden; Jønler, Morten; Pørksen, Nils

2002-02-01

Repaglinide, a novel antidiabetic agent that has a rapid onset and short duration of action, was developed for mealtime dosing. The purpose of this pharmacodynamic study was to validate a prandial regimen of repaglinide by comparing meal-related dosing with a regimen in which the same total daily dose was divided into only two doses at morning and evening meals. The study was a double-blind, randomized, parallel-group trial in 19 antidiabetic agent-naive subjects with type 2 diabetes (mean age 58 years, known duration of diabetes 3.5 years, HbA(1c) 7.3%, and BMI 32 kg/m(2)). Patients were randomly assigned to receive repaglinide either before each of the three main meals or before breakfast and before the evening meal. Patients in both groups received the same total daily dose of repaglinide. Twenty-four hour profiles of blood glucose, plasma insulin, and plasma C-peptide concentrations were measured at baseline and after 4 weeks of treatment. Repaglinide increased postprandial insulin levels and markedly reduced postprandial glucose levels relative to baseline in both groups. Significant reductions were also recorded in fasting blood glucose and HbA(1c) levels. The repaglinide regimen, in which a dose was taken before each main meal, was more effective in improving glycemic control (including postprandial glucose and HbA(1c) levels) than the same total dose of repaglinide divided into morning and evening mealtime doses. These data support the strategy of mealtime dosing with repaglinide. The improvements in glycemic control observed in these patients are encouraging. In addition to classic parameters of glycemic control, improvements in postprandial glucose excursions may prove to be important because postprandial hyperglycemia has been suggested to be an independent risk factor for cardiovascular disease in diabetes.

Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.

PubMed

Svensson, Elin M; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C; Karlsson, Mats O

2018-05-01

Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations. In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation. The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target). The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.

Comparison of safety and immunogenicity of purified chick embryo cell vaccine using Zagreb and Essen regimens in patients with category II exposure in China.

PubMed

Hu, Quan; Liu, Man-Qing; Zhu, Zheng-Gang; Zhu, Ze-Rong; Lu, Sha

2014-01-01

The aim was to compare the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) with Zagreb 2-1-1 and Essen 1-1-1-1-1 regimens in patients with WHO category II exposure in China. Side effects including systemic and local symptoms were recorded for all patients during vaccination with purified chick embryo cell vaccine (PCECV) under Zagreb 2-1-1 or Essen 1-1-1-1-1 regimens, and the rabies neutralization antibody titers in patients' serum at days 0, 7, 14, 45, 365 post-immunization were measured to determine the immunogenicity. Fever and pain were the most common events for systemic and local symptoms respectively, and most side effects (86.78%, 105/121) occurred after the first dose of vaccination. Safety analysis showed differences in side effects in<5-year-old patients between Zagreb and Essen regimens, especially after the first dose of vaccination (P = 0.043). Immunogenicity analysis indicated that Zagreb can achieve higher neutralization antibody titers and a greater seroconversion rate in a shorter time but had less persistence than Essen. When compared with the Essen regimen, the Zagreb regimen had a different immunogenicity in all study subjects, and different safety profile in young children, and a further study with a larger population and longer surveillance is warranted.

Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: results from a phase 2a proof-of-concept study.

PubMed

Archer, David F; Stewart, Elizabeth A; Jain, Rita I; Feldman, Robert A; Lukes, Andrea S; North, Janine D; Soliman, Ahmed M; Gao, Jingjing; Ng, Juki W; Chwalisz, Kristof

2017-07-01

To evaluate the safety and efficacy of elagolix vs. placebo and elagolix with low-dose E 2 /progestogen add-back therapy. Proof-of-concept, dose-ranging, multiple-cohort study. Clinics. Premenopausal women with fibroids and heavy menstrual bleeding (menstrual blood loss [MBL] >80 mL per cycle). Three months' treatment with elagolix alone: 100 mg twice daily (BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 200 mg BID plus continuous low-dose E 2 0.5 mg/norethindrone acetate 0.1 mg or elagolix 300 mg BID plus E 2 1 mg continuously and cyclical P 200 mg. Least-squares mean percentage change in MBL; adverse events (AEs). Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment period. The MBL percentage change from baseline to last 28 days was significantly greater with elagolix alone (range, -72% to -98%; dose-dependent reduction was highest with 300 mg BID) vs. placebo (range, -8% to -41%); mean percentage changes with add-back regimens were -80% to -85%. Overall AEs were dose independent (elagolix alone, 70.0%-81.3%) but lower with placebo (56.0%) and add-back regimens (55.6%-70.6%). Hot flush was the most common AE (elagolix alone, 45.5%-62.5%; placebo, 12.0%; add-back regimens, 18.5%-26.5%). Elagolix significantly reduced heavy menstrual bleeding in women with fibroids. Low-dose add-back regimens substantially reduced flushing. NCT01441635. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Determination of Optimal Amikacin Dosing Regimens for Pediatric Patients With Burn Wound Sepsis.

PubMed

Yu, Tian; Stockmann, Chris; Healy, Daniel P; Olson, Jared; Wead, Stephanie; Neely, Alice N; Kagan, Richard J; Spigarelli, Michael G; Sherwin, Catherine M T

2015-01-01

This study aimed to develop optimal amikacin dosing regimens for the empirical treatment of Gram-negative bacterial sepsis in pediatric patients with burn injuries. A pharmacodynamic (PD) target in which the peak concentration (Cmax) is ≥8 times the minimum inhibitory concentration (MIC) (Cmax/MIC ≥ 8) is reflective of optimal bactericidal activity and has been used to predict clinical outcomes. Population pharmacokinetic modeling was performed in NONMEM 7.2 for pediatric patients with and without burn injuries. Amikacin pharmacokinetic parameters were compared between the two groups and multiple dosing regimens were simulated using MATLAB to achieve the PD target in ≥90% of patients with burn injuries. The pharmacokinetic analysis included 282 amikacin concentrations from 70 pediatric patients with burn injuries and 99 concentrations from 32 pediatric patients without burns. A one-compartment model with first-order elimination described amikacin pharmacokinetics well for both groups. Clearance (CL) was significantly higher in patients with burn injuries than in patients without (7.22 vs 5.36 L/h, P < .001). The volume of distribution (V) was also significantly increased in patients with burn injuries (22.7 vs 18.7 L, P < .01). Weight significantly influenced amikacin CL (P < .001) and V (P < .001) for both groups. Model-based simulations showed that a higher amikacin dose (≥25 mg/kg) achieved a Cmax/MIC ≥8 in ≥90% of patients with assumed infections of organisms with an MIC = 8 mg/L. Amikacin pharmacokinetics are altered in patients with burn injuries, including a significant increase in CL and V. In simulations, increased doses (≥25 mg/kg) led to improved PD target attainment rates. Further clinical evaluation of this proposed dosing regimen is warranted to assess clinical and microbiological outcomes in pediatric patients with burn wound sepsis.

Relative effects of plasma, fibrinogen concentrate, and factor XIII on ROTEM coagulation profiles in an in vitro model of massive transfusion in trauma.

PubMed

Schmidt, David E; Halmin, Märit; Wikman, Agneta; Östlund, Anders; Ågren, Anna

2017-10-01

Massive traumatic haemorrhage is aggravated through the development of trauma-induced coagulopathy, which is managed by plasma transfusion and/or fibrinogen concentrate administration. It is yet unclear whether these treatments are equally potent in ensuring adequate haemostasis, and whether additional factor XIII (FXIII) administration provides further benefits. In this study, we compared ROTEM whole blood coagulation profiles after experimental massive transfusion with different transfusion regimens in an in vitro model of dilution- and transfusion-related coagulopathy. Healthy donor blood was mixed 1 + 1 with six different transfusion regimens. Each regimen contained RBC, platelet concentrate, and either fresh frozen plasma (FFP) or Ringer's acetate (RA). The regimens were further augmented through addition of a low- or medium-dose fibrinogen concentrate and FXIII. Transfusion with FFP alone was insufficient to maintain tissue-factor activated clot strength, coincidental with a deficiency in fibrin-based clot strength. Fibrinogen concentrate conserved, but did not improve coagulation kinetics and overall clot strength. Only combination therapy with FFP and low-dose fibrinogen concentrate improved both coagulation kinetics and fibrin-based clot strength. Administration of FXIII did not result in an improvement of clot strength. In conclusion, combination therapy with both FFP and low-dose fibrinogen concentrate improved clotting time and produced firm clots, representing a possible preferred first-line regimen to manage trauma-induced coagulopathy when RBC and platelets are also transfused. Further research is required to identify optimal first-line transfusion fluids for massive traumatic haemorrhage.

Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz.

PubMed

Wallender, Erika; Vucicevic, Katarina; Jagannathan, Prasanna; Huang, Liusheng; Natureeba, Paul; Kakuru, Abel; Muhindo, Mary; Nakalembe, Mirium; Havlir, Diane; Kamya, Moses; Aweeka, Francesca; Dorsey, Grant; Rosenthal, Philip J; Savic, Radojka M

2018-03-05

A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration >10 ng/mL for >95% of the chemoprevention period. PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), <1% of women achieved defined protective PQ coverage. Weekly (960 mg PQ) or low-dose daily (320 or 160 mg PQ) regimens achieved protective PQ coverage for 34% and >96% of women, respectively. All regimens were safe, with ≤2% of women predicted to have ≥30 msec QTc increase. For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing. NCT02282293. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles.

PubMed

Lea-Henry, Tom N; Carland, Jane E; Stocker, Sophie L; Sevastos, Jacob; Roberts, Darren M

2018-06-22

Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review. Copyright © 2018 by the American Society of Nephrology.

Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.

PubMed

Setyawan, Juliana; Hodgkins, Paul; Guérin, Annie; Gauthier, Geneviève; Cloutier, Martin; Wu, Eric; Erder, M Haim

2013-10-01

To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically significant when compared to OROS MPH and MPH LA patients. This study did not control for ADHD severity. Overall, compared to LDX-treated patients, patients initiated on other ADHD medications were equally or more likely to have a therapy augmentation and more likely to deviate from the recommended once-daily dosing regimen.

Randomized Open Trial Comparing 2-Dose Regimens of the Human Papillomavirus 16/18 AS04-Adjuvanted Vaccine in Girls Aged 9-14 Years Versus a 3-Dose Regimen in Women Aged 15-25 Years.

PubMed

Puthanakit, Thanyawee; Huang, Li-Min; Chiu, Cheng-Hsun; Tang, Ren-Bin; Schwarz, Tino F; Esposito, Susanna; Frenette, Louise; Giaquinto, Carlo; McNeil, Shelly; Rheault, Paul; Durando, Paolo; Horn, Michael; Klar, Maximilian; Poncelet, Sylviane; De Simoni, Stéphanie; Friel, Damien; De Muynck, Benoit; Suryakiran, Pemmaraju V; Hezareh, Marjan; Descamps, Dominique; Thomas, Florence; Struyf, Frank

2016-08-15

This randomized, open trial compared regimens including 2 doses (2D) of human papillomavirus (HPV) 16/18 AS04-adjuvanted vaccine in girls aged 9-14 years with one including 3 doses (3D) in women aged 15-25 years. Girls aged 9-14 years were randomized to receive 2D at months 0 and 6 (M0,6; (n = 550) or months 0 and 12 (M0,12; n = 415), and women aged 15-25 years received 3D at months 0, 1, and 6 (n = 482). End points included noninferiority of HPV-16/18 antibodies by enzyme-linked immunosorbent assay for 2D (M0,6) versus 3D (primary), 2D (M0,12) versus 3D, and 2D (M0,6) versus 2D (M0,12); neutralizing antibodies; cell-mediated immunity; reactogenicity; and safety. Limits of noninferiority were predefined as <5% difference in seroconversion rate and <2-fold difference in geometric mean antibody titer ratio. One month after the last dose, both 2D regimens in girls aged 9-14 years were noninferior to 3D in women aged 15-25 years and 2D (M0,12) was noninferior to 2D (M0,6). Geometric mean antibody titer ratios (3D/2D) for HPV-16 and HPV-18 were 1.09 (95% confidence interval, .97-1.22) and 0.85 (.76-.95) for 2D (M0,6) versus 3D and 0.89 (.79-1.01) and 0.75 (.67-.85) for 2D (M0,12) versus 3D. The safety profile was clinically acceptable in all groups. The 2D regimens for the HPV-16/18 AS04-adjuvanted vaccine in girls aged 9-14 years (M0,6 or M0,12) elicited HPV-16/18 immune responses that were noninferior to 3D in women aged 15-25 years. NCT01381575. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

The efficacy and safety of weekly 35-mg risedronate dosing regimen for Chinese postmenopausal women with osteoporosis or osteopenia: 1-year data.

PubMed

Gu, Jie-mei; Wang, Li; Lin, Hua; Chen, De-cai; Tang, Hai; Jin, Xiao-lan; Xia, Wei-bo; Hu, Yun-qiu; Fu, Wen-zhen; He, Jin-wei; Zhang, Hao; Wang, Chun; Yue, Hua; Hu, Wei-wei; Liu, Yu-juan; Zhang, Zhen-lin

2015-07-01

Oral risedronate is effective in the treatment of postmenopausal osteoporosis when administered daily, weekly, or monthly. In this 1-year, randomized, double-blind, multicenter study we compared the weekly 35-mg and daily 5-mg risedronate dosing regimens in the treatment of Chinese postmenopausal women with osteoporosis or osteopenia. Postmenopausal women with primary osteoporosis or osteopenia were randomly assigned to the weekly group or daily group (n=145 for each) that received oral risedronate 35 mg once a week or 5 mg daily, respectively, for 1 year. The subjects' bone mineral densities (BMDs), bone turnover markers (P1NP and β-CTX), new vertebral fractures, and adverse events were assessed at baseline and during the treatments. All subjects in the weekly group and 144 subjects in the daily group completed the study. The primary efficacy endpoint after 1 year, ie the mean percent changes in the lumbar spine BMD (95% CI) were 4.87% (3.92% to 5.81%) for the weekly group and 4.35% (3.31% to 5.39%) for the daily group. The incidences of clinical adverse events were 48.3% in the weekly group and 54.2% in the daily group. The weekly 35-mg and daily 5-mg risedronate dosing regimens during 1 year of follow-up show similar efficacy in improving BMDs and biochemical markers of bone turnover in Chinese postmenopausal women with osteoporosis or osteopenia. Moreover, the two dosing regimens exhibit similar safety and tolerability.

Vitamin D supplementation in nursing home patients: randomized controlled trial of standard daily dose versus individualized loading dose regimen.

PubMed

Wijnen, Hugo; Salemink, Dayenne; Roovers, Lian; Taekema, Diana; de Boer, Hans

2015-05-01

Supplementation of cholecalciferol 800 IU daily appears to be insufficient to raise vitamin D levels to >75 nmol/l in nursing home (NH) patients. Our objective was to compare the efficacy of an individualized cholecalciferol loading dose (LD) regimen and a daily dose (DD) regimen of cholecalciferol 800 IU in reaching 25-OH vitamin D (25OHD) levels >75 nmol/l. A total of 30 NH patients with 25OHD levels <50 nmol/l were included. Patients were randomized using the minimization method in the LD or DD group. The cholecalciferol LD, calculated with an algorithm based on serum 25OHD level and body weight, was administered in divided doses of 50,000 IU twice a week, followed by a monthly maintenance dose of either 50,000 or 25,000 IU. The DD regimen consisted of cholecalciferol 800 IU daily for 26 weeks. Serum 25OHD, calcium, creatinine, phosphate, and parathyroid hormone were measured, and 2-minute walking test, handgrip strength, and timed get up and go test were assessed at baseline (T 0), after 5 weeks (T 5), 12 weeks (T 12), and 26 weeks (T 26). The primary endpoint was the percentage of patients with 25OHD levels >75 nmol/l at T 5. Secondary endpoints were the proportion of patients with 25OHD levels >75 nmol/l at T 26, safety of LD regimen, and improvement of performance tests with normalization of vitamin D levels. Median baseline 25OHD levels (interquartile range) were comparable between the 14 DD and 16 LD patients: 20.9 (15.9-29.6) and 21.7 (16.4-32.8) nmol/l, respectively. Levels of 25OHD >75 nmol/l at T 5 were reached in 79 % of the 14 LD patients, but in none of the 13 DD patients (p < 0.001). At T 26, 25OHD levels >75 nmol/l were reached in 83 % of the 12 LD patients and in 30 % of the ten DD patients (p < 0.05). Side effects or hypercalcemia were not observed. No improvement of performance tests was observed. In NH patients with severe 25OHD deficiency, an individualized calculated cholecalciferol LD is likely to be superior to a DD of cholecalciferol 800 IU in terms of the ability to rapidly normalize vitamin D levels.

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial: study protocol for a randomized controlled trial

PubMed Central

2012-01-01

Background Second-generation drug-eluting stents (DES) have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES) is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES). In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI). A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT)) was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS) patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT)) is used more commonly than doubling the dose of clopidogrel in high-risk patients. Methods In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES) and antiplatelet regimen (TAT vs DDAT). The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen. Discussion The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI. Trial registration ClincalTrials.gov number NCT01267734. PMID:22463698

Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.

PubMed

Mulhall, Brian P; Younossi, Zobair

2005-01-01

Nearly 4 million people in the United States have evidence of hepatitis C infection (HCV), representing a significant cause of cirrhosis and liver cancer as well a major burden to our healthcare systems and society. Antiviral therapy can successfully eradicate HCV over the long term, potentially reducing the risk of progression and improving patients' quality of life. The currently preferred HCV treatment is a combination of pegylated interferon alfa and ribavirin, which can achieve an overall sustained viral eradication rate of 55%. The duration of this treatment is typically determined by HCV genotype and the patient's early virologic response to the antiviral regimen. Evidence has accumulated over the past few years to indicate that close adherence to the optimal antiviral regimen can enhance sustained virologic response. But optimal treatment outcomes require diligence and careful management of side effects related to combination therapy. Although reducing the dose of pegylated interferon alfa, ribavirin, or both can effectively treat side effects, suboptimal doses of this regimen, especially ribavirin, may negatively affect virologic response. An alternative strategy is to use growth factors to treat cytopenias. This strategy can obviate dose reductions while potentially improving patients' quality of life. Patient support seems especially important early after the initiation of antiviral therapy. Encouraging study findings involving the growth factors, epoetin alfa and darbepoetin alfa, suggest improved anemia and quality of life while maintaining the optimal ribavirin dose. Future work should be aimed at providing stronger evidence for the use of these "supportive products" during anti-HCV therapy. As we strive to develop better treatment options for our HCV patients, the importance of adhering to the treatment regimen continues to play a central role. Effective side effect management is crucial for the success of this treatment because adherence is negatively affected by side effects related to the antiviral regimen. By identifying and addressing the important side effects of combination therapy for HCV, adherence to treatment can be improved and optimal outcomes can be achieved.

Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes (FUTURA/OASIS 8): a randomized trial of intravenous unfractionated heparin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux.

PubMed

Steg, Philippe Gabriel; Mehta, Shamir; Jolly, Sanjit; Xavier, Denis; Rupprecht, Hans-Juergen; Lopez-Sendon, Jose Luis; Chrolavicius, Susan; Rao, Sunil V; Granger, Christopher B; Pogue, Janice; Laing, Shiona; Yusuf, Salim

2010-12-01

There is uncertainty regarding the optimal adjunctive unfractionated heparin (UFH) regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with fondaparinux. The aim of this study is to evaluate the safety of 2 dose regimens of adjunctive intravenous UFH during PCI in high-risk patients with NSTE-ACS initially treated with fondaparinux and referred for early coronary angiography. This is an international prospective cohort study of approximately 4,000 high-risk patients presenting to hospital with unstable angina or non-ST-segment elevation myocardial infarction, treated with fondaparinux as initial medical therapy, and referred for early coronary angiography with a view to revascularization. Within this cohort, 2,000 patients undergoing PCI will be eligible for enrollment into a double-blind international randomized parallel-group trial evaluating standard activated clotting time (ACT)-guided doses of intravenous UFH versus a non-ACT-guided weight-adjusted low dose. The standard regimen uses an 85-U/kg bolus of UFH if there is no platelet glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitor or 60 U/kg if GpIIb-IIIa inhibitor use is planned, with additional bolus guided by blinded ACT measurements. The low-dose regimen uses a 50 U/kg UFH bolus, irrespective of planned GpIIb-IIIa use. The primary outcome is the composite of peri-PCI major bleeding, minor bleeding, or major vascular access site complications. The assessment of net clinical benefit is a key secondary outcome: it addresses the composite of peri-PCI major bleeding with death, myocardial infarction, or target vessel revascularization at day 30. FUTURA/OASIS 8 will help define the optimal UFH regimen as adjunct to PCI in high-risk NSTE-ACS patients treated with fondaparinux. Copyright © 2010 Mosby, Inc. All rights reserved.

Retrospective cross-sectional pilot study of rifaximin dosing for the prevention of recurrent hepatic encephalopathy.

PubMed

Lyon, Kelsey C; Likar, Eric; Martello, Jay L; Regier, Michael

2017-09-01

Standard treatment for hepatic encephalopathy (HE) includes medications that reduce ammonia and bacterial translocation in the gut. Rifaximin can be used off-label for the reduction of overt HE. The study purpose was to determine efficacy of traditional rifaximin dosing (400 mg three times daily) compared with newer dosing (550 mg twice daily) via readmission rates for the prevention of recurrent HE. This was a retrospective, observational, cross-sectional pilot study conducted in a tertiary medical center. A total of 226 patients 18-89 years of age with documentation of HE via ICD-9 code who started rifaximin therapy while inpatient between April 2009 and June 2014 were evaluated. Data collected included rifaximin dosing, other medications used to treat HE, duration of therapy, time to readmission, and various laboratory values. There were no differences in readmission rates at 30 days, 60 days, or 6 months between treatment groups. Additionally, there was no difference in the odds of readmission between the treatment groups (OR = 0.77, 95% CI: [0.201, 4.365], P = 0.718). Patients had a low overall probability of readmission over the observational period. Based on average wholesale price data, the cost for a 9-day supply of rifaximin for the 400-mg dosing regimen is $952.56 versus $605.16 for the 550-mg dosing regimen. The rifaximin 550-mg dosing strategy should be utilized in hospitalized patients for the prevention of recurrent HE as there was no difference in readmission rate or time to readmission between dosing groups. The 550-mg regimen had a lower acquisition cost for a 9-day duration of treatment in the studied institution. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial.

PubMed

Torrico, Faustino; Gascon, Joaquim; Ortiz, Lourdes; Alonso-Vega, Cristina; Pinazo, María-Jesús; Schijman, Alejandro; Almeida, Igor C; Alves, Fabiana; Strub-Wourgaft, Nathalie; Ribeiro, Isabela

2018-04-01

Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in adult chronic indeterminate Chagas disease. In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18-50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 and placebo arms, and assessors were masked to all treatment allocations. The primary efficacy endpoint was parasitological response to E1224 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were parasitological response to benznidazole at end of treatment, assessed by PCR; sustainability of parasitological response until 12 months; parasite clearance and changes in parasite load; incidence of conversion to negative response in conventional and non-conventional (antigen trypomastigote chemiluminescent ELISA [AT CL-ELISA]) serological response; changes in levels of biomarkers; and complete response. The primary analysis population consisted of all randomised patients by their assigned treatment arms. This trial is registered with ClinicalTrials.gov, number NCT01489228. Between July 19, 2011, and July 26, 2012, we screened 560 participants with confirmed Chagas disease, of whom 231 were enrolled and assigned to high-dose E1224 (n=45), low-dose E1224 (n=48), short-dose E1224 (n=46), benznidazole (n=45), or placebo (n=47). Parasite clearance was observed with E1224 during the treatment phase, but no sustained response was seen with low-dose and short-dose regimens, whereas 13 patients (29%, 95% CI 16·4-44·3) had sustained response with the high-dose regimen compared with four (9%, 2·4-20·4) in the placebo group (p<0·0001). Benznidazole had a rapid and sustained effect on parasite clearance, with 37 patients (82%, 67·9-92·0) with sustained response at 12-month follow-up. After 1 week of treatment, mean quantitative PCR repeated measurements showed a significant reduction in parasite load in all treatment arms versus placebo. Parasite levels in the low-dose and short-dose E1224 groups gradually returned to placebo levels. Both treatments were well tolerated. Reversible, dose-dependent liver enzyme increases were seen with E1224 and benznidazole. 187 (81%) participants developed treatment-emergent adverse events and six (3%) developed treatment-emergent serious adverse events. Treatment-emergent adverse events were headaches, nausea, pruritus, peripheral neuropathy, and hypersensitivity. E1224 is the first new chemical entity developed for Chagas disease in decades. E1224 displayed a transient, suppressive effect on parasite clearance, whereas benznidazole showed early and sustained efficacy until 12 months of follow-up. Despite PCR limitations, our results support increased diagnosis and access to benznidazole standard regimen, and provide a development roadmap for novel benznidazole regimens in monotherapy and in combinations with E1224. Drugs for Neglected Diseases initiative. Copyright © 2018 Elsevier Ltd. All rights reserved.

Low-dose metronomic, multidrug therapy with the PEP-C oral combination chemotherapy regimen for mantle cell lymphoma.

PubMed

Coleman, Morton; Martin, Peter; Ruan, Jia; Furman, Richard; Niesvizky, Ruben; Elstrom, Rebecca; George, Patricia; Leonard, John; Kaufmann, Thomas

2008-03-01

The prednisone, etoposide, procarbazine and cyclophosphamide (PEP-C) oral combination chemotherapy regimen (prednisone 20 mg, cyclophosphamide 50 mg, etoposide 50 mg, and procarbazine 50 mg with an oral anti-emetic) was employed at our center to treat 22 patients with heavily pretreated, recurrent mantle cell lymphoma (MCL). All medications were administered daily until leukocytes fell to <3.0 x 10(9)/L whereupon treatment was withheld until recovery from the nadir. Therapy was then reinstituted on a daily, alternate day, or fractionated basis (e.g. 5 of 7 days) depending on patient tolerance. Doses given per day were held constant. Eighty-two percent achieved an objective response with 46% complete responses and 36% partial responses. Median time on therapy was 17 months. The regimen was well tolerated. Our findings demonstrate that low-dose oral agents administered in combination for continuous, prolonged periods with minimal drug-free intervals (metronomic therapy) may represent a novel, effective, easily tolerated approach to MCL and that this treatment approach warrants further exploration.

Moving East: the Euro-Lupus Nephritis regimen in Asia.

PubMed

Houssiau, Frédéric A

2016-01-01

Treatment of lupus nephritis is more evidenced-based than ever. Yet many areas of uncertainty persist. The article by Rathi et al. brings a piece to the puzzle by comparing, in a group of Indian patients, the Euro-Lupus low-dose i.v. cyclophosphamide regimen with mycophenolate mofetil. Although some caveats must be raised, the results suggest that, after crossing the Atlantic, the Euro-Lupus regimen may well be moving East. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Impact of specialty pharmacy on telaprevir-containing 3-drug hepatitis C regimen persistence.

PubMed

Henderson, Rochelle R; Visaria, Jay; Bridges, Gail G; Dorholt, Mary; Levin, Rebecca J; Frazee, Sharon Glave

2014-12-01

Although the recommended treatment of hepatitis C continues to evolve as newer and more effective medications are made available, hepatitis C drug regimens consisting of a 3-drug combination of a protease inhibitor, pegylated interferon, and ribavirin were recommended by the American Association for the Study of Liver Diseases for the HCV genotype I beginning in 2011. Although more effective than the earlier standard of care, these regimens have complex dosing schedules, prolonged duration, and deleterious side effects. It has been shown that patients tend to discontinue these regimens prematurely. Specialty pharmacies offer specialized care management programs to hepatitis C patients, consisting of such services as regularly scheduled patient counseling, assessing regimen appropriateness, monitoring treatment progress, scheduling refill reminders, and coordinating patient care with prescribers. The use of specialty pharmacies by hepatitis C patients may improve persistence on the 3-drug hepatitis C regimens. To examine the association of pharmacy dispensing channel (specialty pharmacy or retail pharmacy) and hepatitis C regimen persistence among patients on a 3-drug hepatitis C regimen containing telaprevir, a widely used hepatitis C protease inhibitor.  A retrospective, observational study was conducted using pharmacy claims data from a national pharmacy benefits manager for the period July 2011 to June 2013. Continuously eligible patients who started a new 3-drug regimen containing telaprevir were included in the study and followed for up to 12 months after the index hepatitis C claim. The study outcome was persistence to the 3-drug regimen at treatment week 24 (day 168), representing the completion of an important milestone in the regimen. Patients were defined as persistent if they filled 84 days' supply of telaprevir and 168 days' supply of pegylated interferon and ribavirin each, as required by the regimen protocol. Multivariate logistic regression was used to evaluate the association between dispensing channel and persistence, controlling for differences in demographics, medication burden, out-of-pocket spend per 30-day adjusted hepatitis C prescription, and average days' supply per unadjusted hepatitis C prescription. The final study sample consisted of 1,475 patients-1,182 in the specialty pharmacy group and 293 in the retail pharmacy group. A significantly greater proportion of patients were persistent to the 3-drug hepatitis C regimen containing telaprevir in specialty pharmacy, compared with retail pharmacy (56.0% vs. 39.9%, P  less than  0.001). After multivariate adjustment, patients in the specialty pharmacy group had 1.89 times greater odds of being persistent to 3-drug hepatitis C regimens containing telaprevir compared with patients in the retail group (95% CI=1.44-2.48). Patients who used a specialty pharmacy offering refill reminders, care management, and care coordination with prescribers were significantly more likely to be persistent to 3-drug hepatitis C regimens, compared with patients using a retail pharmacy.

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.

PubMed

Tran, Jonathan Q; Hartung, Jeffrey P; Peach, Robert J; Boehm, Marcus F; Rosen, Hugh; Smith, Heather; Brooks, Jennifer L; Timony, Gregg A; Olson, Allan D; Gujrathi, Sheila; Frohna, Paul A

2017-08-01

The sphingosine-1-phosphate 1 receptor (S1P 1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P 1R and S1P 5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 hours. Ozanimod produced a robust dose-dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect was observed following the first dose, with the dose-escalation regimen attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once-daily regimens under clinical investigation. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Noninvasive Ocular Drug Delivery System of Dexamethasone Sodium Phosphate in the Treatment of Experimental Uveitis Rabbit.

PubMed

Papangkorn, Kongnara; Prendergast, Eri; Higuchi, John W; Brar, Balbir; Higuchi, William I

2017-12-01

To investigate the efficacy and safety of dexamethasone sodium phosphate administered through Visulex system (DSP-Visulex) in treating experimental uveitis. Uveitis was induced in rabbits by subcutaneous injections of complete Freund's adjuvant and an intravitreal injection of H37RA antigen. After induction, the animals of the control group received no treatment and the others received various treatment regimens of DSP-Visulex. Each regimen was different in DSP strength (4%, 8%, and 15%), application time, or treatment frequency. Efficacy and safety of DSP-Visulex were evaluated by ophthalmic observations and histopathological examinations for ocular inflammations and pathology. The control group exhibited panuveitis with significant inflammation in the vitreous, choroid, and retina, but less in the conjunctiva, cornea, and anterior chamber. The uveitis occurred within 24 h after induction and persisted throughout the study in the control group. All treatments showed some reduction in inflammation in the vitreous, choroid, and retina. The higher dose regimens generally showed more rapid and higher degree of resolution than the lower dose regimens. The posterior eye tissues of the 15% and 8% DSP-Visulex appeared normal with minimal or no inflammation, whereas the untreated eye and the 4% DSP-Visulex eyes showed minimal response. All DSP-Visulex regimens suppressed the signs of inflammation and were well tolerated over the course of a 29-day study. The 8% and 15% DSP-Visulex treatment regimens were safe and efficacious for anterior, intermediate, and posterior uveitis. On the other hand, the 4% DSP-Visulex regimen may only be considered for anterior and intermediate uveitis.

Primary central nervous system lymphoma.

PubMed

Ahluwalia, Manmeet S; Peereboom, David M

2010-07-01

Management goals for patients with primary central nervous system lymphoma (PCNSL) include long-term disease control, management of neurologic complications, and preservation of neurocognitive function. Various treatment options can achieve several of these goals. Chemotherapy as monotherapy or as combination therapy has emerged as the cornerstone of therapy for patients with newly diagnosed PCNSL. Outside of a clinical trial, patients with newly diagnosed PCNSL should receive high-dose intravenous methotrexate (MTX) as a single agent or as part of a combination regimen with radiation therapy reserved for relapse. The regimen should have an adequate MTX dose (>3 g/m(2)) to reach cytotoxic concentrations in the cerebrospinal fluid (CSF) to treat occult leptomeningeal disease (LMD). Alternative modes of chemotherapy delivery for selected patients, preferably in the context of a clinical trial, include high-dose chemotherapy with autologous stem cell rescue and intra-arterial chemotherapy with blood-brain barrier disruption. Whole brain radiation therapy (WBRT) in standard doses and fractionation carries an unacceptable rate of long-term neurocognitive toxicity. However, lower doses in daily divided fractions may offer the possibility of adding this modality with preservation of cognition but should be performed only in the context of a clinical trial. The long-term efficacy and toxicity of this approach is currently under investigation. Certain presentations of PCNSL require different strategies. Patients with ocular lymphoma at diagnosis should receive high-dose MTX as this drug can reach cytotoxic intravitreal concentrations. Recurrence in the eyes is managed with intravitreal chemotherapy including MTX or rituximab or with radiation therapy. The field of treatment (eyes vs whole brain) should be individualized. Intrathecal (IT) MTX should be included in the treatment regimen for those patients with a positive CSF cytology, or in regimens in which lower doses of MTX are delivered over longer periods of time. It is probably reasonable to withhold IT chemotherapy in those patients who have no detectable subarachnoid disease and who can receive higher doses of MTX (>3 g/m(2)) over shorter infusion periods (2-4 h). Patients who develop leptomeningeal involvement despite high- dose MTX can be managed with IT chemotherapy such as liposomal cytarabine or MTX or even rituximab. Areas of bulky or symptomatic LMD should probably be treated with radiation therapy as well. Because PCNSL is an uncommon disease, entry into clinical trials must be pursued to advance the state of the art.

Weight-based dosing in medication use: what should we know?

PubMed Central

Pan, Sheng-dong; Zhu, Ling-ling; Chen, Meng; Xia, Ping; Zhou, Quan

2016-01-01

Background Weight-based dosing strategy is still challenging due to poor awareness and adherence. It is necessary to let clinicians know of the latest developments in this respect and the correct circumstances in which weight-based dosing is of clinical relevance. Methods A literature search was conducted using PubMed. Results Clinical indications, physiological factors, and types of medication may determine the applicability of weight-based dosing. In some cases, the weight effect may be minimal or the proper dosage can only be determined when weight is combined with other factors. Medications within similar therapeutic or structural class (eg, anticoagulants, antitumor necrosis factor medications, P2Y12-receptor antagonists, and anti-epidermal growth factor receptor antibodies) may exhibit differences in requirements on weight-based dosing. In some cases, weight-based dosing is superior to currently recommended fixed-dose regimen in adult patients (eg, hydrocortisone, vancomycin, linezolid, and aprotinin). On the contrary, fixed dosing is noninferior to or even better than currently recommended weight-based regimen in adult patients in some cases (eg, cyclosporine microemulsion, recombinant activated Factor VII, and epoetin α). Ideal body-weight-based dosing may be superior to the currently recommended total body-weight-based regimen (eg, atracurium and rocuronium). For dosing in pediatrics, whether weight-based dosing is better than body surface-area-based dosing is dependent on the particular medication (eg, methotrexate, prednisone, prednisolone, zidovudine, didanosine, growth hormone, and 13-cis-retinoic acid). Age-based dosing strategy is better than weight-based dosing in some cases (eg, intravenous busulfan and dalteparin). Dosing guided by pharmacogenetic testing did not show pharmacoeconomic advantage over weight-adjusted dosing of 6-mercaptopurine. The common viewpoint (ie, pediatric patients should be dosed on the basis of body weight) is not always correct. Effective weight-based dosing interventions include standardization of weight estimation, documentation and dosing determination, dosing chart, dosing protocol, order set, pharmacist participation, technological information, and educational measures. Conclusion Although dosing methods are specified in prescribing information for each drug and there are no principal pros and cons to be elaborated, this review of weight-based dosing strategy will enrich the knowledge of medication administration from the perspectives of safety, efficacy, and pharmacoeconomics, and will also provide research opportunities in clinical practice. Clinicians should be familiar with dosage and administration of the medication to be prescribed as well as the latest developments. PMID:27110105

[Hypofractionated whole breast irradiation (WBRT): Results and indications].

PubMed

Cutuli, B

2016-10-01

Breast irradiation after breast-conserving surgery is essential for maximizing local control and overall survival. The increase of breast cancer (BC) incidence, constraints of classical five weeks (w) radiation regimens and scarcity of radiotherapy units have led to test short hypofractionated WBRT schemes. One pilot study and three prospective randomized trials have tested various hypofractionated regimens of WBRT. About 7000 patients were included and follow-up ranged from 5 to 12 years. The conclusion of these trials is similar, showing local control and toxicity equivalent to these of the standard regimens. Three schemes are now clearly validated: 42.5Gy/16fr/3w, 40Gy/15fr/3w, or 42Gy/13fr/5w. However, the majority of included patients had favorable prognostic factors, were treated to the breast only and the boost dose, when indicated, was delivered with a standard fractionation. Therefore, we recommend the regimens preferentially in patients treated to the breast only, and without nodal involvement. These studies did not evaluate the addition of a boost dose with a hypofractionated scheme. If a boost is to be given, a standard fractionation should be used. Particular care should be taken to avoid heterogeneities leading to high fraction doses to organs at risk (lung and heart). Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Does anesthetic regimen influence implicit memory during general anesthesia?

PubMed

Lequeux, Pierre-Yves; Hecquet, Fidelie; Bredas, Philippe

2014-11-01

Implicit learning of intraoperative auditory stimuli during general anesthesia is very difficult to quantify but may require the presence of noxious stimulation. We hypothesized that an anesthetic regimen with a low dose of opioid would enhance implicit memory, while a regimen with a high dose of opioid would not. One hundred-twenty patients were randomized into 3 groups. All patients were anesthetized with a target-controlled infusion of propofol and remifentanil, targeting a Bispectral Index (BIS) value of 50. The remifentanil effect-site concentration (in ng/mL) was always double that of propofol (in μg/mL) in the first group and half of that in the second group. Patients in these 2 groups were played a list of 20 words via headphones during surgery. The third group served as control for memory tests and was not played any word during anesthesia. BIS was recorded during word presentation. No statistical difference was found among the 3 groups regarding 3 different memory tests although 67.5% [50.7%; 80.9%] of the patients of the high-opioid group and 72.5% [55.9%; 84.9%] of the low-opioid group had at least 1 episode of BIS >60. We could not demonstrate the presence of implicit or explicit memorization under propofol-remifentanil anesthesia either with a low- or a high-dose opioid anesthetic regimen.

Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization

PubMed Central

Cao, G; Zhang, J; Wu, X; Yu, J; Chen, Y; Ye, X; Zhu, D; Zhang, Y; Guo, B; Shi, Y

2013-01-01

What is known and objective The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen. Methods The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fCmax/MIC ≥5 and fAUC24 h/MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated. Results and discussion The results of PK study showed that the Cmax and AUC0–∞ of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean Css,max, Css,min and AUC0–τ of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fCmax/MIC and fAUC/MIC targets. What is new and conclusion The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results. PMID:23701411

Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization.

PubMed

Cao, G; Zhang, J; Wu, X; Yu, J; Chen, Y; Ye, X; Zhu, D; Zhang, Y; Guo, B; Shi, Y

2013-10-01

The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen. The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fC(max) /MIC ≥5 and fAUC(24 h) /MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated. The results of PK study showed that the C(max) and AUC(0-∞) of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean C(ss,max), C(ss,min) and AUC(0-τ) of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fC(max) /MIC and fAUC/MIC targets. The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results. © 2013 John Wiley & Sons Ltd.

Treatment of prednisolone-induced hyperglycaemia in hospitalized patients: Insights from a randomized, controlled study.

PubMed

Radhakutty, Anjana; Stranks, Jessica L; Mangelsdorf, Brenda L; Drake, Sophie M; Roberts, Gregory W; Zimmermann, Anthony T; Stranks, Stephen N; Thompson, Campbell H; Burt, Morton G

2017-04-01

Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine-based basal-bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane-based insulin regimen is safer and more effective than a glargine-based regimen in hospitalized patients. Fifty inpatients prescribed ≥20 mg/day prednisolone acutely with (1) finger prick blood glucose level (BGL) ≥15 mmol/L or (2) BGLs ≥10 mmol/L within the previous 24 hours were randomized to either insulin isophane or glargine before breakfast and insulin aspart before meals. The initial daily insulin dose was 0.5 U/kg bodyweight or 130% of the current daily insulin dose. Glycaemic control was assessed using a continuous glucose monitoring system. On Day 1, there were no significant differences in percentage of time outside a target glucose range of 4 to 10 mmol/L (41.3% ± 5.5% vs 50.0% ± 5.7%, P  = .28), mean daily glucose (10.2 ± 0.7 vs 10.8 ± 0.8 mmol/L, P  = .57) or glucose <4 mmol/L (2.2% ± 1.1% vs 2.0% ± 1.3%, P  = .92) in patients randomized to isophane and glargine. In patients treated for 3 days, the prednisolone dose was reduced ( P  = .02) and the insulin dose was increased over time ( P  = .02), but the percentage of time outside the 4 to 10 mmol/L glucose range did not differ over time ( P  = .45) or between groups ( P  = .24). There were no differences in the efficacy or safety of the isophane and glargine-based insulin regimens. We recommend an initial daily insulin dose of 0.5 units/kg bodyweight if not on insulin, a greater than 30% increase in pre-prednisolone insulin dose and larger insulin dose adjustments in patients with prednisolone-induced hyperglycaemia. © 2016 John Wiley & Sons Ltd.

Antiplatelet regimens in the long-term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta-analysis

PubMed Central

Niu, Peng-Peng; Guo, Zhen-Ni; Jin, Hang; Xing, Ying-Qi; Yang, Yi

2016-01-01

Objective To examine the comparative efficacy and safety of different antiplatelet regimens in patients with prior non-cardioembolic ischaemic stroke or transient ischaemic attack. Design Systematic review and network meta-analysis. Data sources As on 31 March 2015, all randomised controlled trials that investigated the effects of antiplatelet agents in the long-term (≥3 months) secondary prevention of non-cardioembolic transient ischaemic attack or ischaemic stroke were searched and identified. Outcome measures The primary outcome measure of efficacy was serious vascular events (non-fatal stroke, non-fatal myocardial infarction and vascular death). The outcome measure of safety was any bleeding. Results A total of 36 randomised controlled trials (82 144 patients) were included. Network meta-analysis showed that cilostazol was significantly more effective than clopidogrel (OR 0.77, 95% credible interval 0.60–0.98) and low-dose (75–162 mg daily) aspirin (0.69, 0.55–0.86) in the prevention of serious vascular events. Aspirin (50 mg daily) plus dipyridamole (400 mg daily) and clopidogrel reduced the risk of serious vascular events compared with low-dose aspirin; however, the difference was not statistically significant. Furthermore, low-dose aspirin was as effective as higher daily doses. Cilostazol was associated with a significantly lower bleeding risk than most of the other regimens. Moreover, aspirin plus clopidogrel was associated with significantly more haemorrhagic events than other regimens. Direct comparisons showed similar results as the network meta-analysis. Conclusions Cilostazol was significantly more effective than aspirin and clopidogrel alone in the long-term prevention of serious vascular events in patients with prior non-cardioembolic ischaemic stroke or transient ischaemic attack. Cilostazol was associated with a significantly lower bleeding risk than low-dose aspirin (75–162 mg daily) and aspirin (50 mg daily) plus dipyridamole (400 mg daily). Low-dose aspirin was as effective as higher daily doses. However, further large, randomised, controlled, head-to-head trials are needed, especially in non-Asian ethnic groups. PMID:26988347

Cost-effectiveness of single dose cefotaxime plus metronidazole compared with three doses each of cefuroxime plus metronidazole for the prevention of wound infection after colorectal surgery.

PubMed

Davey, P; Lynch, B; Malek, M; Byrne, D; Thomas, P

1992-12-01

The cost-effectiveness of prophylaxis for colonic surgery with single dose cefotaxime plus metronidazole has been compared with that of three doses each of cefuroxime plus metronidazole, by analysing data from a previously published study supplemented with additional data on the hospital and community costs of wound infection after colonic surgery. The original trial included 942 patients having elective colonic surgery in 14 hospitals. The data on costs of wound infection were collected from a further 124 patients undergoing elective colonic surgery at Ninewells Hospital. All these patients received a three dose regimen of cefuroxime plus metronidazole. The Dundee patients received three injections of 0.75 g cefuroxime at 8-hourly intervals whereas the trial patients received a single dose of 1.5 g followed by two further doses of 0.75 g at 8-hourly intervals. The cefuroxime prophylaxis regimen used in the trial cost 24.16 pounds per patient more than the cefotaxime regimen. The components of the excess cost were drugs (15.18 pounds), equipment (6.14 pounds) and staff time (2.84 pounds). The median cost to the hospital of a wound infection was 978.04 pounds (95% CI 482.04 pounds to 1521.22 pounds). The components of the hospital cost of wound infection were: hotel costs 858 pounds (88%), dressing costs 83.02 pounds (8%) and drug costs (excluding prophylaxis) 37.02 pounds (4%). Only five patients received additional antibiotic treatment in the community, and only one required home visits from the District Nurse. Applying the difference in costs of prophylaxis as 21 pounds (costs of drugs plus equipment) and the cost per wound infection as 1000 pounds to the observed wound infection rate of 7% in the cefuroxime group, the wound infection rate in the cefotaxime group would have to be 2.1% higher for the two regimens to be equally cost-effective. The probability that such a difference in efficacy exists is 0.088. A model was developed to calculate the probability of equal cost-effectiveness over a range of costs of wound infection.

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial ▿

PubMed Central

Dunbar, Lala M.; Milata, Joe; McClure, Ty; Wasilewski, Margaret M.

2011-01-01

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA. PMID:21537018

Outcomes of Patients With Revised Stage I Clear Cell Sarcoma of Kidney Treated in National Wilms Tumor Studies 1-5

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

Kalapurakal, John A., E-mail: j-kalapurakal@northwestern.edu; Perlman, Elizabeth J.; Seibel, Nita L.

Purpose: To report the clinical outcomes of children with revised stage I clear cell sarcoma of the kidney (CCSK) using the National Wilms Tumor Study Group (NWTS)-5 staging criteria after multimodality treatment on NWTS 1-5 protocols. Methods and Materials: All CCSK patients enrolled in the National Wilms Tumor Study Group protocols had their pathology slides reviewed, and only those determined to have revised stage I tumors according to the NWTS-5 staging criteria were included in the present analysis. All patients were treated with multimodality therapy according to the NWTS 1-5 protocols. Results: A total of 53 children were identified asmore » having stage I CCSK. All patients underwent primary surgery with radical nephrectomy. The chemotherapy regimens used were as follows: regimen A, C, F, or EE in 4 children (8%); regimen DD or DD4A in 33 children (62%); regimen J in 4 children (8%); and regimen I in 12 children (22%). Forty-six patients (87%) received flank radiation therapy (RT). Seven children (13%) did not receive flank RT. The median delay between surgery and the initiation of RT was 9 days (range, 3-61). The median RT dose was 10.8 Gy (range, 10-36). The flank RT doses were as follows: 10.5 or 10.8 Gy in 25 patients (47%), 11-19.9 Gy in 2 patients (4%), 20-29.9 Gy in 9 patients (17%), and 30-40 Gy in 10 patients (19%). The median follow-up for the entire group was 17 years (range, 2-36). The relapse-free and cancer-specific survival rate was 100% at the last follow-up examination. Conclusions: The present results have demonstrated that children with revised stage I CCSK using the NWTS-5 staging criteria have excellent survival rates despite the use of varying RT doses and chemotherapy regimens in the NWTS 1-5 protocols.« less

A historical cycle control comparison of two drospirenone-containing combined oral contraceptives: ethinylestradiol 30 μg/drospirenone 3 mg administered in a 21/7 regimen versus ethinylestradiol 20 μg/drospirenone 3 mg administered in a 24/4 regimen.

PubMed

Marr, Joachim; Gerlinger, Christoph; Kunz, Michael

2012-05-01

To compare the bleeding patterns and cycle control of an oral contraceptive (OC) containing ethinylestradiol (EE) 30 μg/drospirenone (drsp) 3mg administered in a 21/7 regimen versus a lower-dose OC containing EE 20 μg/drsp 3mg administered in a 24/4 regimen, using data from two identically designed studies. In the first study, 326 healthy women (18-35 years) received EE 30 μg/drsp 3mg in a 21/7 regimen. In the second study, 1027 healthy women (17-36 years) received EE 20 μg/drsp 3mg in a 24/4 regimen. Participants recorded bleeding using daily completed diaries over 13 treatment cycles. During cycles 1-12, the prevalence of scheduled withdrawal bleeding was lower with EE 20 μg/drsp 3mg 24/4 than with EE 30 μg/drsp 3mg 21/7 (82.0-91.7% versus 94.8-100.0% of women, respectively); moreover, a higher proportion of women reported a maximum intensity of light scheduled withdrawal bleeding with EE 20 μg/drsp 3mg 24/4 than with EE 30 μg/drsp 3mg 21/7 (30.9-39.0% versus 13.8-20.5% of women, respectively). In cycles 2-13, unscheduled intracyclic bleeding was reported by 7.7-13.8% of EE 20 μg/drsp 3mg 24/4 recipients and 3.8-7.9% of EE 30 μg/drsp 3mg 21/7 recipients; these were mainly single bleeding days. During reference periods 1-4, the mean number of bleeding episodes was similar between groups (3.1-3.3 episodes with EE 20 μg/drsp 3mg 24/4 versus 3.2 episodes with EE 30 μg/drsp 3mg 21/7). A low-dose 24/4 regimen OC containing EE 20 μg/drsp 3mg is generally comparable in terms of bleeding to a higher-dose 21/7 regimen OC containing EE30 μg/drsp 3mg. Between-treatment differences in bleeding intensity and unscheduled intracyclic bleeding rates were observed. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB

PubMed Central

Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended. PMID:28644875

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

PubMed

Taylor, Olivia; Van Laeken, Nick; Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Radiation therapy for Bowen's disease of the skin

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

Lukas VanderSpek, Lauren A.; Pond, Gregory R.; Wells, Woodrow

2005-10-01

Purpose: To assess the clinical outcome in the radiation therapy (RT) of squamous carcinoma in situ of the skin (Bowen's disease). We focused on the local control rate and the toxicity according to the biologically effective dose (BED). Methods and Materials: A retrospective review was performed on 44 patients with Bowen's disease treated at Princess Margaret Hospital from April 1985 to November 2000. RT was the primary treatment for 32 patients, whereas 12 received RT for residual disease after local ablative therapy. Lesions were located as follows: scalp, 9 patients (20%); face, 12 (27%); trunk, 6 (14%), extremity, 12 (27%),more » perianal, 3 (7%), and penis, 2 (5%). Orthovoltage X-rays were used in the majority (39 of 44, 89%). There was no standard fractionation regimen: some physicians prescribed high doses, as for invasive skin cancer, whereas others prescribed lower doses because of the noninvasive nature of the disease, a sensitive anatomic location (e.g., extremity), or large treatment area. Because of the variations in fractionation regimens, BED was used as a common metric for biologic effect in the comparison of different regimens and analyzed for correlation with recurrence and toxicity. Local control was defined as the lack of persistent or recurrent disease at the treated site for the follow-up period. Grade 4 toxicity was defined as necrosis (cartilage/bone damage) and/or ulceration for a duration of >3 months. Results: The mean patient age was 67.7 years, and the male/female ratio was 29:15. The median pretreatment lesion size was 2.65 cm{sup 2} (range, 0.07-34.56 cm{sup 2}). Complete remission was achieved in 42 patients, with follow-up unavailable for the remaining 2 patients. Subsequently, 3 patients experienced recurrences at 0.2, 1.1, and 1-1.5 years after complete remission. One recurrence was Bowen's disease (local); the others were squamous cell carcinoma (one local, one marginal). Four patients experienced a new squamous lesion at a distant cutaneous site. As of last follow-up, 32 patients (73%) were known to be alive. Median follow-up was 2.6 years (range, 0-11.8 years). All but 3 patients were disease-free at last follow-up, 1 of whom died with distant, but not local disease. The 5-year overall survival rate was 68%. Biologically effective dose was not associated with recurrence. The crude local control rate was 93%. There was a trend toward higher radiation doses for smaller pretreatment tumor and field sizes. The BED did not correlate with Grade 4 toxicity; however, the three cases of Grade 4 toxicity occurred in patients treated with hypofractionated regimens (dose per fraction >4 Gy) for extremity lesions. Conclusions: Radiation therapy is an effective treatment option for Bowen's disease of the skin. Local recurrences seem to be equally low in patients treated with high- and low-dose regimens. Avoiding hypofractionated regimens (dose per fraction >4 Gy) in extremity locations might reduce the risk of Grade 4 toxicity.« less

Barriers to and facilitators of HIV-positive patients' adherence to antiretroviral treatment regimens.

PubMed

Roberts, K J

2000-03-01

HIV-positive patients must strictly adhere to antiretroviral regimens for the medications to work properly. Little, however, is known about the obstacles that patients face in adhering to the regimens or what, if anything, helps patients to adhere. The goals of the project were to describe, from HIV-positive patients' own perspectives, the barriers they face in adhering to antiretroviral regimens and the strategies they use to maximize their adherence. Five main barriers (forgetfulness, social/physical environment, complexity of the regimens, medication side effects, and inadequate patient knowledge) to adherence and six main facilitators (mechanical devices, "making a commitment," "routinizing," health beliefs, social support, and professional support) emerged from the data. Patients may overcome some of these barriers by receiving better health education about the need for adherence, professional and lay support for their efforts, and mechanical devices such as alarm clocks and medi-sets. Other barriers, however, such as the complexity of the medications, highlight the need for simplified antiretroviral regimens.

Weekly Versus Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Cervical Cancer: A Meta-Analysis.

PubMed

Chen, Xingxing; Zou, Haizhou; Li, Huifang; Lin, Ruifang; Su, Meng; Zhang, Wenyi; Zhou, Yongqiang; Zhang, Ping; Hou, Meng; Deng, Xia; Zou, Changlin

2017-02-01

The aim of this study was to evaluate toxicity, compliance, recurrence and the survival of weekly and triweekly cisplatin-based concomitant chemoradiation in treatment of cervical cancer. The databases were searched from 1995 until 2015 to identify eligible studies on weekly versus triweekly cisplatin chemoradiotherapy. The data were analyzed by RevMan 5.3 software. A total of 5 randomized controlled trials were included in this review. Weekly cisplatin regimen significantly reduced the incidence of Hematologic toxicity. However, there was no significantly different between the 2 arms in compliance, recurrence and the survival rate (all P >0.05). Weekly cisplatin regimen had the similar therapeutic effect as the triweekly cisplatin regimen but with less hematologic toxicity. Therefore, we recommend the weekly cisplatin 30 to 40 mg/m chemoradiotherapy as the strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.

Population pharmacokinetics of conventional and intermittent dosing of liposomal amphotericin B in adults: a first critical step for rational design of innovative regimens.

PubMed

Hope, William W; Goodwin, Joanne; Felton, Timothy W; Ellis, Michael; Stevens, David A

2012-10-01

There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (P = 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens.

Population Pharmacokinetics of Conventional and Intermittent Dosing of Liposomal Amphotericin B in Adults: a First Critical Step for Rational Design of Innovative Regimens

PubMed Central

Goodwin, Joanne; Felton, Timothy W.; Ellis, Michael; Stevens, David A.

2012-01-01

There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (P = 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens. PMID:22869566

Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model.

PubMed

Silva, Aleidy; Lee, Bai-Yu; Clemens, Daniel L; Kee, Theodore; Ding, Xianting; Ho, Chih-Ming; Horwitz, Marcus A

2016-04-12

Tuberculosis (TB) remains a major global public health problem, and improved treatments are needed to shorten duration of therapy, decrease disease burden, improve compliance, and combat emergence of drug resistance. Ideally, the most effective regimen would be identified by a systematic and comprehensive combinatorial search of large numbers of TB drugs. However, optimization of regimens by standard methods is challenging, especially as the number of drugs increases, because of the extremely large number of drug-dose combinations requiring testing. Herein, we used an optimization platform, feedback system control (FSC) methodology, to identify improved drug-dose combinations for TB treatment using a fluorescence-based human macrophage cell culture model of TB, in which macrophages are infected with isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible green fluorescent protein (GFP)-expressing Mycobacterium tuberculosis (Mtb). On the basis of only a single screening test and three iterations, we identified highly efficacious three- and four-drug combinations. To verify the efficacy of these combinations, we further evaluated them using a methodologically independent assay for intramacrophage killing of Mtb; the optimized combinations showed greater efficacy than the current standard TB drug regimen. Surprisingly, all top three- and four-drug optimized regimens included the third-line drug clofazimine, and none included the first-line drugs isoniazid and rifampin, which had insignificant or antagonistic impacts on efficacy. Because top regimens also did not include a fluoroquinolone or aminoglycoside, they are potentially of use for treating many cases of multidrug- and extensively drug-resistant TB. Our study shows the power of an FSC platform to identify promising previously unidentified drug-dose combinations for treatment of TB.

Dose-finding trial of a combined regimen with bevacizumab, immunotherapy, and chemotherapy in patients with metastatic renal cell cancer: An Italian Oncology Group for Clinical Research (GOIRC) study.

PubMed

Buti, Sebastiano; Lazzarelli, Silvia; Chiesa, Matteo Dalla; Simonelli, Cecilia; Re, Giovanni Lo; Lheshi, Arvin; Simon, Spazzapan; Mattioli, Rodolfo; Caminiti, Caterina; Mazza, Giancarlo; Donini, Maddalena; Passalacqua, Rodolfo

2010-09-01

The aim of this study was to look for the maximum tolerated dose (MTD) of gemcitabine and 5-fluorouracil in a new regimen also containing the antiangiogenic bevacizumab and immunotherapy (IT) for the treatment of metastatic renal cell cancer. The primary objective of this multicenter dose-finding study was to establish the MTD of chemotherapy (CT) in combination with fixed doses of IT and bevacizumab. The secondary objective was to assess the combination's activity. Five escalated dose levels of CT with intravenous gemcitabine and 5-fluorouracil (days 1 and 8 every 28 d), were associated together with intravenous bevacizumab (10 mg/kg on days 1 and 15 every 28 d), subcutaneous interleukin-2 (1 MIU/m² bid on days 8, 9, 15, 16, and 1 MIU/m²/d on days 10-12 and 17-19), and interferon-α-2a (3 MIU on days 10, 12, 17, 19). Of the 27 enrolled patients, 59% had been pretreated. The MTD was not reached. The highest CT dose studied was gemcitabine 1000 mg/m² and 5-fluorouracil 600 mg/m². More frequent grade 3 to 4 toxicities included neutropenia (63%), thrombocytopenia (33%), and fever (26%). The response rate was 33% according to the Response Evaluation Criteria in Solid Tumors. This is the first study that explored the feasibility and safety of combined bevacizumab, IT, and CT in metastatic renal cell cancer. The activity of this regimen is interesting and its efficacy warrants further trials.

Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.

PubMed

Xu, Yuhui; Wu, Jianan; Liao, Sha; Sun, Zhaogang

2017-10-03

Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

Efficacy, safety and proper dose analysis of PEGylated granulocyte colony-stimulating factor as support for dose-dense adjuvant chemotherapy in node positive Chinese breast cancer patients.

PubMed

Zhang, Fan; LingHu, RuiXia; Zhan, XingYang; Li, Ruisheng; Feng, Fan; Gao, Xudong; Zhao, Lei; Yang, Junlan

2017-10-03

For high-risk breast cancer patients with positive axillary lymph nodes, dose-dense every-two-week epirubicin/cyclophosphamide-paclitaxel (ddEC-P) regimen is the optimal postoperative adjuvant therapy. However, this regimen is limited by the grade 3/4 neutropenia and febrile neutropenia (FN). There is an urgent need to explore the efficacy, safety and proper dosage of PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) as support for ddEC-P in Chinese breast cancer patients with positive axillary lymph nodes. Prospectively, 40 women with stage IIIA to IIIC breast cancer received ddEC-P ± trastuzumab as adjuvant treatment. PEG-G-CSF was injected subcutaneously in a dose of 6 mg or 3 mg on the 2 th day of each treatment cycle. With administration of PEG-G-CSF, all of the 40 patients completed 8 cycles of ddEC-P ± trastuzumab regimen without dose reductions or treatment delays. Moreover, no FN cases were observed. Further analysis showed that the proper dosage of PEG-G-CSF was 6 mg for ddEC treatment, and 3 mg for ddP treatment. PEG-G-CSF exhibits advantages compared with G-CSF in convenient of administration and tolerance for high risk Chinese breast cancer patients. More importantly, the proper dose of PEG-G-CSF for high risk Chinese breast cancer patients during ddEC-P chemotherapy may be 6 mg for ddEC treatment and 3 mg for ddP treatment.

Pharmacogenetic versus clinical dosing of warfarin in individuals of Chinese and African-American ancestry: assessment using data simulation.

PubMed

Syn, Nicholas L X; Lee, Soo-Chin; Brunham, Liam R; Goh, Boon-Cher

2015-10-01

Clinical trials of genotype-guided dosing of warfarin have yielded mixed results, which may in part reflect ethnic differences among study participants. However, no previous study has compared genotype-guided versus clinically guided or standard-of-care dosing in a Chinese population, whereas those involving African-Americans were underpowered to detect significant differences. We present a preclinical strategy that integrates pharmacogenetics (PG) and pharmacometrics to predict the outcome or guide the design of dosing strategies for drugs that show large interindividual variability. We use the example of warfarin and focus on two underrepresented groups in warfarin research. We identified the parameters required to simulate a patient population and the outcome of dosing strategies. PG and pharmacogenetic plus loading (PG+L) algorithms that take into account a patient's VKORC1 and CYP2C9 genotype status were considered and compared against a clinical (CA) algorithm for a simulated Chinese population using a predictive Monte Carlo and pharmacokinetic-pharmacodynamic framework. We also examined a simulated population of African-American ancestry to assess the robustness of the model in relation to real-world clinical trial data. The simulations replicated similar trends observed with clinical data in African-Americans. They further predict that the PG+L regimen is superior to both the CA and the PG regimen in maximizing percentage time in therapeutic range in a Chinese cohort, whereas the CA regimen poses the highest risk of overanticoagulation during warfarin initiation. The findings supplement the literature with an unbiased comparison of warfarin dosing algorithms and highlights interethnic differences in anticoagulation control.

Dose-Reduced Busulfan, Cyclophosphamide, and Autologous Stem Cell Transplantation for Human Immunodeficiency Virus–Associated Lymphoma: AIDS Malignancy Consortium Study 020

PubMed Central

Spitzer, Thomas R.; Ambinder, Richard F.; Lee, Jeannette Y.; Kaplan, Lawrence D.; Wachsman, William; Straus, David J.; Aboulafia, David M.; Scadden, David T.

2013-01-01

Intensive chemotherapy for human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) has resulted in durable remissions in a substantial proportion of patients. High-dose chemotherapy and autologous stem cell transplantation (AuSCT), moreover, has resulted in sustained complete remissions in selected patients with recurrent chemosensitive disease. Based on a favorable experience with dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT for older patients with non-HIV–associated aggressive lymphomas, an AIDS Malignancy Consortium multicenter trial was undertaken using the same dose-reduced busulfan and cyclophosphamide preparative regimen with AuSCT for recurrent HIV-associated NHL and HL. Of the 27 patients in the study, 20 received an AuSCT. The median time to achievement of an absolute neutrophil count (ANC) of ≥ 0.5 × 109/L was 11 days (range, 9-16 days). The median time to achievement of an unsupported platelet count of ≥ 20 × 109/L was 13 days (range, 6-57 days). One patient died on day +33 posttransplantation from hepatic veno-occlusive disease (VOD) and multiorgan failure. No other fatal regimen-related toxicity occurred. Ten of 19 patients (53%) were in complete remission at the time of their day +100 post-AuSCT evaluation. Of the 20 patients, 10 were alive and event-free at a median of 23 weeks post-AuSCT. Median overall survival (OS) was not reached by 13 of the 20 patients alive at the time of last follow-up. This multi-institutional trial demonstrates that a regimen of dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT is well tolerated and is associated with favorable disease-free survival (DFS) and OS probabilities for selected patients with HIV-associated NHL and HL. PMID:18158962

Tumor Control Outcomes Following Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases from Renal Cell Carcinoma

PubMed Central

Zelefsky, Michael J; Greco, Carlo; Motzer, Robert; Magsanoc, Juan Martin; Pei, Xin; Lovelock, Michael; Mechalakos, Jim; Zatcky, Joan; Fuks, Zvi; Yamada, Yoshiya

2014-01-01

Purpose To report tumor local progression-free outcomes following treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Methods and Materials Between 2004 and 2010, a total of 105 lesions from renal cell carcinomas were treated with either SD-IGRT to prescription doses of 18–24 Gy (median, 24 Gy) or hypofractionation (3 or 5 fractions) with prescription doses ranging between 20 and 30 Gy. The median follow-up was 12 months (range, 1–48 months). Results The overall 3-year actuarial local progression-free survival (LPFS) for all lesions was 44%. The 3-year LPFS for those who received high single-dose (24 Gy; n = 45), low single-dose (< 24 Gy; n = 14), and hypofractionation regimens (n = 46) were 88%, 21%, and 17%, respectively (high single dose versus low single dose, p = 0.001; high single dose versus hypofractionation, p < 0.001). Multivariate analysis revealed the following variables as significant predictors of improved LPFS: dose of 24 Gy compared with lower dose (p = 0.009), and single dose versus hypofractionation (p = 0.008). Conclusion High-dose SD-IGRT is a non-invasive procedure resulting in high probability of local tumor control for metastatic renal cell cancers, generally considered radioresistant according to classical radiobiological ranking. PMID:21596489

Evaluation of the effects and adverse drug reactions of low-dose dexamethasone premedication with weekly docetaxel.

PubMed

Kang, Rae Young; Yoo, Kyung Sook; Han, Hyeon Ju; Lee, Ju-Yeun; Lee, Se-Hoon; Kim, Dong-Wan; Lee, Yu Jeung

2017-02-01

A weekly docetaxel regimen had comparable efficacy with a tri-weekly schedule and caused significantly less severe neutropenia and febrile neutropenia. Therefore, a weekly docetaxel regimen has become increasingly common in cancer treatment. Premedication with corticosteroids can effectively prevent or reduce the severity of hypersensitivity and fluid retention. However, no recommended steroid dosage for a weekly docetaxel regimen has been established to date. The aim of this study is to compare the efficacy and complications of two different weekly docetaxel premedication protocols. We retrospectively compared the hypersensitivity, hyperglycemia, and infection incidence associated with two weekly docetaxel premedication protocols. The control group (dexamethasone 10 mg intravenously and 4 mg orally every 12 h for four doses, starting 1 h before docetaxel administration) patients started weekly docetaxel chemotherapy between May 2012 and April 2013 at Seoul National University Hospital, and the experimental group (dexamethasone 10 mg intravenously 1 h prior to each docetaxel administration) patients started weekly docetaxel chemotherapy between May 2013 and April 2014. In total, 109 patients in the control group and 97 patients in the experimental group were included in this study, and there were no statistically significant differences in baseline characteristics between the two groups. The incidence of hypersensitivity and hyperglycemia were similar, but infections were observed significantly less in the experimental group (p = 0.020, OR = 0.408, 0.0190-0.0879). A low-dose dexamethasone premedication protocol has comparable efficacy in the prevention of docetaxel hypersensitivity with fewer infection complications. Therefore, we recommend a low-dose dexamethasone premedication protocol for weekly docetaxel regimens.

Clinical research in the treatment of tuberculosis: current status and future prospects.

PubMed

Chang, K-C; Yew, W-W; Sotgiu, G

2015-12-01

To supplement previous state-of-art reviews on anti-tuberculosis treatment and to pave the way forward with reference to the current status, we systematically reviewed published literature on clinical research on tuberculosis (TB) over the past decade in the treatment of drug-susceptible and multidrug-resistant TB (MDR-TB), with a focus on drugs, dosing factors and regimens. Our review was restricted to Phase II/III clinical trials, cohort and case-control studies, and systematic reviews of clinical studies. TB programmatic and patient behavioural factors, non-TB drugs, adjunctive surgery, new vaccines, immunotherapy, antiretroviral therapy and management of latent tuberculous infection are outside the scope of this review. An algorithm was used to systematically search PubMed for relevant articles published in English from 1 January 2005 to 31 December 2014. Articles without evaluated factors (drugs, dosing factors and regimens) or comparative analysis of specified anti-tuberculosis treatment outcomes were excluded. Of the 399 articles initially identified, 294 were excluded. The main findings of the remaining 105 articles are described under two categories: presumed drug-susceptible TB and MDR-TB. Fifty-nine articles included under drug-susceptible TB were divided into 12 subcategories: isoniazid, rifampicin, pyrazinamide, fluoroquinolones, fixed-dose combination drugs, dosing frequency, treatment phases, treatment duration, experimental regimens for pulmonary (surrogate markers vs. clinical outcomes) and extra-pulmonary TB. Forty-nine articles included under MDR-TB were divided into seven subcategories: fluoroquinolones, pyrazinamide, second-line injectable drugs, World Health Organization Group 4 and Group 5 drugs, MDR-TB regimens and novel drugs. Clinical research in the last decade and ongoing trials might furnish new paradigms for improving the treatment of this recalcitrant ancient disease.

Differences in pharmacokinetics and pharmacodynamics of colistimethate sodium (CMS) and colistin between three different CMS dosage regimens in a critically ill patient infected by a multidrug-resistant Acinetobacter baumannii.

PubMed

Luque, Sònia; Grau, Santiago; Valle, Marta; Sorlí, Luisa; Horcajada, Juan Pablo; Segura, Concha; Alvarez-Lerma, Francisco

2013-08-01

Use of colistin has re-emerged for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria, but information on its pharmacokinetics and pharmacodynamics is limited, especially in critically ill patients. Recent data from pharmacokinetic/pharmacodynamic (PK/PD) population studies have suggested that this population could benefit from administration of higher than standard doses of colistimethate sodium (CMS), but the relationship between administration of incremental doses of CMS and corresponding PK/PD parameters as well as its efficacy and toxicity have not yet been investigated in a clinical setting. The objective was to study the PK/PD differences of CMS and colistin between three different CMS dosage regimens in the same critically ill patient. A critically ill patient with nosocomial pneumonia caused by a MDR Acinetobacter baumannii received incremental doses of CMS. During administration of the different CMS dosage regimens, CMS and colistin plasma concentrations were determined and PK/PD indexes were calculated. With administration of the highest CMS dose once daily (720 mg every 24h), the peak plasma concentration of CMS and colistin increased to 40.51 mg/L and 1.81 mg/L, respectively, and the AUC0-24/MIC of colistin was 184.41. This dosage regimen was efficacious, and no nephrotoxicity or neurotoxicity was observed. In conclusion, a higher and extended-interval CMS dosage made it possible to increase the exposure of CMS and colistin in a critically ill patient infected by a MDR A. baumannii and allowed a clinical and microbiological optimal response to be achieved without evidence of toxicity. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial.

PubMed

Moseley, Merrick J; Wallace, Michael P; Stephens, David A; Fielder, Alistair R; Smith, Laura C; Stewart, Catherine E

2015-04-25

Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction ('optical treatment') followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching ('dose'), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical modelling of previous trial outcome data. Should the personalized dosing strategy demonstrate superiority over the standardized dosing strategy, then its adoption into routine practice could bring practical benefits in reducing the duration of treatment needed to achieve an optimal outcome. ISRCTN ISRCTN12292232.

Gonzalez Regimen (PDQ®)—Patient Version

Cancer.gov

The Gonzalez regimen is a complex treatment plan based on the role of enzymes, vitamins, minerals, and other dietary factors. The US Food and Drug Administration has not approved the Gonzalez regimen or any of its components as a cancer treatment. Learn more in this expert-reviewed summary.

Nitrates for stable angina: a systematic review and meta-analysis of randomized clinical trials.

PubMed

Wei, Jiafu; Wu, Taixiang; Yang, Qing; Chen, Mao; Ni, Juan; Huang, Dejia

2011-01-07

To assess the effect (harms and benefits) of nitrates for stable angina. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Randomized controlled trials with both parallel and crossover design were included. The following outcome measures were evaluated: number of angina attacks weekly and nitroglycerin consumption, quality of life, total exercise duration, time to onset of angina and time to 1 mm ST depression. Fifty-one trials with 3595 patients meeting inclusion criteria were analyzed. Both intermittent and continuous regimens of nitrates lengthened exercise duration significantly by 31 and 53 s respectively. The number of angina attacks was significantly reduced by 2.89 episodes weekly for continuous administration and 1.5 episodes weekly for intermittent administration. With intermittent administration, increased dose provided with 21 s more length of exercise duration. With continuous administration, exercise duration was pronged more in low-dose group. Quality of life was not improved by continuous application of GTN patches and was similar between continuous and intermittent groups. In addition, 51.6% patients receiving nitrates complained with headache. Long-term administration of nitrates was beneficial for angina prophylaxis and improved exercise performance but might be ineffective for improving quality of life. With continuous regimen, low-dose nitrates were more effective than high-dose ones for improving exercise performance. By contrast, with intermittent regimen, high-dose nitrates were more effective. In addition, intermittent administration could bring zero-hour effect. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Population PK Modeling and Target Attainment Simulations to Support Dosing of Ceftaroline Fosamil in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia.

PubMed

Riccobene, Todd A; Khariton, Tatiana; Knebel, William; Das, Shampa; Li, James; Jandourek, Alena; Carrothers, Timothy J; Bradley, John S

2017-03-01

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to <18 years) studies of ceftaroline fosamil were combined with PK data from adults to update a population PK model for ceftaroline and ceftaroline fosamil. This model, based on a data set including 305 children, was used to conduct simulations to estimate ceftaroline exposures and percentage of time that free drug concentrations were above the minimum inhibitory concentration (%fT>MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to <2 years and 12 mg/kg (up to a maximum of 400 mg) q8h in children aged 2 years to <18 years or 600 mg q12h in children aged 12 to <18 years, >90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to <18 years by the FDA and EMA, which are presented. © 2016, The American College of Clinical Pharmacology.

Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia.

PubMed

Shang, De-Wei; Li, Li-Jun; Wang, Xi-Pei; Wen, Yu-Guan; Ren, Yu-Peng; Guo, Wei; Li, Wen-Biao; Li, Liang; Zhou, Tian-Yan; Lu, Wei; Wang, Chuan-Yue

2014-06-01

The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling. Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log-linear, E(max), and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens. A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine. The decrease in total PANSS score during treatment was best characterized using cumulated clozapine area under the curve (AUC) data in the E(max) model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E(max) was 296 mg·L(-1)·h(-1)·d(-1). The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response but with a slower relief of symptoms in dose titration regimen. The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients.

Impacts of 12-dose regimen for latent tuberculosis infection: Treatment completion rate and cost-effectiveness in Taiwan.

PubMed

Huang, Yi-Wen; Yang, Shun-Fa; Yeh, Yen-Po; Tsao, Thomas Chang-Yao; Tsao, Shih-Ming

2016-08-01

Treatment of latent tuberculosis infection (LTBI) is essential for eradicating tuberculosis (TB). Moreover, the patient adherence is crucial in determining the effectiveness of TB control. Isoniazid given by DOTS daily for 9 months (9H) is the standard treatment for LTBI in Taiwan. However, the completion rate is low due to the long treatment period and its side effects. The combined regimen using a high dose of rifapentine/isoniazid once weekly for 12 weeks (3HP) has been used as an alternative treatment option for LTBI in the United States. This may result in a higher completion rate. In this pilot study, patient adherence and cost of these 2 treatment regimens were investigated. Thus, we aimed to assess the treatment completion rate and costs of 3HP and compare to those with 9H.Data from 691 cases of LTBI treatments including 590 cases using the conventional regimen and 101 cases with rifapentine/Isoniazid were collected. The cost was the sum of the cost of treatment with Isoniazid for 9 months or with rifapentin/Isoniazid for 3 months of all contacts. The effectiveness was the cost of cases of tuberculosis avoided.In this study, the treatment completion rate for patients prescribed with the 3 months rifapentine/isoniazid regimen (97.03%) was higher than those given the conventional 9-month isoniazid regimen (87.29%) (P <0.001). The cost of 3HP and 9H was US$261.24 and US$717.3, respectively. The cost-effectiveness ratio with isoniazid for 9 months was US$ 15392/avoided 1 case of tuberculosis and US$ 5225/avoided 1 case of tuberculosis with 3HP. In addition, when compared with the conventional regimen, there were fewer patients discontinued with rifapentine/isoniazid regimen due to undesirable side effects.This was the first study to compare the 2 treatment regimens in Taiwan, and it showed that a short-term high-dosage rifapentine/isoniazid treatment regimen reduced costs and resulted in higher treatment completion than the standard LTBI isoniazid treatment.

Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects.

PubMed

Liu, Shuaibing; Xue, Ling; Shi, Xiangfen; Sun, Zhiyong; Zhu, Zhenfeng; Zhang, Xiaojian; Tian, Xin

2018-06-01

Ticagrelor, the first reversible P2Y 12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease. The objectives of this study were to establish a population pharmacokinetics (PK) and pharmacodynamics (PD) model of ticagrelor and to provide a theoretical basis for the optimization of ticagrelor treatment in clinic. A single oral dose of 180 mg ticagrelor was administered to 14 healthy male subjects in a randomized study. Common single-nucleotide polymorphisms (SNPs) in biotransformation enzymes CYP3A4 and CYP3A5 (CYP3A4*1G and CYP3A5*3) were genotyped by PCR-direct sequencing. Blood samples were collected to measure plasma concentrations of ticagrelor and its active metabolite AR-C124910XX and maximal platelet inhibition. Various models were evaluated to characterize the pharmacokinetics of ticagrelor and AR-C124910XX as well as their PK-PD relationship. Covariates that may potentially affect PK or PD of ticagrelor and AR-C124910XX were included and assessed. Simulation for dosage regimen was performed based on the final PK-PD model. Ticagrelor and AR-C124910XX PK were best described by a two-compartment model with first-order transit absorption model. CYP3A4*1G increased clearance for AR-C124910XX, but had no significant effect on ticagrelor clearance. The relationship between concentration and platelet response of ticagrelor was best described by a turnover model. Simulation results indicated that a lower dosage regimen of 30 mg maintenance dose (MD) could produce an anticipated anti-platelet response in comparison to the routine clinical dosage regimen (180 mg loading dose (LD), 90 mg MD). Our study developed a population PK-PD model for ticagrelor and further simulation for dosage regimen was performed based on the final model. Compared to the current recommended dosage regimen (180 mg LD, 90 mg MD), our simulation result of a relatively lower dose (30 mg MD) could also obtain an acceptable anti-platelet response, which may provide a reference for further dosage regimen design in Chinese population.

Current status of intravenous thrombolysis for acute ischemic stroke in Asia.

PubMed

Sharma, Vijay K; Ng, Kay W P; Venketasubramanian, Narayanaswamy; Saqqur, Maher; Teoh, Hock L; Kaul, Subash; Srivastava, Padma M V; Sergentanis, Theodoris; Suwanwela, Nijasri; Nguyen, Thang H; Lawrence Wong, K S; Chan, Bernard P L

2011-12-01

Data regarding thrombolysis for acute ischemic stroke in Asia are scarce and only a small percentage of patients are thrombolysed. The dose of intravenous tissue plasminogen activator (IV-tPA) in Asia remains controversial. Case-controlled observation studies in Asia included only Japanese patients and suggested the clinical efficacy and safety of low-dose IV-tPA (0.6 mg/kg body weight; max 60 mg) comparable to standard dose (0.9 mg/kg body weight; max. 90 mg). Reduced treatment cost, lower symptomatic intracerebral hemorrhage risk and comparable efficacy encouraged many Asian centers to adopt low-dose or even variable-dose IV-tPA regimens. We evaluated various Asian thrombolysis studies and compared with SITS-MOST registry and NINDS trial. We included the published studies on acute ischemic stroke thrombolysis in Asia. Unadjusted relative risks and 95% Confidence intervals were calculated for each study. Pooled estimates from random effects models were used because the tests for heterogeneity were significant. We found only 18 publications regarding acute ischemic stroke thrombolysis in Asia that included total of 9300 patients. Owing to ethnic differences, stroke severity, small number of cases in individual reports, outcome measures and tPA dose regimes, it is difficult to compare these studies. Functional outcomes were almost similar (to Japanese studies) when lower-dose IV-tPA was used in non-Japanese populations across Asia. Interestingly, with standard dose IV-tPA, considerably better functional outcomes were observed, without increasing symptomatic intracerebral hemorrhage rates. Variable dose regimens of IV-tPA are used across Asia without any reliable or established evidence. Establishing a uniform IV-tPA regimen is essential since the rapid improvements in health-care facilities and public awareness are expected to increase the rates of thrombolysis in Asia. © 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.

Dosing antibiotic prophylaxis during cardiopulmonary bypass-a higher level of complexity? A structured review.

PubMed

Paruk, Fathima; Sime, Fekade B; Lipman, Jeffrey; Roberts, Jason A

2017-04-01

In highly invasive procedures such as open heart surgery, the risk of post-operative infection is particularly high due to exposure of the surgical field to multiple foreign devices. Adequate antibiotic prophylaxis is an essential intervention to minimise post-operative morbidity and mortality. However, there is a lack of clear understanding on the adequacy of traditional prophylactic dosing regimens, which are rarely supported by data. The aim of this structured review is to describe the relevant pharmacokinetic/pharmacodynamic (PK/PD) considerations for optimal antibiotic prophylaxis for major cardiac surgery including cardiopulmonary bypass (CPB). A structured review of the relevant published literature was performed and 45 relevant studies describing antibiotic pharmacokinetics in patients receiving extracorporeal CPB as part of major cardiac surgery were identified. Some of the studies suggested marked PK alterations in the peri-operative period with increases in volume of distribution (V d ) by up to 58% and altered drug clearances of up to 20%. Mechanisms proposed as causing the PK changes included haemodilution, hypothermia, retention of the antibiotic within the extracorporeal circuit, altered physiology related to a systemic inflammatory response, and maldistribution of blood flow. Of note, some studies reported no or minimal impact of the CPB procedure on antibiotic pharmacokinetics. Given the inconsistent data, ongoing research should focus on clarifying the influence of CPB procedure and related clinical covariates on the pharmacokinetics of different antibiotics during cardiac surgery. Traditional prophylactic dosing regimens may need to be re-assessed to ensure sufficient drug exposures that will minimise the risk of surgical site infections. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

A Review of Moxifloxacin for the Treatment of Drug-Susceptible Tuberculosis.

PubMed

Naidoo, Anushka; Naidoo, Kogieleum; McIlleron, Helen; Essack, Sabiha; Padayatchi, Nesri

2017-11-01

Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens. © 2017, The American College of Clinical Pharmacology.

Repaglinide plus single-dose insulin glargine: a safe regimen for low-risk type 2 diabetic patients who insist on fasting in Ramadan.

PubMed

Bakiner, Okan; Ertorer, Melek E; Bozkirli, Emre; Tutuncu, Neslihan B; Demirag, Nilgun G

2009-03-01

Aim of this prospective study is to evaluate the effect of repaglinide t.i.d. (three times a day) plus single-dose insulin glargine regimen in low-risk type 2 diabetic patients during Ramadan fasting. Participants had been taking the regimen for at least 3 months. Patients with a history of diabetic coma, severe hypoglycemic crisis or repeating attacks of hypoglycemia were excluded. Hypoglycemic unawareness, kidney or liver disease or HbA1c over 8% were also accepted as exclusion criteria. Eleven patients who insisted on this worship and eight non-fasting cases were involved. All were told to make home-glucose-monitorisation weekly and report any hypoglycemic event throughout Ramadan. Fasting blood glucose (FBG), post-prandial blood glucose (PBG) and fructosamine levels, body weights and blood pressures were recorded just before and after Ramadan. Seven patients in each group concluded the follow-up. Any significant change was detected in the parameters in either groups (P>0.05). Glucose control remained unchanged; fructosamine 318.14+/-65.38 versus 317.28+/-52.80 mmol/L in fasting group, 290.71+/-38.48 versus 290+/-38.56 mmol/L in non-fasting group. None of them exhibited either a major or a minor hypoglycemic event. The results of this pilot study indicated that repaglinide t.i.d. plus single-dose insulin glargine regimen was safe for low-risk type 2 diabetic patients who insisted on fasting during Ramadan.

Different antivascular endothelial growth factor treatments and regimens and their outcomes in neovascular age-related macular degeneration: a literature review.

PubMed

Lanzetta, Paolo; Mitchell, Paul; Wolf, Sebastian; Veritti, Daniele

2013-12-01

Antivascular endothelial growth factor (anti-VEGF) therapy has revolutionised the treatment of wet age-related macular degeneration (wAMD). Recent research has focused on evaluating competing agents and alternative dosage regimens, providing evidence to help determine optimal treatment strategies. We therefore conducted a review of clinical research studies in wAMD published since 2008 that compared anti-VEGF dosing regimens and therapies; seven studies met our inclusion criteria. Data on baseline disease characteristics, disease outcomes, safety (ocular and systemic) and treatment burden (injection and visit frequencies) were extracted on patients treated with ranibizumab 0.5 mg, bevacizumab 1.25 mg or aflibercept 2.0 mg for up to 2 years. For ranibizumab and bevacizumab, visual and anatomical outcomes at 1 and 2 years were superior using scheduled monthly (or 4 weekly (q4w)) compared with as needed or scheduled quarterly dosing regimens. Treatment outcomes were generally better for both drugs when more aggressive retreatment criteria were used, which resulted in more frequent injections. Bevacizumab, however, was associated with a 30-35% elevated rate of serious systemic adverse events compared with ranibizumab, regardless of dosing interval; further study in larger patient populations will be required to determine the validity of this finding. Intravitreal aflibercept injection every 8 weeks was non-inferior to ranibizumab q4w on all visual and anatomical endpoints at week 52, had a similar safety profile and required five fewer anti-VEGF injections.

Towards earlier inclusion of Children in Tuberculosis (TB) drugs trials: Consensus statements from an Expert Panel

PubMed Central

Nachman, Sharon; Ahmed, Amina; Amanullah, Farhana; Becerra, Mercedes C; Botgros, Radu; Brigden, Grania; Browning, Renee; Gardiner, Elizabeth; Hafner, Richard; Hesseling, Anneke; How, Cleotilde; Jean-Philippe, Patrick; Lessem, Erica; Makhene, Mamodikoe; Mbelle, Nontombi; Marais, Ben; McIlleron, Helen; Mc Neeley, David F; Mendel, Carl; Murray, Stephen; Navarro, Eileen; Oramasionwu, Gloria E; Porcalla, Ariel R; Powell, Clydette; Powell, Mair; Rigaud, Mona; Rouzier, Vanessa; Samson, Pearl; Schaaf, H. Simon; Shah, Seema; Starke, Jeff; Swaminathan, Soumya; Wobudeya, Eric; Worrell, Carol

2015-01-01

Children represent a significant proportion of the global tuberculosis (TB) burden, and may be disproportionately more affected by its most severe clinical manifestations. Currently available treatments for pediatric drug-susceptible (DS) and drug-resistant (DR) TB, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxicities, and an overall lack of suitable, child-friendly formulations. The complex and burdensome nature of administering the existing regimens to treat DS TB also contributes to the rise of DR TB strains. Despite the availability and use of these therapies for decades, a dearth of dosing evidence in children underscores the importance of sustained efforts for TB drug development to better meet the treatment needs of children with TB. Several new TB drugs and regimens with promising activity against both DS and DR TB strains have recently entered clinical development and are in various phases of clinical evaluation in adults or have received marketing authorization for adults. However, initiation of clinical trials to evaluate these drugs in children is often deferred, pending the availability of complete safety and efficacy data in adults or after drug approval. This document summarizes consensus statements from an international panel of childhood TB opinion leaders which support the initiation of evaluation of new TB drugs and regimens in children at earlier phases of the TB Drug development cycle. PMID:25957923

A Pharmacologic Approach to the Use of Glyburide in Pregnancy

PubMed Central

Caritis, Steve N.; Hebert, Mary F.

2017-01-01

Despite widespread use of glyburide to treat pregnancy-related hyperglycemia, the dosing regimen is based in large part on pharmacokinetic and pharmacodynamic studies in men and nonpregnant women. Like many medications used by pregnant women, adequate pharmacokinetic and pharmacodynamic data in pregnancy have been sorely lacking. This lack of information can lead to both overdosing with excessive side effects and under-dosing with an inadequate therapeutic response. Both of these problems may apply to glyburide use in pregnancy. This commentary provides a pharmacologic basis for altering the glyburide administration regimen. Taking glyburide 1 hour before a meal may improve efficacy in patients with pregnancy-related hyperglycemia. PMID:23812467

Comparison of two high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone derived regimens in patients aged under 60 years with low-intermediate risk aggressive lymphoma: a final analysis of the multicenter LNH93-2 protocol.

PubMed

Morel, Pierre; Munck, Jean-Nicolas; Coiffier, Bertrand; Gisselbrecht, Christian; Ranta, Dana; Bosly, Andre; Tilly, Hervé; Quesnel, Bruno; Thyss, Antoine; Mounier, Nicolas; Brière, Josette; Molina, Thierry; Reyes, Felix

2010-09-01

One-third of patients aged

A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

PubMed Central

Cheeseman, S L; Joel, S P; Chester, J D; Wilson, G; Dent, J T; Richards, F J; Seymour, M T

2002-01-01

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified ‘Modified de Gramont’ (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m−2), then ambulatory 46-h fluorouracil infusion (2000–3600 mg m−2, cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m−2. Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m−2 bolus + 2800 mg m−2 46-h infusion. A lower dose of 400 mg m−2 bolus + 2400 mg m−2 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC0–48 h) at this lower dose is equivalent to dG. With OxMdG, grade 3–4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea <1% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. MdG and OxMdG are convenient and well-tolerated. OxMdG was particularly active as 1st-line treatment of advanced colorectal cancer. Both regimens are being further evaluated in the current UK MRC phase III trial. British Journal of Cancer (2002) 87, 393–399. doi:10.1038/sj.bjc.6600467 www.bjcancer.com © 2002 Cancer Research UK PMID:12177775

Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

PubMed Central

Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity. PMID:24963332

Clinical study on prospective efficacy of all-trans Acid, realgar-indigo naturalis formula combined with chemotherapy as maintenance treatment of acute promyelocytic leukemia.

PubMed

Xiang-Xin, Li; Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity.

Synergistic Cytotoxicity of Lenalidomide and Dexamethasone in Mantle Cell Lymphoma via Cereblon-dependent Targeting of the IL-6/STAT3/PI3K Axis.

PubMed

Ma, Jiexian; Wu, Kefei; Bai, Weiya; Cui, Xiaoxian; Chen, Yan; Xie, Youhua; Xie, Yanhui

2017-06-01

At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways. The two drugs synergistically inhibit the same pathways, but through different sites. Cereblon was found expressed in most of the MCL tissues (91.3% positivity). Moreover, cereblon expression is positively correlated with LD regimen sensitivity: long-term lenalidomide exposure downregulates cereblon and induces multi-drug resistance against lenalidomide, dexamethasone, cytarabine, cisplatin, and methotrexate in vitro. Removal of lenalidomide resensitizes lenalidomide-resistant MCL cells to lenalidomide and dexamethasone. Our work suggests that rotating the LD regimen with other regimens would improve MCL maintenance therapy. Copyright © 2017. Published by Elsevier B.V.

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.

Ifosfamide in the treatment of recurrent or disseminated lung cancer: a phase II study of two dose schedules.

PubMed

Costanzi, J J; Gagliano, R; Loukas, D; Panettiere, F J; Hokanson, J A

1978-05-01

Ifosfamide was administered to 21 patients with recurrent or disseminated lung cancer at a dose of 4.0 gm/M2 iv every 3 weeks. The response rate was 33% with an additional 14% showing no response or stable disease. At a dose of 1.2 gm/M2 daily for 5 days every 4 weeks, 57% of 14 patients responded with 35% showing no response or stable disease. The majority of the patients (28) had epidermoid carcinoma. Two (7%) had complete response with 9 (32%) showing partial responses. Other responses included 1/2 oat cell carcinomas and 3/6 large cell undifferentiated carcinomas. Toxicity was equal in both regimens for nausea, vomiting, increased serum LDH and neutropenia but the 5 day program had significantly less hemorrhagic cystitis. Survival was greatly influenced by response. There was no statistical difference in overall length of response between responders and the non responding/stable disease patients. But these two groups had a very significant survival advantage when compared to those patients with increasing disease. Similarly, there was a significant improvement in response duration for the low dosage regimen. Therefore, the low dose 5 day regimen is recommended because of its response rate, it has less hemorrhagic cystitis and it has better patient acceptance in that it can be given as an outpatient and does not require a Foley catheter.

Highly specific reasons for nonadherence to antiretroviral therapy: results from the German adherence study.

PubMed

Boretzki, Johanna; Wolf, Eva; Wiese, Carmen; Noe, Sebastian; Balogh, Annamaria; Meurer, Anja; Krznaric, Ivanka; Zink, Alexander; Lersch, Christian; Spinner, Christoph D

2017-01-01

Reasons for and frequency of nonadherence to antiretroviral therapy (ART) may have changed due to pharmacological improvements. In addition, the importance of known non-pharmacologic reasons for nonadherence is unclear. We performed a cross-sectional, noninterventional, multicenter study to identify current reasons for nonadherence. Patients were categorized by physicians into the following adherence groups: good, unstable, or poor adherence. Co-variables of interest included age, sex, time since HIV diagnosis, ART duration, current ART regimen, HIV transmission route, comorbidity, HIV-1 RNA viral load (VL), and CD4 cell count. Patients self-reported the number of missed doses and provided their specific reasons for nonadherent behavior. Statistical analyses were performed using Fisher's extended exact test, Kruskal-Wallis test, and logistic regression models. Our study assessed 215 participants with good (n=162), unstable (n=36), and poor adherence (n=17). Compared to patients with good adherence, patients with unstable and poor adherence reported more often to have missed at least one dose during the last week (good 11% vs unstable 47% vs poor 63%, p <0.001). Physicians' adherence assessment was concordant with patients' self-reports of missed doses during the last week (no vs one or more) in 81% cases. Similarly, we found a strong association of physicians' assessment with viral suppression. Logistic regression analysis showed that "reduced adherence" - defined as unstable or poor - was significantly associated with patients <30 years old, intravenous drug use, history of acquired immune deficiency syndrome (AIDS), and psychiatric disorders ( p <0.05). Univariate analyses showed that specific reasons, such as questioning the efficacy/dosing of ART, HIV stigma, interactive toxicity beliefs regarding alcohol and/or party drugs, and dissatisfaction with regimen complexity, correlated with unstable or poor adherence ( p <0.05). Identification of factors associated with poor adherence helps in identifying patients with a higher risk for nonadherence. Reasons for nonadherence should be directly addressed in every patient, because they are common and constitute possible adherence intervention points.

Evaluation and optimisation of current milrinone prescribing for the treatment and prevention of low cardiac output syndrome in paediatric patients after open heart surgery using a physiology-based pharmacokinetic drug-disease model.

PubMed

Vogt, Winnie

2014-01-01

Milrinone is the drug of choice for the treatment and prevention of low cardiac output syndrome (LCOS) in paediatric patients after open heart surgery across Europe. Discrepancies, however, among prescribing guidance, clinical studies and practice pattern require clarification to ensure safe and effective prescribing. However, the clearance prediction equations derived from classical pharmacokinetic modelling provide limited support as they have recently failed a clinical practice evaluation. Therefore, the objective of this study was to evaluate current milrinone dosing using physiology-based pharmacokinetic (PBPK) modelling and simulation to complement the existing pharmacokinetic knowledge and propose optimised dosing regimens as a basis for improving the standard of care for paediatric patients. A PBPK drug-disease model using a population approach was developed in three steps from healthy young adults to adult patients and paediatric patients with and without LCOS after open heart surgery. Pre- and postoperative organ function values from adult and paediatric patients were collected from literature and integrated into a disease model as factorial changes from the reference values in healthy adults aged 20-40 years. The disease model was combined with the PBPK drug model and evaluated against existing pharmacokinetic data. Model robustness was assessed by parametric sensitivity analysis. In the next step, virtual patient populations were created, each with 1,000 subjects reflecting the average adult and paediatric patient characteristics with regard to age, sex, bodyweight and height. They were integrated into the PBPK drug-disease model to evaluate the effectiveness of current milrinone dosing in achieving the therapeutic target range of 100-300 ng/mL milrinone in plasma. Optimised dosing regimens were subsequently developed. The pharmacokinetics of milrinone in healthy young adults as well as adult and paediatric patients were accurately described with an average fold error of 1.1 ± 0.1 (mean ± standard deviation) and mean relative deviation of 1.5 ± 0.3 as measures of bias and precision, respectively. Normalised maximum sensitivity coefficients for model input parameters ranged from -0.84 to 0.71, which indicated model robustness. The evaluation of milrinone dosing across different paediatric age groups showed a non-linear age dependence of total plasma clearance and exposure differences of a factor 1.4 between patients with and without LCOS for a fixed dosing regimen. None of the currently used dosing regimens for milrinone achieved the therapeutic target range across all paediatric age groups and adult patients, so optimised dosing regimens were developed that considered the age-dependent and pathophysiological differences. The PBPK drug-disease model for milrinone in paediatric patients with and without LCOS after open heart surgery highlights that age, disease and surgery differently impact the pharmacokinetics of milrinone, and that current milrinone dosing for LCOS is suboptimal to maintain the therapeutic target range across the entire paediatric age range. Thus, optimised dosing strategies are proposed to ensure safe and effective prescribing.

High-dose Versus Low-dose Tranexamic Acid to Reduce Transfusion Requirements in Pediatric Scoliosis Surgery.

PubMed

Johnson, Daniel J; Johnson, Christine C; Goobie, Susan M; Nami, Nina; Wetzler, Joshua A; Sponseller, Paul D; Frank, Steven M

2017-12-01

Our objective was to quantify blood loss and transfusion requirements for high-dose and low-dose tranexamic acid (TXA) dosing regimens in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis. Previous investigators have established the efficacy of TXA in pediatric scoliosis surgery; however, the dosing regimens vary widely and the optimal dose has not been established. We retrospectively analyzed electronic medical records for 116 patients who underwent spinal fusion surgery for idiopathic scoliosis by a single surgeon and were treated with TXA. In total, 72 patients received a 10 mg/kg loading dose with a 1 mg/kg/h maintenance dose (low-dose) and 44 patients received 50 mg/kg loading dose with a 5 mg/kg/h maintenance dose (high-dose). Estimated blood loss and transfusion requirements were compared between dosing groups. Patient characteristics were nearly identical between the 2 groups. Compared with the low-dose TXA group, the high-dose TXA group had decreased estimated blood loss (695 vs. 968 mL, P=0.01), and a decrease in both intraoperative (0.3 vs. 0.9 units, P=0.01) and whole hospitalization (0.4 vs. 1.0 units, P=0.04) red blood cell transfusion requirements. The higher-dose TXA was associated with decreased intraoperative (P=0.01), and whole hospital transfusion (P=0.01) requirements, even after risk-adjustment for potential confounding variables. High-dose TXA is more effective than low-dose TXA in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery. Level-III, retrospective cohort study.

Pharmacokinetics and Pharmacodynamics of Twice Daily and Once Daily Regimens of Empagliflozin in Healthy Subjects.

PubMed

Macha, Sreeraj; Brand, Tobias; Meinicke, Thomas; Link, Jasmin; Broedl, Uli C

2015-08-01

This study was undertaken to compare the steady-state pharmacokinetic and pharmacodynamic properties of empagliflozin 5 mg twice daily (BID) and 10 mg once daily (QD) in healthy subjects. In an open-label, 2-way crossover study, subjects (n = 16) received empagliflozin 5 mg BID for 5 days and empagliflozin 10 mg QD for 5 days in a randomized order, with a washout period of ≥6 days between each treatment. The primary objective was the comparison of the overall exposure during a 24-hour period at steady state (AUC0-24,ss) for empagliflozin, based on standard bioequivalence criteria, with BID and QD dose regimens. The study population comprised 7 (43.8%) men and 9 (56.3%) women with a baseline median age of 38.0 years (range, 23-47 years) and a median body mass index of 23.3 kg/m(2) (range, 19.8-27.8 kg/m(2)). Based on standard bioequivalence criteria, there was no difference in the overall exposure of empagliflozin between BID and QD dose regimens (geometric mean ratio of AUC0-24,ss for empagliflozin 5 mg BID compared with empagliflozin 10 mg QD = 99.36%; 90% CI, 94.29-104.71). For empagliflozin 10 mg QD, mean (%CV) AUC during the dosing interval was 1900 nmol · h/L (20.6%), mean (%CV) Cmax,ss was 330 nmol/L (25.3%), and median (range) Tmax,ss was 1.0 hour (0.7-2.0 hours). For empagliflozin 5 mg BID, mean (%CV) AUC during the dosing interval was 1010 nmol · h/L (15.1%) and 867 nmol · h/L (18.6%) after the morning and evening dose, respectively, mean (%CV) Cmax,ss was 193 nmol/L (16.5%) and 120 nmol/L (21.0%), respectively, and median Tmax,ss was 1.0 hour (range, 0.7-2.0 hours) and 2.0 hours (range, 1.0-4.0 hours), respectively. The mean (%CV) cumulative amount of glucose excreted in urine during 24 hours was 52.1 g (32.1%) with empagliflozin 5 mg BID and 43.9 g (30.3%) with empagliflozin 10 mg QD. Adverse events were reported in six subjects (37.5%) receiving empagliflozin 5 mg BID and four (25.0%) receiving empagliflozin 10 mg QD. Headache was the most frequent AE. No severe, serious, or drug-related AEs were reported. There were no clinically relevant differences in pharmacokinetic or pharmacodynamic properties between BID and QD dose regimens of empagliflozin in healthy subjects. Both dose regimens were well tolerated. EU Clinical Trials Register (EudraCT) number: 2009-012524-90. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

PubMed Central

2011-01-01

Background Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU. Trial Registration The clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient. PMID:21619673

Tumor Control Outcomes After Hypofractionated and Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases From Renal Cell Carcinoma

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

Zelefsky, Michael J., E-mail: zelefskm@mskcc.org; Greco, Carlo; Motzer, Robert

2012-04-01

Purpose: To report tumor local progression-free outcomes after treatment with single-dose, image-guided, intensity-modulated radiotherapy and hypofractionated regimens for extracranial metastases from renal cell primary tumors. Patients and Methods: Between 2004 and 2010, 105 lesions from renal cell carcinoma were treated with either single-dose, image-guided, intensity-modulated radiotherapy to a prescription dose of 18-24 Gy (median, 24) or hypofractionation (three or five fractions) with a prescription dose of 20-30 Gy. The median follow-up was 12 months (range, 1-48). Results: The overall 3-year actuarial local progression-free survival for all lesions was 44%. The 3-year local progression-free survival for those who received a highmore » single-dose (24 Gy; n = 45), a low single-dose (<24 Gy; n = 14), or hypofractionation regimens (n = 46) was 88%, 21%, and 17%, respectively (high single dose vs. low single dose, p = .001; high single dose vs. hypofractionation, p < .001). Multivariate analysis revealed the following variables were significant predictors of improved local progression-free survival: 24 Gy dose compared with a lower dose (p = .009) and a single dose vs. hypofractionation (p = .008). Conclusion: High single-dose, image-guided, intensity-modulated radiotherapy is a noninvasive procedure resulting in high probability of local tumor control for metastatic renal cell cancer generally considered radioresistant according to the classic radiobiologic ranking.« less

[Sinusal penetration of amoxicillin-clavulanic acid. Formulation 1 g./125 mg., twice daily versus formulation 500 mg./125 mg., three times daily].

PubMed

Jehl, F; Klossek, J M; Peynegre, R; Serrano, E; Castillo, L; Bobin, S; Desprez, D; Renault, C; Neel, V; Rouffiac, E; Borie, C

2002-10-19

In order to meet the evolution of pneumococcus resistance to beta-lactam antibiotics, a new formulation of amoxicillin (AMX) and clavulanic acid (CA), with twice as much AMX (1 g/125 mg vs. 500 mg/125 mg) was developed for the treatment of acute pneumonia in patients at risk. This formulation can also be used in the treatment of acute maxillary sinusitis using a 1 g/125 mg regimen twice-daily. Compare the sinusal penetration of AMX and CA (1 g/125 mg twice-daily vs. 500 mg/125 mg three times a day) when administered at both regimens to demonstrate equivalent pharmacokinetic and pharmacodynamic behaviour of the former when compared to the latter. Concentrations of AMX and CA were measured in the anterior ethmoid, maxillary, posterior ethmoid sinus and in the middle nasa concha in 62 patients undergoing surgery for nasosinusal polyps. Patients randomised in two groups corresponding to 2 oral regimens, received either 1 g/125 mg twice a day or 500 mg/125 mg three times a day for 4 days. The last dose in both groups was administered 1 h 30, 3, 5 or 8 hrs prior to surgery. Serum samples were taken simultaneously to tissue samples. AMX and CA were measured by high performance liquid chromatography. Exogenous and above all endogenous blood contamination were taken into account with the hematocrit as well as blood and tissue haemoglobin concentrations. Comparisons of tissue concentrations were made for each sampling time, according to values obtained for a specific tissue with both doses on one hand, and on the other to values obtained with a specific dose in different tissues. The calculated pharmacodynamic parameters, which are considered to be predictive for bacteriological and clinical efficacy, result directly from tissue concentrations of AMX. tissue inhibitory quotients (IQtissue = Tissue concentration/MIC). time above MICs for serum and tissue concentrations (T > MIC). As regards AMX, whatever the dose, at 1 h 30 and at 3 hrs, tissue concentrations did not differ significantly whatever the tissue studied (from 1.1 to 2.5 micrograms/g). Conversely, at 5 and 8 hrs, they were greater than after the 1 g/125 mg regimen given twice-daily (0.06-0.7 vs. 0.7-1.8 micrograms/g). If we consider a given dose, the comparison between the various tissues showed identical concentrations in the four tissues studied at each sampling time, except in two cases with the dose of 500 mg/125 mg 3 times a day. T > MIC for serum and tissue showed higher values than those required for AMX/pneumococcus association (40-50%) with, nevertheless, greater tissue values for the 1 g/125 mg dose given twice-daily when MIC was of 1 microgram/ml (40-52% vs. 50-66%). The maximum tissue inhibitory quotients were also greater with the twice-daily 1 g/125 mg dose, when calculated with MIC 50 or 90 of S. Pneumoniae, H. influenzae, M. catarrhalis or S. pyogenes. As for CA, concentrations were equivalent for both doses at each sampling time and greater than those required in vitro during respectively 4 and 5 hours for beta-lactamases H. influenzae and M. catarrhalis. A least an equivalence between both dose regimens was observed, with occasionally a superiority of the twice-daily 1 g/125 mg dose, in terms of pharmacokinetics, tissue penetration and pharmacodynamics for both AMX and CA. This new regimen therefore appears more appropriate for the treatment of acute maxillary sinusitis in adults.

A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

PubMed

Daftarian, Pirouz M; Stone, Geoffrey W; Kovalski, Leticia; Kumar, Manoj; Vosoughi, Aram; Urbieta, Maitee; Blackwelder, Pat; Dikici, Emre; Serafini, Paolo; Duffort, Stephanie; Boodoo, Richard; Rodríguez-Cortés, Alhelí; Lemmon, Vance; Deo, Sapna; Alberola, Jordi; Perez, Victor L; Daunert, Sylvia; Ager, Arba L

2013-12-01

Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host. We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/LAmB vs full dose LAmB. PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice. PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.

Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog.

PubMed

Jeunesse, Elisabeth C; Schneider, Marc; Woehrle, Frederique; Faucher, Mathieu; Lefebvre, Herve P; Toutain, Pierre-Louis

2013-12-11

Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin-induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model). Analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs.For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD).The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 μg/L for creeping speed, 284 μg/L for the lameness score, 161 μg/L for the ground reaction vertical force and 193 μg/L for the body temperature.To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg/kg daily was determined for confirmatory clinical trials.

A novel and well tolerated mite allergoid subcutaneous immunotherapy: evidence of clinical and immunologic efficacy

PubMed Central

Roger, Albert; Depreux, Nathalie; Jurgens, Yani; Heath, Matthew D; Garcia, Gloria; Skinner, Murray A

2014-01-01

Allergy to house dust mite is one of the most common causes of allergic rhinitis. A novel tyrosine-adsorbed, modified allergen product, Acarovac Plus, developed for the treatment of perennial mite allergy seeks to address the underlying cause of allergic rhinitis in this instance. One of two dosing regimens may be used, either the Conventional Regimen or the Cluster Regimen. We sought to compare the efficacy and safety of a specific immunotherapy, developed for the treatment of perennial mite allergy, administered under a Conventional and Clustered dosing schedule in patients with persistent allergic rhinitis. Thirty adult patients, between 18 and 65 years old, with allergic rhinitis and/or asthma secondary to hypersensitivity to Dermatophagoides pteronyssinus were administered with either conventional or cluster initial regime, with a final visit one week after the last dose administration. The efficacy to the Conventional and Cluster regimens was measured using a Nasal Challenge Test monitoring clinical symptoms and peak nasal inspiratory flow. Total IgE, serum-specific inmunoglobulins (IgE and IgG4) to Dermatophagoides pteronyssinus and relevant cytokines (IFN-γ, IL-4, IL-5, IL-10 and IL-13) were assessed. A Satisfaction Questionnaire (TSQM) was completed after each patient's final visit. The tolerability of the vaccine was assessed monitoring adverse reactions. No adverse events were recorded in either conventional or cluster regime. The specific Nasal Challenge Test led to a decrease in symptom scores and a significant decrease in mean nasal peak inspiratory flow drop was recorded in both dosing regimen groups. A significant increase in IgG4-specific antibody titres was assessed. No significant changes were observed in concentrations of total IgE, specific IgE or cytokines (IFN-γ, IL-4, IL-5, IL-10 and IL-13). Patients declared themselves most satisfied in relation to “Secondary effects”, with high overall satisfaction in both groups. Cluster and conventional specific immunotherapy resulted in no adverse reaction(s) and led to similar improvements in immunological parameters, clinical efficacy (Nasal Challenge Test) and high overall satisfaction. PMID:25400929

Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog

PubMed Central

2013-01-01

Background Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin–induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model). Results Analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs. For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD). The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 μg/L for creeping speed, 284 μg/L for the lameness score, 161 μg/L for the ground reaction vertical force and 193 μg/L for the body temperature. To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. Conclusions Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg/kg daily was determined for confirmatory clinical trials. PMID:24330630

Choline magnesium trisalicylate: comparative pharmacokinetic study of once-daily and twice-daily dosages.

PubMed

Levitt, M J; Kann, J

1984-07-01

This randomized crossover study compared the pharmacokinetics of choline magnesium trisalicylate tablets administered once daily (3000 mg of salicylate) or twice daily (1500 mg of salicylate) for six d. Serum salicylate levels were measured by HPLC. Mean "trough" concentrations fell within the therapeutic range (5-30 mg/dL) with either regimen and were relatively constant, indicating that the steady state had been reached. The 24-h area under the salicylate curve (AUC0-24 h) after the final 3000-mg salicylate dose averaged about twice the mean 12-h AUC after the last 1500-mg dose, indicating that the two dosing regimens were equally bioavailable. Clinical observations and results of laboratory safety studies indicate that both dosage schedules of the drug are well tolerated. The present findings support the once-daily therapeutic use of choline magnesium trisalicylate.

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.

Results From the First‐in‐Human Study With Ozanimod, a Novel, Selective Sphingosine‐1‐Phosphate Receptor Modulator

PubMed Central

Hartung, Jeffrey P.; Peach, Robert J.; Boehm, Marcus F.; Rosen, Hugh; Smith, Heather; Brooks, Jennifer L.; Timony, Gregg A.; Olson, Allan D.; Gujrathi, Sheila; Frohna, Paul A.

2017-01-01

Abstract The sphingosine‐1‐phosphate 1 receptor (S1P1R) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune‐mediated, inflammatory diseases. This first‐in‐human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose‐escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose‐limiting toxicities. The most common ozanimod‐related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady‐state volume of distribution (73–101 L/kg), moderate oral clearance (204–227 L/h), and an elimination half‐life of approximately 17 to 21 hours. Ozanimod produced a robust dose‐dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose‐dependent negative chronotropic effect was observed following the first dose, with the dose‐escalation regimen attenuating the first‐dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once‐daily regimens under clinical investigation. PMID:28398597

Light delivery over extended time periods enhances the effectiveness of photodynamic therapy.

PubMed

Seshadri, Mukund; Bellnier, David A; Vaughan, Lurine A; Spernyak, Joseph A; Mazurchuk, Richard; Foster, Thomas H; Henderson, Barbara W

2008-05-01

The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high-irradiance treatments, recent preclinical and clinical studies have focused on low-irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose, and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model. Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations was evaluated. Magnetic resonance imaging and oxygen tension measurements were done along with the Evans blue exclusion assay to assess vascular response, oxygenation status, and tumor necrosis. In contrast to high-incident laser power (150 mW), low-power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens using treatment times of 120 to 240 min showed marked reduction in signal intensity in T2-weighted magnetic resonance images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared with short-duration (6-11 min) regimens. Significantly greater reductions in pO(2) were observed with extended exposures, which persisted after completion of treatment. These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor, and suggest that duration of light treatment (time) may be an important new treatment variable.

Light Delivery Over Extended Time Periods Enhances the Effectiveness of Photodynamic Therapy

PubMed Central

Seshadri, Mukund; Bellnier, David A.; Vaughan, Lurine A.; Spernyak, Joseph A.; Mazurchuk, Richard; Foster, Thomas H.; Henderson, Barbara W.

2009-01-01

Purpose The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high irradiance treatments, recent preclinical and clinical studies have focused on low irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model. Experimental Design Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations were evaluated. Magnetic resonance imaging (MRI) and oxygen tension measurements were performed along with the Evans blue exclusion assay to assess vascular response, oxygenation status and tumor necrosis. Results In contrast to high incident laser power (150 mW), low power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens utilizing treatment times of 120–240 mins showed marked reduction in signal intensity in T2-weighted MR images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared to short duration (6–11 mins) regimens. Significantly greater reductions in pO2 were observed with extended exposures, which persisted after completion of treatment. Conclusions These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor and suggest that duration of light treatment (time) may be an important new treatment parameter. PMID:18451247

Boron Neutron Capture Therapy for HER2+ breast cancers: A feasibility study evaluating BNCT for potential role in breast conservation therapies

NASA Astrophysics Data System (ADS)

Jenkins, Peter Anthony

A novel Boron Neutron Capture Therapy (BNCT) regimen for the treatment of HER2+ breast cancers has been proposed as an alternative to whole breast irradiation for breast conservation therapy patients. The proposed therapy regimen is based on the assumed production of boron delivery agents that would be synthesized from compounds of Trastuzumab (Herceptin ®) and oligomeric phosphate diesters (OPDs). The combination of the anti-HER2 monoclonal antibody and the high boron loading capability of OPDs has led to the assumption that boron could be delivered to the HER2+ cancer cells at Tumor to Healthy Tissue ratios (T:H) of up to 35:1 and boron concentrations above 50 μg/g. This significantly increased boron delivery efficiency has opened new BNCT possibilities. This proof of concept study examined treatment parameters derived as the results in previous efforts in the context of patient-specific geometry and compared calculated dose results to those observed during actual patient therapy. These results were based on dose calculations performed with a set of calculated Kerma coefficients derived from tissues specific to the regions of interest for breast cancer. A comparison was made of the dose to the tumor region, the patient's skin, and the peripheral organs. The results of this study demonstrated that, given the performance of the proposed boron delivery agent, the BNCT treatment regimen is feasible. The feasibility is based on the findings that the equivalent dose could be delivered to the treatment volume with less dose to the skin and peripheral organs. This is anticipated to improve the treatment outcomes by maintaining local control of tumor cells while reducing dose to healthy tissues.

Every-other-day Dosing of Oral Viscous Budesonide Is not Effective in the Management of Eosinophlic Esophagitis.

PubMed

Rubinstein, Eitan; Hait, Elizabeth E; Mitchell, Paul D; Lee, John J

2018-03-01

Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized histologically by esophageal eosinophilia. Oral viscous budesonide (OVB) is an effective treatment with remission rates reported between 55% and 87%; however, topical corticosteroids are associated with increased risk of candidal esophagitis and adrenal suppression. Attempts to decrease the daily dose of topical steroids have resulted in disease relapse. The objective of this study was to determine whether or not reducing the frequency of OVB administration would be effective in controlling esophageal eosinophilia in children and adolescents. Data were obtained by retrospective chart review of patients at Boston Children's Hospital diagnosed with EoE, based on endoscopic findings of >15 eosinophils per high power field (eos/HPF) on esophageal biopsies while on acid blockade. Patients with histologic evidence of response (<15 eos/HPF) while on daily OVB had been offered the option of maintenance therapy based on a Monday-Wednesday-Friday (MWF) dosing regimen. Changes in peak esophageal eosinophil counts over time were examined. Eight male patients ages 5 to 18 years attained clinical response while receiving daily OVB and were subsequently maintained on a MWF OVB dosing regimen for 3 to 7 months. All 8 patients showed an increase in peak esophageal eosinophils, with 7 of 8 (88%) experiencing disease relapse. In fact, the distribution of peak esophageal eosinophils after MWF dosing was not statistically different from peak levels at diagnosis (P = 0.95). An MWF dosing regimen of OVB was not effective at maintaining histologic response in children and adolescents with EoE. Larger prospective studies are warranted to confirm these results.

Differential pharmacodynamic effects of paclitaxel formulations in an intracranial rat brain tumor model.

PubMed

Zhou, Rong; Mazurchuk, Richard V; Tamburlin, Judith H; Harrold, John M; Mager, Donald E; Straubinger, Robert M

2010-02-01

Nano- and microparticulate carriers can exert a beneficial impact on the pharmacodynamics of anticancer agents. To investigate the relationships between carrier and antitumor pharmacodynamics, paclitaxel incorporated in liposomes (L-pac) was compared with the clinical standard formulated in Cremophor-EL/ethanol (Cre-pac) in a rat model of advanced primary brain cancer. Three maximum-tolerated-dose regimens given by intravenous administration were investigated: 50 mg/kg on day 8 (d8) after implantation of 9L gliosarcoma tumors; 40 mg/kg on d8 and d15; 20 mg/kg on d8, d11, and d15. Body weight change and neutropenia were assessed as pharmacodynamic markers of toxicity. The pharmacodynamic markers of antitumor efficacy were increase in lifespan (ILS) and tumor volume progression, measured noninvasively by magnetic resonance imaging. At equivalent doses, neutropenia was similar for both formulations, but weight loss was more severe for Cre-pac. No regimen of Cre-pac extended survival, whereas L-pac at 40 mg/kg x2 doses was well tolerated and mediated 26% ILS (p < 0.0002) compared with controls. L-pac at a lower cumulative dose (20 mg/kg x3) was even more effective (40% ILS; p < 0.0001). In striking contrast, the identical regimen of Cre-pac was lethal. Development of a novel semimechanistic pharmacodynamic model permitted quantitative hypothesis testing with the tumor volume progression data, and suggested the existence of a transient treatment effect that was consistent with sensitization or "priming" of tumors by more frequent L-pac dosing schedules. Therefore, improved antitumor responses of carrier-based paclitaxel formulations can arise both from dose escalation, because of reduced toxicity, and from novel carrier-mediated alterations of antitumor pharmacodynamic effects.

Investigating the Implications of a Variable RBE on Proton Dose Fractionation Across a Clinical Pencil Beam Scanned Spread-Out Bragg Peak

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

Marshall, Thomas I.; Chaudhary, Pankaj; Michaelidesová, Anna

2016-05-01

Purpose: To investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited. Methods and Materials: Human fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfractionmore » period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism. Results: Significant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens. Conclusions: The RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used by the modeling community for the optimization of fractionated proton therapy.« less

Increased medication compliance of liver transplant patients switched from a twice-daily to a once-daily tacrolimus-based immunosuppressive regimen.

PubMed

Eberlin, M; Otto, G; Krämer, I

2013-01-01

Compliance with immunosuppressive therapy plays a major role in the long-term success of liver transplantation. Thus, the development of strategies to promote compliance of liver transplant patients and its evaluation over time are of particular interest. The main objective of this study was to compare medication compliance rates among liver transplant patients over time after transplantation where switched from a twice- to once-daily tacrolimus-based regimen. Sixty-five liver transplant patients being administered tacrolimus-based therapy were classified into three subgroups with regard to time posttransplantation. Medication compliance with tacrolimus-based therapy was measured using an electronic medication event monitoring system over a 12-month period: for 6 months tacrolimus was administered twice-daily and for 6 months, once-daily. Dosing, taking, and timing compliance as well as drug holidays were compared intra-individually between twice- and once-daily intake and among the three subgroups. In addition, patient compliance and quality of life were evaluated using questionnaires. A per protocol analysis of electronically obtained data showed 63 patients to be eligible. The resulting dosing, taking, and timing compliance rates of the patients were higher during the once-daily dosing period. No significant differences in compliance rates with tacrolimus therapy were observed among three subgroups independent of the dosing regimen. More patients failed the correct timing of the evening compared to the morning dose. Missing doses occurred particularly during weekends. Compliance variables measured by questionnaires (Morisky score, self-report, Medication Experience Scale for Immunosuppressants (MESI) score) and the Hospital Anxiety and Depression Scale score were similar in the two dosing periods. The short-form health survey (SF-36) score was higher with once-daily intake. The high measured compliance rates did not vary significantly dependent upon the time after transplantation. Nevertheless, compliance rates were greater using once-daily tacrolimus dosing. Copyright © 2013 Elsevier Inc. All rights reserved.

[Pretreatment doses of antithymocyte globubin-fresenius for allogeneic hematopoietic stem cell transplantation for beta-thalassemia major].

PubMed

Li, Chunfu; Wang, Yanhua; Wu, Xuedong; Pei, Fuyu; He, Yuelin; Feng, Xiaoqin; Liu, Huaying

2012-05-01

To investigate the effects of different doses of antithymocyte globubin-fresenius (ATG-F) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with beta-thalassemia Major. Sixty-four children with beta-thalassemia major undergoing allo-HSCT were divided into two equal groups to receive ATG-F pretreatments at high (30 mg/kg) or low (15 mg/kg) doses as part of the conditioning regimen including mainly cyclophosphamide, busulfan, fludarabine, and thiotepa. The outcomes of the patients were compared between the two groups. No obvious difference were noted in the time to leukocyte and platelet engraftment between the two groups. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) appeared to be higher in the low-dose group than in the high-dose group (12.5% vs 9.4%). The incidence of grade III-IV aGVHD was also higher in the low dose group (12.5% vs 6.3%), but the difference was not statistically significant. Application of high-dose ATG-F was associated with a higher rate of probable and possible fungal infection (P<0.05). The two doses of ATG-F is feasible as a part of the conditioning regimen for allo-HSCT in children with beta-thalassemia major.

New regimens for intravenous acetylcysteine, where are we now?

PubMed

Bateman, D Nicholas; Dear, James W; Thomas, Simon H L

2016-01-01

Acetylcysteine has been used as a treatment for paracetamol overdose as a 20.25- or 21-h infusion for nearly 40 years. These regimens give 50% of the dose in the first 15 min or 1 h, and are associated with high rates of adverse reactions. A randomised controlled trial has demonstrated that a shorter (12 h) and simpler (two infusions) acetylcysteine regimen using a slower initial infusion rate produces lower rates of adverse events than the original 20.25-h regimen. However, this study was not sufficiently large to show therapeutic equivalence as a hepatoprotective therapy in paracetamol overdose. Two further studies are now reported, which also suggest lower rates of adverse reactions with lower initial rates of acetylcysteine administration. These modified regimens can now be accepted as better tolerated, but it is unlikely that a randomised study of sufficient size to demonstrate non-inferiority of any novel regimen would ever be funded. Against this background we suggest what can be done to establish the efficacy of these less toxic and potentially shorter alternative acetylcysteine regimens and to establish them into routine clinical use.

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

Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines.

PubMed

Kim, Dae Sik; Kang, Ka-Won; Lee, Se Ryeon; Park, Yong; Sung, Hwa Jung; Kim, Seok Jin; Choi, Chul Won; Kim, Byung Soo

2015-09-01

We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3 + 7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m(2)) or combination of intermediate-dose cytarabine (1 g/m(2)) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p = 0.045; RFS, 38.6 months vs. 11.0 months, p = 0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p = 0.001). This study suggests that high-dose cytarabine consolidation may produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification.

Effect of 2',3'-didehydro-3'-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies.

PubMed Central

Bilello, J A; Bauer, G; Dudley, M N; Cole, G A; Drusano, G L

1994-01-01

We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D4T) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HIV DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents. PMID:8092842

The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis.

PubMed

Concoff, Andrew; Sancheti, Parag; Niazi, Faizan; Shaw, Peter; Rosen, Jeffrey

2017-12-21

Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens. We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline. Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2-4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = -0.76; -0.98 to -0.53, 95% CI, P < 0.00001, and SMD = -0.36; -0.63 to -0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ≥5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2-4 injection subgroups. Overall, 2-4 and ≥5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2-4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.

Phase I and pharmacokinetic evaluation of floxuridine/leucovorin given on the Roswell Park weekly regimen.

PubMed

Creaven, P J; Rustum, Y M; Petrelli, N J; Meropol, N J; Raghavan, D; Rodriguez-Bigas, M; Levine, E G; Frank, C; Udvary-Nagy, S; Proefrock, A

1994-01-01

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (> 200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified.

Review article: new drug formulations, chemical entities and therapeutic approaches for the management of ulcerative colitis.

PubMed

Ng, S C; Kamm, M A

2008-10-01

Treatment options for ulcerative colitis (UC) are expanding with the development of novel drug formulations and dosing regimens and new chemical entities. Although the goals of medical therapy for UC remain unchanged, that is to induce and to maintain remission, focus has also centred on improving patient compliance, modifying the natural course of disease and healing the mucosa. To examine novel formulations, new chemical entities and novel therapeutic approaches to the management of UC. Searches for all studies related to UC treatment in Medline and abstracts from major national and international meetings published in the last 10 years. 5-Aminosalicylic acids (5-ASA) remain the standard first-line treatment for patients with mild to moderately active UC. New formulations with altered delivery, and new dosing regimens have demonstrated possible improvements in efficacy compared with historically available preparations and dosing patterns. Once-daily dosing, micropellet formulations,and high-dose tablets offer enhanced efficacy and improved compliance. 5-ASA is now recognized as a ligand for peroxisome proliferator activated receptor-gamma (PPAR-gamma) and it has a role as a chemo-preventive agent in long-standing UC. New colonic release corticosteroid formulations help to limit systemic toxicity; turmeric, tacrolimus and infliximab have shown promising results. New anti-inflammatory targeted therapies include an anti-CD3 antibody, selective integrin blockers, anti-IL-2 antibody and PPAR-gamma agonists. The evolution of novel oral 5-ASA formulations and dosage regimens,and recent development of new molecules have expanded the therapeutic armamentarium of UC.

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.

PubMed

Dietrich, Sascha; Pircher, Andreas; Endris, Volker; Peyrade, Frédéric; Wendtner, Clemens-Martin; Follows, George A; Hüllein, Jennifer; Jethwa, Alexander; Ellert, Elena; Walther, Tatjana; Liu, Xiyang; Dyer, Martin J S; Elter, Thomas; Brummer, Tilman; Zeiser, Robert; Hermann, Michael; Herold, Michael; Weichert, Wilko; Dearden, Claire; Haferlach, Torsten; Seiffert, Martina; Hallek, Michael; von Kalle, Christof; Ho, Anthony D; Gaehler, Anita; Andrulis, Mindaugas; Steurer, Michael; Zenz, Thorsten

2016-06-09

The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n = 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care. © 2016 by The American Society of Hematology.

Derivation of mean dose tolerances for new fractionation schemes and treatment modalities

NASA Astrophysics Data System (ADS)

Perkó, Zoltán; Bortfeld, Thomas; Hong, Theodore; Wolfgang, John; Unkelbach, Jan

2018-02-01

Avoiding toxicities in radiotherapy requires the knowledge of tolerable organ doses. For new, experimental fractionation schemes (e.g. hypofractionation) these are typically derived from traditional schedules using the biologically effective dose (BED) model. In this report we investigate the difficulties of establishing mean dose tolerances that arise since the mean BED depends on the entire spatial dose distribution, rather than on the dose level alone. A formula has been derived to establish mean physical dose constraints such that they are mean BED equivalent to a reference treatment scheme. This formula constitutes a modified BED equation where the influence of the spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 24 liver cancer patients for whom both proton and photon IMRT treatment plans were available. The results show that the standard BED equation—neglecting the spatial dose distribution—can overestimate mean dose tolerances for hypofractionated treatments by up to 20%. The shape difference between photon and proton dose distributions can cause 30-40% differences in mean physical dose for plans having identical mean BEDs. Converting hypofractionated, 5/15-fraction proton doses to mean BED equivalent photon doses in traditional 35-fraction regimens resulted in up to 10 Gy higher doses than applying the standard BED formula. The dose shape effect should be accounted for to avoid overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. Additionally, tolerances established for one treatment modality cannot necessarily be applied to other modalities with drastically different dose distributions, such as proton therapy. Last, protons may only allow marginal (5-10%) dose escalation if a fraction-size adjusted organ mean dose is constraining instead of a physical dose.

New onset somnambulism associated with different dosage of mirtazapine: a case report.

PubMed

Yeh, Yi-Wei; Chen, Chun-Hsiung; Feng, Hui-Ming; Wang, Sheng-Chiang; Kuo, Shin-Chang; Chen, Chih-Kang

2009-01-01

Somnambulism consists of variously complex behaviors that may result in harm to self or to others. Many different medications have been reported to induce somnambulism, and a few of them are newer antidepressants. A 40-year-old woman with history of major depression who experienced new onset somnambulism for successive 3 nights, whereas the antidepressant mirtazapine was increased from 30 to 45 mg/d. The notable and complex sleepwalking symptoms terminated dramatically on the first night after withdrawal of mirtazapine. There is clearly a cause-and-effect relationship between the treatment of higher-dosage mirtazapine and development of somnambulism. It might be related to the different affinities to 5-hydroxytryptamine 2 (5-HT(2)) and H(1) receptors at different dosages of mirtazapine, which explain the patient experiencing sleepwalking episodes exclusively at higher doses of mirtazapine. Clinical physicians should be aware of this adverse effect and taper or discontinue the regimen if sleepwalking develops.

Duration of treatment for asymptomatic bacteriuria during pregnancy.

PubMed

Widmer, Mariana; Lopez, Ivana; Gülmezoglu, A Metin; Mignini, Luciano; Roganti, Ariel

2015-11-11

A previous Cochrane systematic review has shown that antibiotic drug treatment of asymptomatic bacteriuria in pregnant women substantially decreases the risk of pyelonephritis and reduces the risk of preterm delivery. However, it is not clear whether single-dose therapy is as effective as longer conventional antibiotic treatment. To assess the effects of different durations of treatment for asymptomatic bacteriuria in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2015) and reference lists of identified articles. Randomized and quasi-randomized trials comparing antimicrobial therapeutic regimens that differed in duration (particularly comparing single dose with longer duration regimens) in pregnant women diagnosed with asymptomatic bacteriuria. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. We included 13 studies, involving 1622 women. All were comparisons of single-dose treatment with short-course (four- to seven-day) treatments. The risk of bias of trials included in this review was largely unclear, and most trials were at high risk of performance bias. The quality of the evidence was assessed using the GRADE approach. When the any antibiotic agent was used, the 'no cure' rate for asymptomatic bacteriuria in pregnant women was slightly lower for the short-course treatment over the single-dose treatment, although there was evidence of statistical heterogeneity (average risk ratio (RR) 1.28, 95% confidence interval (CI) 0.87 to 1.88; women = 1502, studies = 13; I² = 56%; very low quality evidence). Data from only good quality trials also showed better cure rates with short (four- to seven-day) regimens of the same microbial agent (average RR 1.72, 95% CI 1.27 to 2.33; women = 803, studies = two; I² = 0%; high quality evidence). There was no clear difference in the recurrence of asymptomatic bacteriuria rate between treatment and control groups, whether the same or different microbial agents were used (RR 1.13, 95% CI 0.77 to 1.66; 445 women studies = eight; I² = 0%; very low quality evidence). Differences were detected for low birthweight babies, favoring a short course (four- to seven-day treatment) of the same microbial agent, although the data come from a single trial (RR 1.65, 95% CI 1.06 to 2.57; 714 women; high quality evidence), but no differences were observed for preterm delivery (RR 1.17, 95% CI 0.77 to 1.78; women = 804; studies = three; I² = 23%; moderate quality) or pyelonephritis (RR 3.09, 95% CI 0.54 to 17.55; women = 102; studies = two; I² = 0%; very low quality evidence). Finally, single-dose treatment of any microbial agent was associated with a decrease in reports of 'any side effects' (RR 0.70, 95% CI 0.56 to 0.88; 1460 women, studies = 12; I² = 9%; low quality evidence). Evidence was downgraded for risk of bias concerns in trials contributing data and for imprecise effect estimates (wide confidence intervals crossing the line of no effect, and in some cases, small studies with few events). A single-dose regimen of antibiotics may be less effective than a short-course (four- to seven-day) regimen, but more evidence is needed from large trials measuring important outcomes, such as cure rate. Women with asymptomatic bacteriuria in pregnancy should be treated by the standard regimen of antibiotics until more data become available testing seven-day treatment compared with shorter courses of three- or five-day regimens.

Successful use of high-dose cytarabine in a patient with acute myeloid leukemia and severe hepatic dysfunction.

PubMed

Barker, Jacob A; Marini, Bernard L; Bixby, Dale; Perissinotti, Anthony J

2016-12-01

Acute myeloid leukemia is a hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and other tissues. Prognosis is poor with 5-year survival rates ranging from 5-65% depending on demographic and clinical features. Outcomes are worse for patients that have an antecedent myeloproliferative neoplasm that evolves to acute myeloid leukemia, with a survival rate of <10%. Treatment for acute myeloid leukemia has remained cytarabine and an anthracycline given in the standard 3 + 7 regimen. However, for patients with liver dysfunction this regimen, among many others, cannot be given safely. There is currently a lack of data regarding the use of cytarabine in patients with severe hepatic dysfunction. In this case report, we present a patient with secondary acute myeloid leukemia who successfully received a modified regimen of high-dose cytarabine while in severe hepatic dysfunction (bilirubin >15 mg/dL). © The Author(s) 2015.

Treatment of chancroid, 1997.

PubMed

Schmid, G P

1999-01-01

Since the 1993 treatment guidelines for sexually transmitted diseases were published by the Centers for Disease Control and Prevention, experience has indicated that the regimens recommended then remain largely effective. The recommended therapies--with azithromycin (1 g orally, once), ceftriaxone (250 mg intramuscularly, once), or erythromycin (500 mg orally, four times a day for 7 days)--appear highly effective in the United States; limited data from Kenya suggest that the ceftriaxone regimen may not be as effective there as it once was. The alternative regimen of ciprofloxacin proposed in 1993 (500 mg orally, twice a day for 3 days) is as effective as the recommended therapies, but new information indicates that single-dose therapy with 500 mg orally is not as effective as the use of either larger single doses or more prolonged therapy. Persons who are infected with human immunodeficiency virus (HIV) do not respond as well as those who are not HIV-infected, and males who are uncircumcised appear not to respond as well as those who are circumcised.

An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future.

PubMed

Pasipanodya, Jotam; Gumbo, Tawanda

2011-01-01

Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.

Dose-Effect Relationships for Recurrence of Keloid and Pterygium After Surgery and Radiotherapy

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

Kal, Henk B.; Veen, Ronald E.; Juergenliemk-Schulz, Ina M.

2009-05-01

Purpose: To show radiation dose-response relationships for recurrence of keloid and pterygium after radiotherapy following surgery. Methods and Materials: Using PubMed, we performed a retrospective review of articles reporting incidences and/or dose-response relationships for recurrence of keloid and pterygium after radiotherapy following surgery. The irradiation regimens identified were normalized by use of the linear-quadratic model; biologically effective doses (BEDs) were calculated. Results: For keloid recurrence after radiotherapy following keloid removal, with either teletherapy or brachytherapy, the recurrence rate after having delivered a BED greater than 30 Gy is less than 10%. For pterygium recurrence after bare sclera surgery and {supmore » 90}Sr {beta}-irradiation, a BED of about 30 Gy seems to be sufficient also to reduce the recurrence rate to less than 10%. Conclusions: Most of the doses in the radiotherapy schemes used for prevention of keloid recurrence after surgery are too low. In contrast, the doses applied in most regimens to prevent pterygium recurrence are too high. A scheme with a BED of 30 to 40 Gy seems to be sufficient to prevent recurrences of keloid as well as pterygium.« less

Efficacy of Continuous Dosing of Tadalafil Once Daily vs Tadalafil On Demand in Clinical Subgroups of Men With Erectile Dysfunction: A Descriptive Comparison Using the Integrated Tadalafil Databases.

PubMed

Brock, Gerald; Ni, Xiao; Oelke, Matthias; Mulhall, John; Rosenberg, Matt; Seftel, Allen; D'Souza, Deborah; Barry, Jane

2016-05-01

Various factors play a role in the development of erectile dysfunction (ED). To provide a descriptive comparison of erectile function response for tadalafil on-demand (PRN) and once-daily (OAD) dosing regimens in patients with common comorbid conditions, treatments, or risk factors that can be considered when treating ED. In total, 17 PRN and 4 OAD placebo-controlled studies were included in the integrated database in these pooled analyses. Data were analyzed from patients treated with placebo, tadalafil 10 mg (low dose), and 20 mg (high dose) for the PRN studies and placebo, tadalafil 2.5 mg (low dose), and 5 mg (high dose) for the OAD studies. The effects of tadalafil were measured using the International Index of Erectile Function administered from baseline to week 12. A descriptive comparison of the efficacy of tadalafil PRN vs OAD was examined in the clinical populations. Baseline characteristics of 4,354 men were comparable between the PRN and OAD groups, with differences seen only in the variables of race, body mass index (BMI) of at least 30 kg/m(2), and alcohol use. Tadalafil was efficacious at improving erectile function for all clinical populations, except for the low-dose OAD group, which demonstrated a weaker effect vs placebo than the high-dose OAD group, and the low- and high-dose PRN groups vs placebo for patients with BMI of at least 30 kg/m(2) for patients without a cardiovascular disorder, smokers, patients with ED duration shorter than 1 year, and patients without previous phosphodiesterase type 5 inhibitor use. Tadalafil was efficacious for patients with or without diabetes mellitus, arterial hypertension, hyperlipidemia, and alcohol use at baseline. Tadalafil OAD and PRN regimens showed efficacy in patients with ED. No clinical populations of patients with ED seemed to benefit overwhelmingly from one dose regimen over the other. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (``Ecstasy'')

NASA Astrophysics Data System (ADS)

Ricaurte, George A.; Yuan, Jie; Hatzidimitriou, George; Cord, Branden J.; McCann, Una D.

2002-09-01

The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or ``ecstasy'') is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

Dosimetric Anchoring of In Vivo and In Vitro Studies for Perfluorooctanoate and Perfluorooctanesulfonate

EPA Science Inventory

In order to compare between in vivo toxicity studies, dosimetry is needed to translate study-specific dose regimens into dose metrics such as tissue concentration. These tissue concentrations may then be compared with in vitro bioactivity assays to perhaps identify mechanisms rel...

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

PubMed

Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns.

PubMed

Dornelles, Laura Vargas; Corso, Andréa Lúcia; Silveira, Rita de Cássia; Procianoy, Renato Soibelmann

2016-01-01

To compare the efficacy of intravenous ibuprofen at high (20-10-10mg/kg/dose) and low doses (10-5-5mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p=0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p>0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p=0.86). There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

[Analysis of individualized primary prophylactic treatment of 19 cases of children with severe hemophilia A].

PubMed

Liu, G Q; Tang, L; Wu, X Y; Zhen, Y Z; Li, G; Chen, Z P; Wang, Y; Zhang, N N; Zhang, J S; Yu, G X; Wu, R H

2016-12-02

Objective: To study the current situation of primary prophylaxis in severe hemophilia A children and to explore rational regimen in order to provide evidence for the development of primary prophylaxis in China. Method: A retrospective clinical data collection and analysis was conducted for 19 severe hemophilia A children who received primary prophylaxis in Beijing Children's Hospital outpatient clinic between February 2011 and September 2015 and evaluated the regimen and efficacy. Result: (1) Primary prophylaxis regimen: the median beginning age 1.8 (range 0.5-2.9) years, the median FⅧ preparation using dosage 16.7 (8.0-23.5) U/(kg·time), the median using frequency was 1.0 (1.0-3.0) time/week. Eight cases among the patients received escalation of treatment intensity because of the poor bleeding control. (2) Efficacy: the median annual bleeding rate (ABR) was 1.9 (0-6.0) times/year, the median annual joint bleeding rate (AJBR) was 0 (0-3.3) times/year, without life threatening bleeding. All of them kept in 4th scale of Beijing Children Hospital daily activity level. The median annual factor consumption was 1 844 (840-5 040) U/kg. Conclusion: Low-dose primary prophylaxis regimen which were in low-dose /low frequencies and adjusted by bleeding frequency could decrease bleeding and joint bleeding frequency significantly, maintained the normal daily activity capacity and saved the factor consumption compared to standard regimen in severe hemophilia A children.

Comparison of a four-drug fixed-dose combination regimen with a single tablet regimen in smear-positive pulmonary tuberculosis.

PubMed

Bartacek, A; Schütt, D; Panosch, B; Borek, M

2009-06-01

To compare the efficacy, safety and acceptability of two short-course regimens of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) given either as fixed-dose combination (4-FDC) tablets or as single tablets (ST) in patients with newly diagnosed pulmonary tuberculosis (PTB). This randomised, open, multicentre, multinational study was conducted in 26 centres and included 1159 patients with smear-positive PTB. 4-FDC daily for 2 months then H+R for 4 months, or single preparations of H, R, Z and E for 2 months followed by H and R for 4 months were administered daily. Sputum smear conversion rates at 2, 4 and 6 months (end of treatment [EOT], primary endpoint) and at 9 and 12 months (follow-up) were measured, together with adverse events and the acceptability of the formulations. Smear conversion rates for 4-FDC and ST at EOT were 80.4% (468/582 patients) vs. 82.7% (477/577) in the intent-to-treat (ITT) population, and 98.1% (404/412) vs. 98.6% (416/422) in the per-protocol (PP) subgroup. Non-inferiority of 4-FDC was demonstrated at month 2, EOT and follow-up in both the ITT and the PP populations. Overall numbers of adverse events were not significantly different between the groups. The efficacy of the 4-FDC regimen was non-inferior to that of the ST regimens, but patient acceptability significantly improved with 4-FDC.

Analysis of clinical efficacy, side effects, and laboratory changes among patients with acne vulgaris receiving single versus twice daily dose of oral isotretinoin.

PubMed

Ahmad, Hesham M

2015-01-01

Acne vulgaris is a debilitating disorder and requires proper treatment. This work evaluates the clinical efficacy, side effects, and laboratory changes of serum lipids and liver function during oral isotretinoin therapy for acne vulgaris, comparing single versus twice daily dose. Fifty-eight patients with acne vulgaris were included and randomized into group I (26 patients), who received once daily dose, and group II (32 patients), who received twice daily dose of oral isotretinoin. Global acne scoring system was used to evaluate acne severity and post-treatment improvement. Both regimens resulted in highly significant clinical improvement of acne with no significant difference. However, side effects were significantly more common among patients of group I. Both regimens caused mild rise of serum cholesterol, alanine transaminase (ALT), and aspartate aminotransferase (AST) with more prominent rise of triglycerides especially with twice daily dose. Oral isotretinoin is a very effective treatment for acne vulgaris with no statistically significant difference in clinical efficacy between once and twice daily doses. However, dividing dose to twice per day might cause fewer incidence of side effects without reducing clinical efficacy. The drug causes mild clinically insignificant rise of serum cholesterol, triglycerides, AST, and ALT. © 2015 Wiley Periodicals, Inc.

Dose-dense weekly chemotherapy in advanced ovarian cancer: An updated meta-analysis of randomized controlled trials.

PubMed

Marchetti, C; De Felice, F; Di Pinto, A; D'Oria, O; Aleksa, N; Musella, A; Palaia, I; Muzii, L; Tombolini, V; Benedetti Panici, P

2018-05-01

The use of dose-dense weekly chemotherapy in the management of advanced ovarian cancer (OC) remains controversial. The aim of this meta-analysis was to evaluate the efficacy of dose-dense regimen to improve clinical outcomes in OC patients with the inclusion of new trials. For this updated meta-analysis, PubMed Medline and Scopus databases and meeting proceedings were searched for eligible studies with the limitation of randomized controlled trials, comparing dose-dense chemotherapy versus standard treatment. Trials were grouped in two types of dose-dense chemotherapy: weekly dose-dense (both paclitaxel and carboplatin weekly administration) and semi-weekly dose-dense (weekly paclitaxel and three weekly carboplatin administration). Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (http://www.cochrane.org). Primary end-point was progression-free survival (PFS). Four randomized controlled trials comprising 3698 patients were identified as eligible. Dose-dense chemotherapy had not a significant benefit on PFS (HR 0.92, 95% CI 0.81-1.04, p = 0.20). When the analysis was restricted to both weekly and semi-weekly dose-dense data, a no significant interaction between dose-dense and standard regimen was confirmed (HR 1.01, 95% CI 0.93-1.10 and HR 0.82, 95% CI 0.63-1.08, respectively). In the absence of PFS superiority of dose-dense schedule, three weekly schedule should remain the standard of care for advanced OC. Copyright © 2018 Elsevier B.V. All rights reserved.

Development of a twice daily dosing regimen of amoxicillin/clavulanate.

PubMed

Bax, Richard

2007-12-01

Amoxicillin/clavulanate was first launched as a three times daily dosage for the treatment of a range of community-acquired infections. A decade later, it became necessary to introduce a twice daily dosage for reasons of convenience, compliance and to remain competitive with other recently launched antibacterials. Twice daily formulations of amoxicillin/clavulanate were developed in which the amount of amoxicillin was increased relative to clavulanate to provide equivalent bacteriological and clinical efficacy with no change in the safety profile. Equivalence of the two dosing regimens was confirmed by randomised clinical trials in adults (in skin and soft tissue, urinary tract and lower respiratory tract infections, sinusitis and recurrent tonsillitis) and paediatrics (in lower respiratory tract infections, otitis media and recurrent tonsillitis). An improvement in the safety profile, specifically gastrointestinal effects, due to the reduced daily dose of clavulanate, was noted for all patients, but particularly in children.

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

PubMed

Home, Philip D; Dain, Marie-Paule; Freemantle, Nick; Kawamori, Ryuzo; Pfohl, Martin; Brette, Sandrine; Pilorget, Valérie; Scherbaum, Werner A; Vespasiani, Giacomo; Vincent, Maya; Balkau, Beverley

2015-05-01

It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

SU-E-T-289: Dose-Volume-Effect Relationships for Lung Cancer Patients Treated with SBRT On a Prospective Protocol

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

Mayyas, E; Brown, S; Liu, J

Purpose: Stereotactic body radiotherapy (SBRT) is commonly used to treat early stage lung tumors. This study was designed to evaluate associations between dose, volume and clinical outcomes including analysis of both clinical toxicity scores and quality of life (QOL) data for non-small cell lung cancer patients treated with SBRT. Preliminary results are presented. Methods: Sixty-seven NSCLC patients, 46 primarily with early stage, and 21 with recurrent disease were treated with dose regimens consisting mainly of 12 Gy x 4 fractions, and 3 or 5 fractions at lower dose, for patients with recurrent disease (Table 1). Follow-up data is being collectedmore » at baseline, after treatment and at 3, 6, 12, 18 and 24 months post-treatment. Clinical follow-up data acquired to date was assessed using the Charlson Comorbidity Clinical and Toxicity Scoring forms. QOL data was evaluated using the EQ-5D, and FACT-TOI validated surveys. All outcomes surveys are collected within an “in-house” developed outcomes database. Results: The median follow-up was 3.5±0.8 months. Mean lung doses (MLD) were converted to BED-2 Gy using the linear-quadratic model with an alpha/beta=3.0. Average MLD was 3.7+3.1 Gy (range: 0.4–20.9 Gy). The percentages of patients with > grade 2 cough, dyspnea and fatigue were 13.3, 17.0, 6.3%, respectively. Preliminary analyses (at 3 months after SBRT) show a mild correlation between MLD > 2 Gy and > grade 2 cough (borderline significant) and dyspnea (significant, p<0.05). One patient was observed with a grade 3 cough. Given the short follow-up, tumor control is not yet assessable. Conclusion: The SBRT dose fractionation regimen of 12 Gy x 4 was well tolerated at early time points. Additional follow-up is required to assess the long-term clinical outcome efficacy and toxicity profiles of the dose regimen.« less

Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support.

PubMed Central

van Warmerdam, L. J.; Rodenhuis, S.; van der Wall, E.; Maes, R. A.; Beijnen, J. H.

1996-01-01

The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR. PMID:8611435

Designing drug regimens for special intensive care unit populations

PubMed Central

Erstad, Brian L

2015-01-01

This review is intended to help clinicians design drug regimens for special populations of critically ill patients with extremes of body size, habitus and composition that make drug choice or dosing particularly challenging due to the lack of high-level evidence on which to make well-informed clinical decisions. The data sources included a literature search of MEDLINE and EMBASE with reviews of reference lists of retrieved articles. Abstracts of original research investigations and review papers were reviewed for their relevance to drug choice or dosing in the following special critically ill populations: patients with more severe forms of bodyweight or height, patients with amputations or missing limbs, pregnant patients, and patients undergoing extracorporeal membrane oxygenation or plasma exchange. Relevant papers were retrieved and evaluated, and their associated reference lists were reviewed for citations that may have been missed through the electronic search strategy. Relevant original research investigations and review papers that could be used to formulate general principles for drug choice or dosing in special populations of critically ill patients were extracted. Randomized studies with clinically relevant endpoints were not available for performing quantitative analyses. Critically ill patients with changes in body size, habitus and composition require special consideration when designing medication regimens, but there is a paucity of literature on which to make drug-specific, high-level evidence-based recommendations. Based on the evidence that is available, general recommendations are provided for drug choice or dosing in special critically ill populations. PMID:25938029

The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific.

PubMed

Elmes, N J; Nasveld, P E; Kitchener, S J; Kocisko, D A; Edstein, M D

2008-11-01

Tafenoquine is being developed for radical cure and post-exposure prophylaxis of Plasmodium vivax malaria. In an open-label study, 1512 Australian Defence Force personnel received one of three tafenoquine 3 d regimens [400 mg once daily (od), 200 mg twice daily (bid), 200 mg od] or daily primaquine (22.5 mg) plus doxycycline (100 mg) over 14 d in Bougainville and in Timor-Leste for post-exposure prophylaxis. The relapse rate of subjects treated in Bougainville with tafenoquine (n=173) was 1.2% (200 mg bid x 3 d) and 2.3% (400 mg od x 3 d), while primaquine plus doxycycline (n=175) was 3.4%. For subjects treated in Timor-Leste with tafenoquine (n=636), the relapse rate was 4.9% (200 mg od x 3 d), 5.3% (200 mg bid x 3 d) and 11.0% (400 mg od x 3d), while primaquine plus doxycycline (n=289) was 10.0%. The most frequent adverse events reported across all groups were nausea, abdominal distress and diarrhoea. There was a dose-dependent reduction in adverse events with a reduced dose of tafenoquine, with the lowest dose (total 600 mg over 3 d) producing rates of adverse events equivalent to that of primaquine plus doxycycline. The much shorter dosing regimen of tafenoquine should increase compliance, which is often suboptimal with primaquine after leaving an endemic area. [Australian New Zealand Clinical Trials Registry Number 12607000588493].

Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

PubMed

Biggin, Andrew; Briody, Julie N; Ormshaw, Elizabeth; Wong, Karen K Y; Bennetts, Bruce H; Munns, Craig F

2014-01-01

Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.

Antibiotic prophylaxis and complications following prostate biopsies - a systematic review.

PubMed

Klemann, Nina; Helgstrand, John Thomas; Brasso, Klaus; Vainer, Ben; Iversen, Peter; Røder, Martin Andreas

2017-01-01

Transrectal ultrasound-guided biopsies (TRUS-gb) are associated with both mild and serious complications. Prophylactic antibiotics reduce the risk of septicaemia and mortality; however, no international consensus exists on the timing and duration of antibiotics, including the optimal drug strategy. We reviewed the current evidence supporting use of prophylactic antibiotics and the risk of complications following prostate biopsies. This review was drafted in accordance with the Prisma Guidelines. The PubMed, Embase and Cochrane databases were searched. A total of 19 eligible trials were identified. One trial demonstrated a significant reduction in the risk of infection after biopsy and reported that oral ciprofloxacin as either a single-dose or a three-day regimen was superior to oral chloramphenicol and norfloxacin. Of three studies investigating the timing of the first dose of antibiotic, one study found that administration 24 h before biopsy versus administration immediately before reduced the relative risk of post-biopsy infection by 55%. Seven studies compared different durations of antibiotic prophylaxis. None showed any benefit from continuing prophylaxis beyond a single dose or a one-day regimen. Evidence supporting a specific antibiotic regimen for TRUS-gb prophylaxis is scarce. Widespread use of fluoroquinolone prophylaxis may be associated with an increase in resistant Escherichia coli strains, posing a potentially major health issue in the future.  .

Addition of Ceftriaxone and Amikacin to a Ciprofloxacin plus Metronidazole Regimen for Preventing Infectious Complications of Transrectal Ultrasound-Guided Prostate Biopsy: A Randomized Controlled Trial

PubMed Central

Izadpanahi, Mohammad-Hossein; Majidi, Seyed Mahmood; Khorrami, Mohammad-Hatef; Mohammadi-Sichani, Mehrdad

2017-01-01

Background. The objective of this study was to evaluate the efficacy of adding single doses of ceftriaxone and amikacin to a ciprofloxacin plus metronidazole regimen on the reduction of infectious complications following transrectal ultrasound-guided prostate biopsy (TRUS Bx). Materials and Methods. Four hundred and fifty patients who were candidates for TRUS Bx were divided into two groups of 225 each. The control group received ciprofloxacin 500 mg orally every 12 hours together with metronidazole 500 mg orally every 8 hours from the day prior to the procedure until the fifth postoperative day. In the second group, single doses of ceftriaxone 1 g by intravenous infusion and amikacin 5 mg/kg intramuscularly were administered 30–60 minutes before TRUS Bx in addition to the oral antimicrobials described for group 1. The incidence of infection was compared between the groups. Results. The incidence of infectious complications in the intervention group was significantly lower than that in the control group (4.6% versus 0.9%, p = 0.017). Conclusion. The addition of single doses of intramuscular amikacin and intravenously infused ceftriaxone to our prophylactic regimen of ciprofloxacin plus metronidazole resulted in a statistically significant reduction of infectious complications following TRUS Bx. PMID:28167960

Addition of Ceftriaxone and Amikacin to a Ciprofloxacin plus Metronidazole Regimen for Preventing Infectious Complications of Transrectal Ultrasound-Guided Prostate Biopsy: A Randomized Controlled Trial.

PubMed

Izadpanahi, Mohammad-Hossein; Nouri-Mahdavi, Kia; Majidi, Seyed Mahmood; Khorrami, Mohammad-Hatef; Alizadeh, Farshid; Mohammadi-Sichani, Mehrdad

2017-01-01

Background. The objective of this study was to evaluate the efficacy of adding single doses of ceftriaxone and amikacin to a ciprofloxacin plus metronidazole regimen on the reduction of infectious complications following transrectal ultrasound-guided prostate biopsy (TRUS Bx). Materials and Methods. Four hundred and fifty patients who were candidates for TRUS Bx were divided into two groups of 225 each. The control group received ciprofloxacin 500 mg orally every 12 hours together with metronidazole 500 mg orally every 8 hours from the day prior to the procedure until the fifth postoperative day. In the second group, single doses of ceftriaxone 1 g by intravenous infusion and amikacin 5 mg/kg intramuscularly were administered 30-60 minutes before TRUS Bx in addition to the oral antimicrobials described for group 1. The incidence of infection was compared between the groups. Results. The incidence of infectious complications in the intervention group was significantly lower than that in the control group (4.6% versus 0.9%, p = 0.017). Conclusion. The addition of single doses of intramuscular amikacin and intravenously infused ceftriaxone to our prophylactic regimen of ciprofloxacin plus metronidazole resulted in a statistically significant reduction of infectious complications following TRUS Bx.

Rationale for eliminating the hormone-free interval in modern oral contraceptives.

PubMed

London, Andrew; Jensen, Jeffrey T

2016-07-01

Although most low-dose combined oral contraceptives (COCs) include 7-day hormone-free intervals (HFIs), these COCs could incompletely suppress ovarian activity. To review the impact of HFIs on ovarian suppression and tolerability, and evaluate the utility of COCs without traditional 7-day HFIs. PubMed was searched for clinical studies published in English between January 1980 and April 2015 on the impact of HFIs and HFI modifications in COCs. Articles assessing contraceptive efficacy or tolerability as the primary focus were included. Abstracts of 319 articles were screened. Analysis of the 161 articles selected revealed that suppression of ovarian activity with low-dose COCs with 7-day HFIs is suboptimal. Loss of ovarian suppression during 7-day HFIs is commonly associated with follicular development, and most dominant follicles appear during this period. By contrast, increased ovarian suppression was noted in regimens that shortened or eliminated the HFI, or that substituted low-dose ethinyl estradiol for the HFI. Extended regimens with modified HFIs may provide greater ovarian suppression with the potential for increased contraceptive effectiveness. Additional research is needed to evaluate whether COC regimens that include 10μg ethinyl estradiol instead of an HFI may improve tolerability. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Gentamicin Nephrotoxicity in Subclinical Renal Disease.

NASA Astrophysics Data System (ADS)

Frazier, Donita L.

The purpose of the present study was to examine the pharmacokinetic disposition of gentamicin and to define the mechanisms which predispose to nephrotoxicity in subclinical renal disease. Subtotally nephrectomized beagle dogs were used as a model for human beings with compromised renal function secondary to a reduced number of functional nephrons. Using ultrastructural morphometry, light microscopy and clinical chemistry data, the model was defined and the nephrotoxic responses of intact dogs administered recommended doses of drug were compared to the response of subtotally nephrectomized dogs administered reduced doses based on each animal's clearance of drug. Lysosomal and mitochondrial morphometric changes suggested mechanisms for increased sensitivity. To determine if increased sensitivity in this model was dependent on altered serum concentrations, variable rate infusions based on individual pharmacokinetic disposition of drug were administered using computer-driven infusion pumps. Identical serum concentration-time profiles were achieved in normal dogs and subtotally nephrectomized dogs, however, toxicity was significantly greater in nephrectomized dogs. The difference in the nephrotoxic response was characterized by administering supratherapeutic doses of drug to dogs. Nephrectomized dogs given a recommended dose of gentamicin became oliguric during the second week of treatment and increasingly uremic after withdrawal of drug. In contrast, intact dogs administered 2 times the recommended dose of gentamicin become only slightly polyuric during week 4 of treatment. The need to individualize dosage regimens based on drug clearance and not serum creatinine nor creatinine clearance alone was substantiated by describing the pharmacokinetic disposition of gentamicin in spontaneously occurring disease states. Four individualized dosage regimens with differing predicted efficacy were then administered to nephrectomized dogs to determine their relative nephrotoxic potential. Conclusions from these studies include (1) nephrectomized dogs are more susceptible to gentamicin-induced nephrotoxicity than intact dogs, (2) sensitivity is not totally dependent on serum drug concentrations, (3) nephrectomized dogs have hypertrophied nephrons with subcellular alterations in proximal tubule cells, (4) unlike intact dogs, the toxic response in nephrectomized dogs is characterized by oliguria and irreversibility, (5) dosage regimens of aminoglycosides should be based on individual drug disposition since it varies greatly in spontaneous disease states and (6) altered dosage regimens may decrease toxicity and increase efficacy.

A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors.

PubMed

Bauer, Todd M; Patel, Manish R; Forero-Torres, Andres; George, Thomas J; Assad, Albert; Du, Yining; Hurwitz, Herbert

2018-01-01

Aberrant activation of the Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is associated with increased malignant cell proliferation and survival. This Phase Ib study evaluated ruxolitinib, a potent JAK1/2 inhibitor, in combination with gemcitabine with or without nab-paclitaxel in patients with advanced solid tumors. Patients received ruxolitinib + gemcitabine (regimen A) or ruxolitinib + gemcitabine + nab-paclitaxel (regimen B). The objective of the dose-finding phase was to identify the maximum tolerated doses (MTDs) of ruxolitinib plus gemcitabine with or without nab-paclitaxel. Among 42 patients enrolled, the median age was 62.5 years, 81.0% had pancreatic cancer, and almost 62% had received prior systemic therapy. Regimen A was tolerated with standard doses of gemcitabine; regimen B was tolerated with reduced doses of gemcitabine/nab-paclitaxel or concomitant granulocyte colony-stimulating factor. The sponsor decided to terminate the study early due to the interim analysis results of the Phase III JANUS 1 study. Discontinuations were mainly due to radiologic or clinical disease progression (81.0% of patients). Median treatment durations were 55.5 days (cohort A0) and 150.5 days (pooled B cohorts). Four patients (pooled B cohorts) had dose-limiting toxicities: grade 3 pneumonia (n=1), grade 4 neutropenia (n=1), and grade 4 thrombocytopenia (n=2). The most common grade 3/4 hematologic adverse events (AEs) were anemia, thrombocytopenia, and neutropenia. Serious AEs occurring in ≥2 patients in cohort A0 or pooled B cohorts were abdominal pain, sepsis (cohort A0), dehydration, anemia, and asthenia (pooled B cohorts). Overall response rates (ORRs) were 12.5% in cohort A0 and 38.5% in pooled B cohorts. Among patients with pancreatic cancer, ORR was 23.5% (14.0% cohort A0 30.0% pooled B cohorts). The study was terminated early prior to reaching MTDs per sponsor decision; although ruxolitinib plus gemcitabine with or without nab-paclitaxel was generally safe and well tolerated in patients with advanced solid tumors, this combination will not be pursued further.

Multicenter trial of prophylaxis with clindamycin plus aztreonam or cefotaxime in gynecologic surgery.

PubMed

Mangioni, C; Bianchi, L; Bolis, P F; Lomeo, A M; Mazzeo, F; Ventriglia, L; Scalambrino, S

1991-01-01

A prospective, randomized, multicenter study was conducted on the efficacy and safety of two prophylactic antibiotic regimens in both abdominal and vaginal hysterectomy. Patients received three intravenous doses of clindamycin (900 mg) plus either aztreonam (1 g) or cefotaxime (1 g); the doses were given at the induction of anesthesia and 8 and 16 hours later. A total of 170 patients undergoing abdominal hysterectomy and 142 patients undergoing vaginal hysterectomy completed the trial and were evaluated. Following abdominal hysterectomy infections occurred at the operative site in 1.2% of patients given a regimen including aztreonam and in 4.7% of those given a regimen including cefotaxime; the difference between the two groups was not significant. Neither were significant differences observed in the incidence of fever, the incidence of bacteriuria, the need for postoperative antibiotics, or the duration of postoperative hospitalization, although results were slightly better for patients receiving clindamycin plus aztreonam. Following vaginal hysterectomy, slightly but not significantly better results for the same parameters were obtained in the group given clindamycin plus cefotaxime. Diarrhea was the only adverse reaction attributable to antibiotic treatment and occurred more frequently in patients given cefotaxime. It was concluded that the two regimens were similarly effective and safe in preventing infections following hysterectomy.

Two medical abortion regimens for late first-trimester termination of pregnancy: a prospective randomized trial.

PubMed

Dalenda, Chelly; Ines, Najar; Fathia, Boudaya; Malika, Affes; Bechir, Zouaoui; Ezzeddine, Sfar; Hela, Chelly; Badis, Channoufi Mohamed

2010-04-01

Medical abortion regimens based on the use of either misoprostol alone or in association with mifepristone have shown high efficacy and excellent safety profile in early pregnancy abortion. However, no clear recommendation is available for late first-trimester termination of pregnancy. A prospective randomized controlled trial included 122 women seeking medical abortion at 9 to 12 weeks of gestation. Seventy-three patients were given a fixed protocol of 200 mg of mifepristone followed 48 h later by 400 mcg oral misoprostol (Group 1). The second group of 49 patients was administered 800-mcg intravaginal single-dose misoprostol (Group 2). This study sought to compare safety, efficacy and acceptability of these two nonsurgical abortion regimens. Fifty-nine (80.8%) women in Group 1 had complete abortion vs. 38 (77.4%) women in Group 2 (p=.66). Abdominal pain was observed significantly more often in Group 2 (35/49 (71.4%) vs. 32/73 (43.8%) in Group 1, p<.0001. Medical abortion was equally acceptable among the two groups [37/49 (75.5%) and 55/73 (75.7%), p=.89]. For late first-trimester termination, a single 800-mcg vaginal dose of misoprostol seems to be as effective as the mifepristone+misoprostol regimen, with acceptable side effects. Copyright 2010 Elsevier Inc. All rights reserved.

Adjuvant chemotherapy for osteosarcoma.

PubMed

Eilber, F R; Rosen, G

1989-08-01

From this review of chemotherapy trials, several observations can be made. Osteosarcoma is a complex disease involving multiple histologies, each with a different prognosis. Prognostic factors that have been shown to be important include anatomic location of the primary tumor, stage at presentation (patients with metastatic or local recurrent disease fair far worse than those with primary disease), age at onset (children fair worse than the teenager with osteosarcoma), and location within the extremity (patients with more distal tumors fairing better than patients with more proximal tumors). There is convincing evidence for the efficacy of chemotherapeutic agents such as methotrexate in high doses (at least 8 g/m2 for adults, 12 g/m2 for children), Adriamycin, and cisplatin. The combination of Adriamycin and cisplatin appears to be more beneficial relative to either one of these agents alone. The efficacy of the combination of BCD as a triple-drug regimen, although useful in several different trials, has not been convincingly shown. Finally, from several of the recent randomized trials, it appears, that chemotherapeutic regimens containing an Adriamycin and cisplatin combination appear to be superior to those that do not include this combination. However, these observations are made from a historical perspective and have not been conclusively proven by randomized prospective investigations. The observations concerning the natural history of the disease and the activity of various chemotherapeutic agents suggest certain clinical practice algorithms. Essential staging procedures would include a bone scan looking for multifocal or metastatic disease, and CT scans of the chest looking for metastases to the lung. From all studies, it is apparent that surgery is mandatory for the primary tumor and should be an integral portion of all treatment methods. Chemotherapy should be considered for all patients with osteosarcoma, and the essential drugs in the regimen appear at present to minimally include high-dose methotrexate, Adriamycin, and cisplatin. It would also appear from several of these reports that not only is the adjuvant use of these chemotherapeutic agents indicated, but that the preoperative use of these agents has had significant advantages. The neoadjuvant chemotherapy begins the essential systemic chemotherapy at a very early stage, allows histologic assessment of treatment effect, permits altering drug regimens postoperative, and in many reported trials has allowed less than amputative surgery (limb salvage) to be performed. Finally, close follow-up of patients with osteosarcoma has therapeutic value.(ABSTRACT TRUNCATED AT 400 WORDS)

A comparative 2-year study of the effects of sequential regimens of 1 mg 17beta-estradiol and trimegestone with a regimen containing estradiol valerate and norethisterone on the bleeding profile and endometrial safety in postmenopausal women.

PubMed

Koninckx, P R; Spielmann, D

2005-08-01

To compare the bleeding profiles and endometrial protection of two sequential regimens of 17beta-estradiol (17beta-E2) and trimegestone (TMG) with a sequential estradiol valerate (E2V)/norethisterone (NET) regimen. This was a randomized, double-blind, multicenter study conducted in eight countries in healthy, postmenopausal women with an intact uterus. A total of 1218 women were enrolled into the initial 1-year study (13 cycles), and subsequently 531 of these received treatment for a further year (26 cycles). Treatment regimens were 1 mg 17beta-E2 on days 1-14 and 1 mg 17beta-E2/0.125 mg TMG or 1 mg 17beta-E2/0.25 mg TMG on days 15-28, and 1 mg E2V on days 1-16 and 1 mg E2V/1 mg NET on days 17-28. Mean percentage of women reporting onset of withdrawal bleeding episodes during the week following discontinuation of progestogen was higher in the 1 mg 17beta-E2/0.25 mg TMG group than in the other two treatments, showing a more efficient progestogen effect on the endometrium and good predictability of bleeding onset with this treatment. The mean numbers and average lengths of bleeding episodes were similar in the three treatment groups. Overall, the bleeding profile was more favorable with 1 mg 17beta-E2/0.25 mg TMG than with the lower-dose TMG preparation. Both of the TMG regimens demonstrated a good protective effect on endometrial proliferation, with the 0.25 mg TMG dose showing a lower incidence of proliferative endometrium. The 1 mg 17beta-E2/0.25 mg TMG regimen showed an adequate protection of the endometrium, with an overall favorable bleeding profile.

Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India.

PubMed

Ranjalkar, Jaya; Mathew, Sumith K; Verghese, Valsan Philip; Bose, Anuradha; Rose, Winsley; Gupta, Dulari; Fleming, Denise H; Mathew, Binu Susan

2018-05-01

Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2-16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6 h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (C max ), the area under the concentration-time curve from 0-6 h (AUC 0-6h ) and treatment outcome were determined. Ninety-two percent of patients had an INH C max  > 3 µg/mL. Seventy-seven percent of patients had a RIF C max  < 8 µg/mL and 28% of patients had a RIF AUC 0-24h  < 13 mg ⋅ h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease.

PubMed

Tawfic, Qutaiba A; Faris, Ali S; Kausalya, Rajini

2014-02-01

Acute pain is one of the main causes of hospital admission in sickle cell disease, with variable intensity and unpredictable onset and duration. We studied the role of a low-dose intravenous (IV) ketamine-midazolam combination in the management of severe painful sickle cell crisis. A retrospective analysis was performed with data from nine adult patients who were admitted to the intensive care unit with severe painful sickle cell crises not responding to high doses of IV morphine and other adjuvant analgesics. A ketamine-midazolam regimen was added to the ongoing opioids as an initial bolus of ketamine 0.25mg/kg, followed by infusion of 0.2-0.25mg/kg/h. A midazolam bolus of 1mg followed by infusion of 0.5-1mg/h was added to reduce ketamine emergence reactions. Reduction in morphine daily requirements and improvement in pain scores were the determinants of ketamine-midazolam effect. The t-tests were used for statistical analysis. Nine patients were assessed, with mean age of 27±11 years. Morphine requirement was significantly lower after adding the IV ketamine-midazolam regimen. The mean±SD IV morphine requirement (milligram/day) in the pre-ketamine day (D0) was 145.6±16.5, and it was 112±12.2 on Day 1 (D1) of ketamine treatment (P=0.007). The Numeric Rating Scale scores on D0 ranged from eight to ten (mean 9.1), but improved to range from five to seven (mean 5.7) on D1. There was a significant improvement in pain scores after adding ketamine-midazolam regimen (P=0.01). Low-dose ketamine-midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis. Further controlled studies are required to prove this effect. Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

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.

The clinical efficacy of a clarithromycin-based regimen for Mycobacterium avium complex disease: A nationwide post-marketing study.

PubMed

Kadota, Jun-Ichi; Kurashima, Atsuyuki; Suzuki, Katsuhiro

2017-05-01

The revised 2007 American Thoracic Society/Infectious Diseases Society of America statement recommend clarithromycin-based combination therapy for treatment of Mycobacterium avium complex lung disease and stipulates approximately 1 year of continuous treatment after bacilli negative conversion. However, supporting data are insufficient. Our objective was to obtain data on the clinical outcome of clarithromycin-based daily regimens by conducting a nationwide retrospective post-marketing study of M. avium complex lung disease. In accordance with the Japanese guidelines, patients were enrolled in this survey according to their chest radiographic findings and microbiologic test results. They were treated with a multidrug regimen including clarithromycin, rifampicin, and ethambutol (clarithromycin-based regimen) until bacilli negative conversion, and the treatment was continued for approximately 1 year after the initial conversion. Data were collected before administration, at the time of bacilli negative conversion, at the end of treatment, and at 6 months after the end of treatment. Of the 466 subjects enrolled in the study, 271 patients who received clarithromycin at 800 mg/day underwent evaluation for M. avium complex disease. The final bacilli negative conversion rate in those patients was 94.7%. The bacteriological relapse rate was 5.0% (5/100 patients). Bacteriological relapse was noted in patients treated for less than 15 months after conversion. No life-threatening or serious adverse drug reactions were observed. This study demonstrated that a clarithromycin-based daily regimen can yield a high bacteriological conversion rate in M. avium complex disease. After conversion, treatment for less than 15 months might be insufficient to prevent bacteriological relapse. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Human papillomavirus-associated oropharynx cancer (HPV-OPC): treatment options.

PubMed

Chau, Nicole G; Rabinowits, Guilherme; Haddad, Robert I

2014-12-01

Human papillomavirus-associated oropharynx cancer (HPV-OPC) is growing in incidence and has distinct clinical, pathologic, molecular, and epidemiologic features. However, the management of HPV-OPC does not presently differ from HPV-negative OPC based on the current evidence and requires complex multidisciplinary approaches. The superior prognosis of HPV-OPC and the toxicities of current multimodality treatment in a young population serve as the impetus to evaluate de-intensification treatment regimens aimed at reducing toxicity while maintaining therapeutic efficacy. Clinical trials are underway to evaluate reduced doses of radiation or less toxic systemic therapy regimens in HPV-OPC. Minimally invasive surgical approaches in the HPV-OPC population with early tumor stage also are being investigated. De-intensification strategies should only be employed in the context of clinical trials, and HPV-OPC patients should be offered clinical trials' participation. Appropriate patient selection is critical to the development of de-intensification regimens, and this requires greater understanding of risk factors within the HPV-OPC population, HPV-OPC biology, and how HPV modulates response to specific therapies. Smoking history and bulky nodal disease have been shown to impact negatively the favorable prognosis of HPV association. Validated biomarkers within the HPV-OPC population are lacking, although alterations in the PI3K pathway and markers of immune response may emerge as important considerations in the future. Novel therapeutic strategies are desperately needed particularly for HPV-OPC patients who fail definitive therapy, and select patients with recurrent or metastatic disease may benefit from aggressive approaches.

Penicillin dosing for pneumococcal pneumonia.

PubMed

Bryan, C S; Talwani, R; Stinson, M S

1997-12-01

Most textbook authors still endorse penicillin G as the specific antibiotic of choice for pneumococcal pneumonia. However, problems with early precise etiologic diagnosis of pneumonia and the emergence of drug-resistant pneumococci cause penicillin to be seldom used for this purpose today. A third explanation for the infrequent use of penicillin is lack of clear consensus dosing guidelines. Emergence of pneumococci resistant to the newer cephalosporins and concerns about overuse of vancomycin, however, have prompted renewed interest in the development of precise, rapid methods for diagnosis of pneumococcal pneumonia with the implication that penicillin might be used more frequently. We review several issues concerning penicillin dosing: intermittent vs continuous therapy, high dose vs low dose, relationship of dose to resistance, and cost-effective pharmacology. An optimum "high-dose" regimen for life-threatening pneumococcal pneumonia in a 70-kg adult consists of a 3 million unit (mu) loading dose followed by continuous infusion of 10 to 12 mu of freshly prepared drug every 12 h. The maintenance dose should be reduced in elderly patients and in patients with renal failure according to the following formula: dose (mu/24 h = 4+[creatinine clearance divided by 7]). This regimen provides a penicillin serum level of 16 to 20 microg/mL, which should suffice for all but the most highly resistant strains (minimum inhibitory concentration > or = 4 microg/mL). Newer cephalosporins and vancomycin can be reserved for patients with suspected meningitis or endocarditis or for localities in which highly resistant pneumococci are known to be prevalent.

Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after single and multiple oral administration: A comparative study in the rat.

PubMed

Gonçalves, Daniela; Alves, Gilberto; Fortuna, Ana; Soares-da-Silva, Patrício; Falcão, Amílcar

2017-05-15

Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n=8 per group) were orally treated with single (30, 60 or 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24h post-dosing through a cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration≤2h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30-90mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58-4.50h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen. Copyright © 2017 Elsevier Inc. All rights reserved.

Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies.

PubMed

Cirik, Derya Akdag; Kinay, Tugba; Keskin, Ugur; Ozden, Eda; Altay, Metin; Gelisen, Orhan

2016-04-01

To compare the success of the single-dose methotrexate regimen and the requirement for a second or third dose of methotrexate between women with their first ectopic pregnancy (EP) and those with previous EP. In a retrospective cohort study, data were analyzed from women treated for EP by single-dose methotrexate at a Turkish tertiary referral center between January 2010 and December 2013. Data were compared between women with at least one previous EP and those with their first EP. The success rate of the protocol in the first and previous EP groups was similar: 93.0% (320/344) and 87.3% (48/55), respectively. History of previous EP was not a predictor of treatment failure. However, the requirement for additional methotrexate doses was significantly higher in the previous EP group (16/48 [33.4%]) than in the first EP group (55/320 [17.2%]; P=0.03). Multivariate analysis showed that history of tubal surgery (P=0.006) and initial levels of the β-subunit of human chorionic gonadotropin (P=0.001) were significant predictors of treatment failure. Although the single-dose regimen had similar success rates in the previous EP and first EP groups, additional doses of methotrexate were more frequently required in the previous EP group. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Glecaprevir + pibrentasvir for treatment of hepatitis C.

PubMed

Carrion, Andres F; Martin, Paul

2018-03-01

Glecaprevir/pibrentasvir is a fixed-dose combination regimen of a new generation NS3/4A inhibitor and an NS5A inhibitor with potent antiviral activity against all hepatitis C virus (HCV) genotypes. This regimen offers a shorter course of therapy (8 weeks) for selected patients regardless of genotype and has demonstrated high virological efficacy for retreatment of individuals who previously failed an NS5A containing regimen. Glecaprevir and pibrentasvir are minimally excreted by the kidneys; thus this regimen can safely be used in individuals with severe chronic kidney disease (CKD), including those undergoing hemodialysis. Areas covered: This review covers the mechanism of action, pharmacokinetics, clinical applications, efficacy, and safety profile of glecaprevir/pibrentasvir. It also covers key phase 2 and 3 clinical trials that led to licensure of this regimen. Expert opinion: Glecaprevir/pibrentasvir is the latest antiviral regimen licensed in the United States for treatment of HCV infection. Although several other direct-acting antiviral agents (DAAs) are currently available, glecaprevir/pibrentasvir has some unique characteristics that expand treatment options for HCV infection, including patients with comorbidities such as advanced stage CKD or prior treatment failure to antiviral regimens containing other DAAs.

Pharmacokinetic Dashboard-Recommended Dosing Is Different than Standard of Care Dosing in Infliximab-Treated Pediatric IBD Patients.

PubMed

Dubinsky, Marla C; Phan, Becky L; Singh, Namita; Rabizadeh, Shervin; Mould, Diane R

2017-01-01

Standard of care (SOC; combination of 5-10 mg/kg and an interval every 6-8 weeks) dosing of infliximab (IFX) is associated with significant loss of response. Dashboards using covariates that influence IFX pharmacokinetics (PK) may be a more precise way of optimizing anti-TNF dosing. We tested a prototype dashboard to compare forecasted dosing regimens with actual administered regimens and SOC. Fifty IBD patients completing IFX induction were monitored during maintenance (weeks 14-54). Clinical and laboratory data were collected at each infusion; serum was analyzed for IFX concentrations and anti-drug antibodies (ADA) at weeks 14 and 54 (Prometheus Labs, San Diego). Dosing was blinded to PK data. Dashboard-based assessments were conducted on de-identified clinical, laboratory, and PK data. Bayesian algorithms were used to forecast individualized troughs and determine optimal dosing to maintain target trough concentrations (3 μg/mL). Dashboard forecasted dosing post-week 14 was compared to actual administered dose and frequency and SOC. Using week 14 clinical data only, the dashboard recommended either a dose or an interval change (<0.5 mg/kg or <1 week difference) in 43/50 patients; only 44% recommended to have SOC dosing. When IFX14 concentration and ADA status were added to clinical data, dose and/or interval changes based on actual dosing were recommended in 48/50 (96%) patients; SOC dosing was recommended in only 11/50 (22%). Dashboard recommended SOC IFX dosing in a minority of patients. Dashboards will be an important tool to individualize IFX dosing to improve treatment durability.

Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins.

PubMed

Ternant, David; Paintaud, Gilles

2005-09-01

Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell's receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration-effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration-effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose-response relationships must be studied by PK-PD modelling.

Immunogenicity, safety and antibody persistence of a purified vero cell cultured rabies vaccine (Speeda) administered by the Zagreb regimen or Essen regimen in post-exposure subjects.

PubMed

Shi, Nianmin; Zhang, Yibin; Zheng, Huizhen; Zhu, Zhenggang; Wang, Dingming; Li, Sihai; Li, Yuhua; Yang, Liqing; Zhang, Junnan; Bai, Yunhua; Lu, Qiang; Zhang, Zheng; Luo, Fengji; Yu, Chun; Li, Li

2017-06-03

To compare the safety, immunogenicity and long-term effect of a purified vero cell cultured rabies vaccine in post-exposure subjects following 2 intramuscular regimens, Zagreb or Essen regimen. Serum samples were collected before vaccination and on days 7, 14, 42, 180 and 365 post vaccination. Solicited adverse events were recorded for 7 d following each vaccine dose, and unsolicited adverse events throughout the entire study period. This study was registered with ClinicalTrials.gov (NCT01821911 and NCT01827917). No serious adverse events were reported. Although Zagreb regimen had a higher incidence of adverse reactions than Essen regimen at the first and second injection, the incidence was similar at the third and fourth injection between these 2 groups as well. At day 42, 100% subjects developed adequate rabies virus neutralizing antibody concentrations (≥ 0.5IU/ml) for both regimens. At days 180 and 365, the antibody level decreased dramatically, however, the percentage of subjects with adequate antibody concentrations still remained high (above 75% and 50% respectively). None of confirmed rabies virus exposured subjects had rabies one year later, and percentage of subjects with adequate antibody concentrations reached 100% at days 14 and 42. Rabies post-exposure prophylaxis vaccination with PVRV following a Zagreb regimen had a similar safety, immunogenicity and long-term effect to the Essen regimen in China.

Strategies to tackle the challenges of external beam radiotherapy for liver tumors.

PubMed

Lock, Michael I; Klein, Jonathan; Chung, Hans T; Herman, Joseph M; Kim, Edward Y; Small, William; Mayr, Nina A; Lo, Simon S

2017-05-18

Primary and metastatic liver cancer is an increasingly common and difficult to control disease entity. Radiation offers a non-invasive treatment alternative for these patients who often have few options and a poor prognosis. However, the anatomy and aggressiveness of liver cancer poses significant challenges such as accurate localization at simulation and treatment, management of motion and appropriate selection of dose regimen. This article aims to review the options available and provide information for the practical implementation and/or improvement of liver cancer radiation programs within the context of stereotactic body radiotherapy and image-guided radiotherapy guidelines. Specific patient inclusion and exclusion criteria are presented given the significant toxicity found in certain sub-populations treated with radiation. Indeed, certain sub-populations, such as those with tumor thrombosis or those with larger lesions treated with transarterial chemoembolization, have been shown to have significant improvements in outcome with the addition of radiation and merit special consideration. Implementing a liver radiation program requires three primary challenges to be addressed: (1) immobilization and motion management; (2) localization; and (3) dose regimen and constraint selection. Strategies to deal with motion include simple internal target volume (ITV) expansions, non-gated ITV reduction strategies, breath hold methods, and surrogate marker methods to enable gating or tracking. Localization of the tumor and organs-at-risk are addressed using contrast infusion techniques to take advantage of different normal liver and cancer vascular anatomy, imaging modalities, and margin management. Finally, a dose response has been demonstrated and dose regimens appear to be converging. A more uniform approach to treatment in terms of technique, dose selection and patient selection will allow us to study liver radiation in larger and, hopefully, multicenter randomized studies.

Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit

PubMed Central

Yamane, Hiroshi; Takakura, Aya; Shimadzu, Yukari; Kodama, Toshiyuki; Lee, Ji-Won; Isogai, Yukihiro; Ishizuya, Toshinori; Takao-Kawabata, Ryoko

2017-01-01

Teriparatide [human parathyroid hormone (1–34)], which exerts an anabolic effect on bone, is used for the treatment of osteoporosis in patients who are at a high risk for fracture. That the once-daily administration of teriparatide causes an increase in cortical porosity in animal models and clinical studies has been a matter of concern. However, it is not well documented that the frequency of administration and/or the total dose of teriparatide affect the cortical porosity. The present study developed 4 teriparatide regimens [20 μg/kg/day (D20), 40 μg/kg/day (D40), 140 μg/kg/week (W140) and 280 μg/kg/week (W280)] in the rabbit as a model animal with a well-developed Haversian system and osteons. The total weekly doses were equivalent in the low-dose groups (D20 and W140) and in the high-dose groups (D40 and W280). After the short-term (1 month) administration of TPDT, micro-CT, histomorphometry and three-dimensional second harmonic generation (3D-SHG) imaging to visualize the bone collagen demonstrated that daily regimens but not weekly regimens were associated with the significant development of cortical porosity and endosteal naïve bone formation by marrow fibrosis. We concomitantly monitored the pharmacokinetics of the plasma teriparatide levels as well as the temporal changes in markers of bone formation and resorption. The analyses in the present study suggested that the daily repeated administration of teriparatide causes more deleterious changes in the cortical microarchitecture than the less frequent administration of higher doses. The findings of the present study may have some implications for use of teriparatide in clinical treatment. PMID:28394900

Neutrophil dynamics during concurrent chemotherapy and G-CSF administration: Mathematical modelling guides dose optimisation to minimise neutropenia.

PubMed

Craig, Morgan; Humphries, Antony R; Nekka, Fahima; Bélair, Jacques; Li, Jun; Mackey, Michael C

2015-11-21

The choice of chemotherapy regimens is often constrained by the patient's tolerance to the side effects of chemotherapeutic agents. This dose-limiting issue is a major concern in dose regimen design, which is typically focused on maximising drug benefits. Chemotherapy-induced neutropenia is one of the most prevalent toxic effects patients experience and frequently threatens the efficient use of chemotherapy. In response, granulocyte colony-stimulating factor (G-CSF) is co-administered during chemotherapy to stimulate neutrophil production, increase neutrophil counts, and hopefully avoid neutropenia. Its clinical use is, however, largely dictated by trial and error processes. Based on up-to-date knowledge and rational considerations, we develop a physiologically realistic model to mathematically characterise the neutrophil production in the bone marrow which we then integrate with pharmacokinetic and pharmacodynamic (PKPD) models of a chemotherapeutic agent and an exogenous form of G-CSF (recombinant human G-CSF, or rhG-CSF). In this work, model parameters represent the average values for a general patient and are extracted from the literature or estimated from available data. The dose effect predicted by the model is confirmed through previously published data. Using our model, we were able to determine clinically relevant dosing regimens that advantageously reduce the number of rhG-CSF administrations compared to original studies while significantly improving the neutropenia status. More particularly, we determine that it could be beneficial to delay the first administration of rhG-CSF to day seven post-chemotherapy and reduce the number of administrations from ten to three or four for a patient undergoing 14-day periodic chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pharmacokinetics after intravenous, subcutaneous, and oral administration of enrofloxacin to alpacas.

PubMed

Gandolf, A Rae; Papich, Mark G; Bringardner, Amy B; Atkinson, Mark W

2005-05-01

To determine plasma concentrations of enrofloxacin and the active metabolite ciprofloxacin after p.o, s.c., and i.v. administration of enrofloxacin to alpacas. 6 adult female alpacas. A crossover design was used for administration of 3 single-dose treatments of enrofloxacin to alpacas, which was followed by an observational 14-day multiple-dose regimen. Single-dose treatments consisted of i.v. and s.c. administration of injectable enrofloxacin (5 mg/kg) and p.o administration of enrofloxacin tablets (10 mg/kg) dissolved in grain to form a slurry. Plasma enrofloxacin concentrations were measured by use of high-performance liquid chromatography. The multiple-dose regimen consisted of feeding a mixture of crushed and moistened enrofloxacin tablets mixed with grain. Behavior, appetite, and fecal quality were monitored throughout the 14-day treatment regimen and for 71 additional days following treatment. Mean half-life following i.v., s.c., and p.o. administration was 11.2, 8.7, and 16.1 hours, respectively. For s.c. and p.o administration, mean total systemic availability was 90.18% and 29.31%, respectively; mean maximum plasma concentration was 3.79 and 1.81 microg/mL, respectively; and area under the curve (AUC) was 50.05 and 33.97 (microg x h)/mL, respectively. The s.c. or p.o administration of a single dose of enrofloxacin yielded a ratio for AUC to minimum inhibitory concentration > 100 for many grampositive and gram-negative bacterial pathogens common to camelids. Conclusions and Clinical Relevance-The administration of enrofloxacin (5 mg/kg, s.c., or 10 mg/kg, p.o) may be appropriate for antimicrobial treatment of alpacas.

Strategies to tackle the challenges of external beam radiotherapy for liver tumors

PubMed Central

Lock, Michael I; Klein, Jonathan; Chung, Hans T; Herman, Joseph M; Kim, Edward Y; Small, William; Mayr, Nina A; Lo, Simon S

2017-01-01

Primary and metastatic liver cancer is an increasingly common and difficult to control disease entity. Radiation offers a non-invasive treatment alternative for these patients who often have few options and a poor prognosis. However, the anatomy and aggressiveness of liver cancer poses significant challenges such as accurate localization at simulation and treatment, management of motion and appropriate selection of dose regimen. This article aims to review the options available and provide information for the practical implementation and/or improvement of liver cancer radiation programs within the context of stereotactic body radiotherapy and image-guided radiotherapy guidelines. Specific patient inclusion and exclusion criteria are presented given the significant toxicity found in certain sub-populations treated with radiation. Indeed, certain sub-populations, such as those with tumor thrombosis or those with larger lesions treated with transarterial chemoembolization, have been shown to have significant improvements in outcome with the addition of radiation and merit special consideration. Implementing a liver radiation program requires three primary challenges to be addressed: (1) immobilization and motion management; (2) localization; and (3) dose regimen and constraint selection. Strategies to deal with motion include simple internal target volume (ITV) expansions, non-gated ITV reduction strategies, breath hold methods, and surrogate marker methods to enable gating or tracking. Localization of the tumor and organs-at-risk are addressed using contrast infusion techniques to take advantage of different normal liver and cancer vascular anatomy, imaging modalities, and margin management. Finally, a dose response has been demonstrated and dose regimens appear to be converging. A more uniform approach to treatment in terms of technique, dose selection and patient selection will allow us to study liver radiation in larger and, hopefully, multicenter randomized studies. PMID:28588749

Concurrent Etoposide, Steroid, High-dose Ara-C and Platinum chemotherapy with radiation therapy in localised extranodal natural killer (NK)/T-cell lymphoma, nasal type.

PubMed

Michot, Jean-Marie; Mazeron, Renaud; Danu, Alina; Lazarovici, Julien; Ghez, David; Antosikova, Anna; Willekens, Christophe; Chamseddine, Ali N; Minard, Veronique; Dartigues, Peggy; Bosq, Jacques; Carde, Patrice; Koscielny, Serge; De Botton, Stéphane; Ferme, Christophe; Girinsky, Theodore; Ribrag, Vincent

2015-11-01

Radiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen. An induction phase with two upfront courses of CCRT delivering a 40Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2-3 cycles of ESHAP chemotherapy alone. Thirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3-4 haematological toxicity. The main non-haematological grade 3-4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%. With optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type. Copyright © 2015 Elsevier Ltd. All rights reserved.

Economic evaluation of 3-drug antiretroviral regimens for the prevention of mother-to-child HIV transmission in Thailand.

PubMed

Werayingyong, Pitsaphun; Phanuphak, Nittaya; Chokephaibulkit, Kulkunya; Tantivess, Sripen; Kullert, Nareeluk; Tosanguan, Kakanang; Butchon, Rukmanee; Voramongkol, Nipunporn; Boonsuk, Sarawut; Pilasant, Songyot; Kulpeng, Wantanee; Teerawattananon, Yot

2015-03-01

The current program for prevention of mother-to-child HIV transmission in Thailand recommends a 2-drugs regimen for HIV-infected pregnant women with a CD4 count >200 cells/mm(3). This study assesses the value for money of 3 antiretroviral drugs compared with zidovudine (AZT)+single-dose nevirapine (sd-NVP). A decision tree was constructed to predict costs and outcomes using the governmental perspective for assessing cost-effectiveness of 3-drug regimens: (1) AZT, lamivudine, and efavirenz and (2) AZT, 3TC, and lopinavir/ritonavir, in comparison with the current protocol, AZT+sd-NVP. The 3-drug antiretroviral regimens yield lower costs and better health outcomes compared with AZT+sd-NVP. Although these 3-drug regimens offer higher program costs and health care costs for premature birth, they save money significantly in regard to pediatric HIV treatment and treatment costs for drug resistance in mothers. The 3-drug regimens are cost-saving interventions. The findings from this study were used to support a policy change in the national recommendation. © 2013 APJPH.

The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency--results from a randomized controlled trial.

PubMed

Werumeus Buning, Jorien; Brummelman, Pauline; Koerts, Janneke; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Tucha, Oliver; Wolffenbuttel, Bruce H R; van Beek, André P

2015-05-01

A wide variety in hydrocortisone (HC) substitution dose-regimens are considered physiological for patients with secondary adrenal insufficiency (SAI). However, it is likely that cognition is negatively influenced by higher cortisol exposure to the brain. To examine the effects of a high physiological HC dose in comparison to a low physiological HC dose on cognition. This study was a randomized double blind cross-over study at the University Medical Center Groningen. This study is registered with ClinicalTrials.gov, number NCT01546922. Forty-seven patients (29 males, 18 females; mean [SD] age, 51 [14] years, range 19-73) with SAI participated. Patients randomly received first a low dose of HC (0.2-0.3 mg/kg body weight/day) during 10 weeks followed by a high dose (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. HC substitution was given in three divided doses with the highest dose in the morning. Cognitive performance (memory, attention, executive functioning and social cognition) of patients was measured at baseline and after each treatment period using a battery of 12 standardized cognitive tests. The higher dose of HC resulted in significantly higher systemic cortisol exposure for example measured at 1h after first dose ingestion (mean [SD], low dose: 653 [281] nmol/L; high dose: 930 [148] nmol/L; P<0.001). No differences in cognitive performance were found between the two dose regimens. No negative influence on memory, attention, executive functioning and social cognition was observed after 10 weeks of treatment with a higher physiological dose of HC in patients with SAI when compared to a lower dose. Copyright © 2015 Elsevier Ltd. All rights reserved.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

PubMed

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Reyes, Antonio; Majercak, Ivan; Andreka, Peter; Shehova-Yankova, Nina; Anand, Inder; Yilmaz, Mehmet B; Gogia, Harinder; Martinez-Selles, Manuel; Fischer, Steffen; Zilahi, Zsolt; Cosmi, Franco; Gelev, Valeri; Galve, Enrique; Gómez-Doblas, Juanjo J; Nociar, Jan; Radomska, Maria; Sokolova, Beata; Volterrani, Maurizio; Sarkar, Arnab; Reimund, Bernard; Chen, Fabian; Charney, Alan

2016-09-01

To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group. © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults.

PubMed

Phillips, Christine L; Davies, Stella M; McMasters, Richard; Absalon, Michael; O'Brien, Maureen; Mo, Jun; Broun, Randall; Moscow, Jeffrey A; Smolarek, Teresa; Garzon, Ramiro; Blum, William; Schwind, Sebastian; Marcucci, Guido; Perentesis, John P

2013-05-01

Low-dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2.5 cycles (range 1-4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long-term CR. © 2013 Blackwell Publishing Ltd.

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

PubMed

Vučićević, Katarina; Jovanović, Marija; Golubović, Bojana; Kovačević, Sandra Vezmar; Miljković, Branislava; Martinović, Žarko; Prostran, Milica

2015-02-01

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects

PubMed Central

Rocha, José Francisco; Almeida, Luis; Falcão, Amílcar; Palma, P Nuno; Loureiro, Ana I; Pinto, Roberto; Bonifácio, Maria João; Wright, Lyndon C; Nunes, Teresa; Soares-da-Silva, Patrício

2013-01-01

Aims The aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. Methods This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. Results Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT–opicapone complex. Conclusion Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen. PMID:23336248

Differential Effects of Intermittent versus Continuous Haloperidol Treatment throughout Adolescence on Haloperidol Sensitization and Social Behavior in Adulthood

PubMed Central

Gao, Jun; Li, Ming

2014-01-01

Animal work on the behavioral effects of antipsychotic treatment suggests that different dosing regimens could affect drug sensitivity differently, with an intermittent treatment regimen tending to cause a sensitization effect, while a continuous treatment causing a tolerance. In this study, we explored how haloperidol (HAL) sensitization induced throughout adolescence and tested in adulthood was differentially impacted by these two dosing regimens in the conditioned avoidance response (CAR) test. We also examined how these two dosing regiments affected social interaction and social memory in adulthood. Male adolescent Sprague-Dawley rats were treated with HAL via either osmotic minipump (HAL-0.25 CONT; 0.25 mg/kg/day, n = 14) or daily injection (HAL-0.05 INT; 0.05 mg/kg/injection/day, sc, n = 14), or sterile water (n = 14) from postnatal days (PND) 44 to 71. HAL sensitization was assessed in a challenge test in which all rats were injected with HAL (0.025 and 0.05 mg/kg, sc) on PND 80 and PND 82. Two days later, half of the rats from each group (n = 7/group) were assayed in two 4-trial social interaction tests in which a subject rat was given four 5-min social encounters with a familiar or novel juvenile rat (PND 35–40) at 10 min intervals. Another half were tested in a quinpirole-induced hyperlocomotion assay to assess the potential HAL-induced change in D2-mediated function. Results show that only the intermittent dosing group under the HAL 0.05 mg/kg challenge showed a robust sensitization effect as rats in this group made significantly fewer avoidance responses than those in the vehicle and HAL-0.25 CONT groups. Adolescent HAL treatment did not affect social behavior and social memory, as rats from all 3 groups exhibited a similar level of social interaction and showed a similar level of sensitivity to the change of social stimuli. Similarly, adolescent HAL treatment also did not produce a long-lasting change in D2 function, as all 3 groups exhibited a similar level of increase in motor activity under quinpirole challenge. These findings suggest that HAL sensitization is a dosing-specific phenomenon. It is more likely to be seen under an intermittent dosing regimen than under a continuous dosing one. The findings that the intermittent HAL treatment did not impair social functioning and did not alter D2 function suggest a dissociation between drug-induced alterations in drug sensitivity and those in social function and neuroreceptors. PMID:24942467

Single-dose ceftriaxone for chancroid.

PubMed Central

Bowmer, M I; Nsanze, H; D'Costa, L J; Dylewski, J; Fransen, L; Piot, P; Ronald, A R

1987-01-01

Men with genital ulcers that were culture positive for Haemophilus ducreyi were treated with intramuscular ceftriaxone and randomized to three different dose regimens. All but 1 of 50 men treated with 1 g of intramuscular ceftriaxone were cured. Similarly, 0.5 and 0.25 g cured 43 of 44 men and 37 of 38 men, respectively. A single dose of 250 mg of intramuscular ceftriaxone is an effective treatment for chancroid. PMID:3566241

Acute Care Management of the HIV-Infected Patient: A Report from the HIV Practice and Research Network of the American College of Clinical Pharmacy.

PubMed

Durham, Spencer H; Badowski, Melissa E; Liedtke, Michelle D; Rathbun, R Chris; Pecora Fulco, Patricia

2017-05-01

Patients infected with human immunodeficiency virus (HIV) admitted to the hospital have complex antiretroviral therapy (ART) regimens with an increased medication error rate upon admission. This report provides a resource for clinicians managing HIV-infected patients and ART in the inpatient setting. A survey of the authors was conducted to evaluate common issues that arise during an acute hospitalization for HIV-infected patients. After a group consensus, a review of the medical literature was performed to determine the supporting evidence for the following HIV-associated hospital queries: admission/discharge orders, antiretroviral hospital formularies, laboratory monitoring, altered hepatic/renal function, drug-drug interactions (DDIs), enteral administration, and therapeutic drug monitoring. With any hospital admission for an HIV-infected patient, a specific set of procedures should be followed including a thorough admission medication history and communication with the ambulatory HIV provider to avoid omissions or substitutions in the ART regimen. DDIs are common and should be reviewed at all transitions of care during the hospital admission. ART may be continued if enteral nutrition with a feeding tube is deemed necessary, but the entire regimen should be discontinued if no oral access is available for a prolonged period. Therapeutic drug monitoring is not generally recommended but, if available, should be considered in unique clinical scenarios where antiretroviral pharmacokinetics are difficult to predict. ART may need adjustment if hepatic or renal insufficiency ensues. Treatment of hospitalized patients with HIV is highly complex. HIV-infected patients are at high risk for medication errors during various transitions of care. Baseline knowledge of the principles of antiretroviral pharmacotherapy is necessary for clinicians managing acutely ill HIV-infected patients to avoid medication errors, identify DDIs, and correctly dose medications if organ dysfunction arises. Timely ambulatory follow-up is essential to prevent readmissions and facilitate improved transitions of care. © 2017 Pharmacotherapy Publications, Inc.

The White Diet is preferred, better tolerated, and non-inferior to a clear-fluid diet for bowel preparation: A randomized controlled trial.

PubMed

Butt, Joshua; Bunn, Cate; Paul, Eldho; Gibson, Peter; Brown, Gregor

2016-02-01

Dietary restrictions contribute to the unpleasantness of bowel preparation for colonoscopy. We compare the effectiveness and tolerability of a low residue diet of white-colored foods ("White Diet") with a clear-fluid diet the day prior to colonoscopy in an endoscopist-blinded randomized non-inferiority trial. Adults undergoing outpatient colonoscopy were randomized with stratification by procedure timing to a White Diet or clear-fluid diet. All received a 2-L polyethylene glycol lavage solution with ascorbate, sodium sulfate, and electrolytes, the day-before for morning and as a split-dose for afternoon procedures. The primary end-point was successful bowel preparation (A or B on the Harefield Cleansing Scale). Regimen tolerance/acceptance was assessed by questionnaire. An intention-to-treat analysis with a predefined non-inferiority margin of 15% was used to compare efficacy. A total of 226 patients (average age 52 years, 51% male) were randomized (111 clear diet, 115 White Diet). Bowel preparation was successful in 91% on the clear-fluid diet vs 84.4% on the White Diet, difference being -6.6% (lower one sided 95% CI -13.8%), with no difference according to diet. The split-dose regimen (in 55%) had a higher success rate than day-before regimen (96% vs 80%, p < 0.001). The White Diet was preferred with less hunger and interference with daily activities (p < 0.001). Procedural/withdrawal time and polyp/adenoma detection were similar between groups. The White Diet was preferred and better tolerated by patients without detriment to the success of bowel preparation or colonoscopy performance, especially with the split-dose regimen. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen.

PubMed

Andersen, Rikke; Donia, Marco; Ellebaek, Eva; Borch, Troels Holz; Kongsted, Per; Iversen, Trine Zeeberg; Hölmich, Lisbet Rosenkrantz; Hendel, Helle Westergren; Met, Özcan; Andersen, Mads Hald; Thor Straten, Per; Svane, Inge Marie

2016-08-01

Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen. Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625). Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment. TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res; 22(15); 3734-45. ©2016 AACR. ©2016 American Association for Cancer Research.

Best practice guidelines for idiopathic nephrotic syndrome: recommendations versus reality.

PubMed

Pasini, Andrea; Aceto, Gabriella; Ammenti, Anita; Ardissino, Gianluigi; Azzolina, Vitalba; Bettinelli, Alberto; Cama, Elena; Cantatore, Sante; Crisafi, Antonella; Conti, Giovanni; D'Agostino, Maria; Dozza, Alessandra; Edefonti, Alberto; Fede, Carmelo; Groppali, Elena; Gualeni, Chiara; Lavacchini, Alessandra; Lepore, Marta; Maringhini, Silvio; Mariotti, Paola; Materassi, Marco; Mencarelli, Francesca; Messina, Giovanni; Negri, Amata; Piepoli, Marina; Ravaglia, Fiammetta; Simoni, Angela; Spagnoletta, Laura; Montini, Giovanni

2015-01-01

The optimal therapeutic regimen for managing childhood idiopathic nephrotic syndrome (INS) is still under debate. We have evaluated the choice of steroid regimen and of symptomatic treatment adopted by pediatricians and pediatric nephrologists in a large number of centers as the first step towards establishing a shared protocol This was a multicenter, retrospective study. A total of 231 children (132 admitted to pediatric units) aged 6 months to <15 years who presented with onset of nephrotic syndrome to 54 pediatric units and six pediatric nephrology units in Italy between 2007 and 2009 were eligible for entry into the study. Median steroid dosing was 55 (range 27-75) mg/m(2)/day. The overall median cumulative dose regimen for the first episode was 3,440 (1,904-6,035) mg/m(2), and the median duration of the therapeutic regimen was 21 (9-48) weeks. The total duration and cumulative steroid dose were significantly higher in patients treated by pediatricians than in those treated by pediatric nephrologists (p = 0.001 and p = 0.008). Among the patient cohort, 55, 64 and 22 % received albumin infusions, diuretics and acetyl salicylic acid treatment, respectively, but the laboratory and clinical data did not differ between children treated or not treated with symptomatic drugs. Albumin and diuretic use did not vary between patients in pediatric units and those in pediatric nephrology units. This study shows major differences in steroid and symptomatic treatment of nephrotic syndrome by pediatricians and pediatric nephrologists. As these differences can influence the efficacy of the treatments and the appearance of side-effects, shared guidelines and their implementation through widespread educational activities are necessary.

Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.

PubMed

Khatri, Amit; Trinh, Roger; Zhao, Weihan; Podsadecki, Thomas; Menon, Rajeev

2016-10-01

The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

[Influence of dose regimen on gentamycin nephrotoxicity in rats].

PubMed

Oliveira, V C; Tejos, C R; Hosaka, E M; Andrade, S C; Araújo, M; Vattimo, M F

2001-06-01

The acute renal failure (ARF), that still presents a right mortality rate (50%) can be defined as an abrupt decline of the glomerular filtration, resultant of ischemic or toxicity event. The drugs nephrotoxicity is one of the most frequent cause (27%) of ARF and it is suggested that the interval of administration of the drug can interfere in this side effect, however the best administration regimen is not very well established. This study evaluated the renal function of rats that received gentamicin (100 mg/kg) in one dose or in two doses (2 x 50 mg/kg), by intraperitoneal infusion. The results obtained in this research, indicated that the single infusion of gentamicin determined smaller nephrotoxicity by the reduction of serum concentration of this drug in 24 hours, decreasing the intracellular accumulation of this gentamicin, which is one of the main cellular mechanisms of this renal injury. The single dose treatment regime, otherwise, shows advantages not only related to the nephrotoxicity effect, but also it is relevant to the cost and safety, which can be rationable factors in the administration of this drug.

Adapting to the global shortage of cholera vaccines: targeted single dose cholera vaccine in response to an outbreak in South Sudan.

PubMed

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Ciglenecki, Iza; Luquero, Francisco J; Azman, Andrew S; Cabrol, Jean-Clement

2017-04-01

Shortages of vaccines for epidemic diseases, such as cholera, meningitis, and yellow fever, have become common over the past decade, hampering efforts to control outbreaks through mass reactive vaccination campaigns. Additionally, various epidemiological, political, and logistical challenges, which are poorly documented in the literature, often lead to delays in reactive campaigns, ultimately reducing the effect of vaccination. In June 2015, a cholera outbreak occurred in Juba, South Sudan, and because of the global shortage of oral cholera vaccine, authorities were unable to secure sufficient doses to vaccinate the entire at-risk population-approximately 1 million people. In this Personal View, we document the first public health use of a reduced, single-dose regimen of oral cholera vaccine, and show the details of the decision-making process and timeline. We also make recommendations to help improve reactive vaccination campaigns against cholera, and discuss the importance of new and flexible context-specific dose regimens and vaccination strategies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunogenicity and safety of a quadrivalent meningococcal polysaccharide CRM conjugate vaccine in infants and toddlers.

PubMed

Tregnaghi, Miguel; Lopez, Pio; Stamboulian, Daniel; Graña, Gabriela; Odrljin, Tatjana; Bedell, Lisa; Dull, Peter M

2014-09-01

This phase III study assessed the safety and immunogenicity of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, administered with routine vaccines starting at 2 months of age. Healthy infants received MenACWY-CRM in a two- or three-dose primary infant series plus a single toddler dose. In addition, a two-dose toddler catch-up series was evaluated. Immune responses to MenACWY-CRM were assessed for serum bactericidal activity with human complement (hSBA). Reactogenicity and safety results were collected systematically. After a full infant/toddler series or two-dose toddler catch-up series, MenACWY-CRM elicited immune responses against the four serogroups in 94-100% of subjects. Noninferiority of the two- versus three-dose MenACWY-CRM infant dosing regimen was established for geometric mean titers for all serogroups. Following the three-dose infant primary series, 89-98% of subjects achieved an hSBA ≥ 8 across all serogroups. Immune responses to concomitant routine vaccines given with MenACWY-CRM were noninferior to responses to routine vaccines alone, except for pertactin after the two-dose infant series. Noninferiority criteria were met for all concomitant antigens after the three-dose infant series. MenACWY-CRM vaccination regimens in infants and toddlers were immunogenic and well tolerated. No clinically meaningful effects of concomitant administration with routine infant and toddler vaccines were observed. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

An unintended consequence of electronic prescriptions: prevalence and impact of internal discrepancies

PubMed Central

Palchuk, Matvey B; Fang, Elizabeth A; Cygielnik, Janet M; Labreche, Matthew; Shubina, Maria; Ramelson, Harley Z; Hamann, Claus; Broverman, Carol; Einbinder, Jonathan S

2010-01-01

Many e-prescribing systems allow for both structured and free-text fields in prescriptions, making possible internal discrepancies. This study reviewed 2914 electronic prescriptions that contained free-text fields. Internal discrepancies were found in 16.1% of the prescriptions. Most (83.8%) of the discrepancies could potentially lead to adverse events and many (16.8%) to severe adverse events, involving a hospital admission or death. Discrepancies in doses, routes or complex regimens were most likely to have a potential for a severe event (p=0.0001). Discrepancies between structured and free-text fields in electronic prescriptions are common and can cause patient harm. Improvements in electronic medical record design are necessary to minimize the risk of discrepancies and resulting adverse events. PMID:20595316

Comparing twice- versus four-times daily insulin in mothers with gestational diabetes in Pakistan and its implications.

PubMed

Saleem, Nazish; Godman, Brian; Hussain, Shahzad

2016-08-01

Gestational diabetes mellitus is a common medical problem associated with maternal and fetal complications. Good glycemic control is the cornerstone of treatment. Compare outcomes between four times (q.i.d) and twice daily (b.i.d) regimens. The morning dose of the b.i.d regimen contained two-thirds of the total insulin, comprising a third human regular insulin and two-thirds human intermediate insulin; equal amounts in the evening. 480 women at >30 weeks with gestational diabetes mellitus with failure to control blood glucose were randomly assigned to either regimen. Mean time to the control of blood glucose was significantly less and glycemic control significantly increased with the q.i.d regimen. Operative deliveries, extent of neonatal hypoglycemia, babies with low Agpar scores and those with hyperbilirubinemia were significantly higher with the b.i.d daily regimen. The q.i.d daily regime was associated with improved fetal and maternal outcomes. Consequently should increasingly be used in Pakistan, assisted by lower acquisition costs.

The incidence of acute oxaliplatin-induced neuropathy and its impact on treatment in the first cycle: a systematic review.

PubMed

Gebremedhn, Endale Gebreegziabher; Shortland, Peter John; Mahns, David Anthony

2018-04-12

Although acute oxaliplatin-induced neuropathy (OXIPN) is frequently regarded to be transient, recent studies have reported prolongation of infusion times, dose reduction and treatment cessation following the first dose of oxaliplatin in quarter of patients. Acute OXIPN is also a well-established risk factor for chronic neuropathy. However, there is underreporting of these parameters during the acute phase (≤ 14 days). This paper systematically reviews the incidence of acute OXIPN and its impact on treatment in the first cycle. A systematic literature search was performed using PubMed and Medline. Published original articles were included if they described details about prevalence of oxaliplatin-induced acute neuropathy. Fourteen studies, comprised of 6211 patients were evaluated. The majority of patients were treated with oxaliplatin in combination with leucovorin and fluorouracil (FOLFOX). Most studies used the National Cancer Institute Common Toxicity Criteria to assess acute neuropathy. Acute neuropathy (Grades 1-4) was the most common event with prevalence ranging from 4-98%, followed by haematological (1.4-81%) and gastrointestinal (1.2-67%) toxicities, respectively. Drug regimens, starting dose of oxaliplatin and neuropathy assessment tools varied across studies. In addition, moderate to severe toxicities were common in patients that received a large dose of oxaliplatin (> 85 mg/m 2 ) and/ or combined drugs. The majority of studies did not report the factors affecting acute neuropathy namely the range (minimal) doses required to evoke acute neuropathy, patient and clinical risk factors. In addition, there was no systematic reporting of the number of patients subjected to prolonged infusion, dose reduction, treatment delay and treatment cessation during the acute phase. Despite the heterogeneity of studies regarding oxaliplatin starting dose, drug regimen, neuropathy assessment tools and study design, a large number of patients developed acute neuropathy. To develop a better preventive and therapeutic guideline for acute/chronic neuropathy, a prospective study should be conducted in a large cohort of patients in relation to drug regimen, starting/ranges (minimal) of doses producing acute neuropathy, treatment compliance, patient and clinical risk factors using a standardised neuropathy assessment tool.

Dose-response relationship in the treatment of gastrointestinal disorders.

PubMed

Weihrauch, T R; Demol, P

1989-08-01

Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

Effect of smoking status on the efficacy of the SMART regimen in high risk asthma.

PubMed

Pilcher, Janine; Patel, Mitesh; Reddel, Helen K; Pritchard, Alison; Black, Peter; Shaw, Dominick; Holt, Shaun; Weatherall, Mark; Beasley, Richard

2016-07-01

The optimal management of people with asthma with a significant smoking history is uncertain. The aim of this study was to determine whether the efficacy/safety profile of single combination inhaled corticosteroid (ICS)/long acting beta-agonist (LABA) inhaler maintenance and reliever therapy is influenced by smoking status. We undertook secondary analyses from an open-label 24-week randomized study of 303 high risk adult asthma patients randomized to budesonide/formoterol 200/6-µg-metred dose inhaler for maintenance (two actuations twice daily) and either budesonide/formoterol 200/6-µg-metred dose inhaler one actuation ('single ICS/LABA maintenance and reliever therapy (SMART)' regimen) or salbutamol 100 µg 1-2 actuations for symptom relief ('Standard' regimen). Smoking status was classified in to three groups, as 'current', 'ex' or 'never', and a smoking/treatment interaction term tested for each outcome variable. The primary outcome variable was number of participants with at least one severe exacerbation. There were 59 current, 97 ex and 147 never smokers included in the analyses. The smoking status/treatment interaction term was not statistically significant for any of the outcome measures. With adjustment for smoking status, the number of participants with severe exacerbations was lower with the SMART regimen (OR 0.45, 95% CI: 0.26-0.77, P = 0.004; P value for interaction between smoking status and treatment 0.29). We conclude that the favourable safety/efficacy profile of the SMART regimen applies to patients with high risk asthma, irrespective of smoking status. © 2016 Asian Pacific Society of Respirology.

Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: Its utility for local siRNA delivery.

PubMed

Xu, Leyuan; Yeudall, W Andrew; Yang, Hu

2017-07-15

The utility of folic acid (FA)-decorated polyamidoamine dendrimer G4 (G4-FA) as a vector was investigated for local delivery of siRNA. In a xenograft HN12 (or HN12-YFP) tumor mouse model of head and neck squamous cell carcinomas (HNSCC), intratumorally (i.t.) injected G4-FA exhibited high tumor uptake and sustained highly localized retention in the tumors according to near infrared (NIR) imaging assessment. siRNA against vascular endothelial growth factor A (siVEGFA) was chosen as a therapeutic modality. Compared to the nontherapeutic treatment groups (PBS solution or dendrimer complexed with nontherapeutic siRNA against green fluorescent protein (siGFP)), G4-FA/siVEGFA showed tumor inhibition effects in single-dose and two-dose regimen studies. In particular, two doses of G4-FA/siVEGFA i.t. administered eight days apart resulted in a more profound inhibition of tumor growth, accompanied with significant reduction in angiogenesis, as judged by CD31 staining and microvessel counts. Tumor size reduction in the two-dose regimen study was ascertained semi-quantitatively by live fluorescence imaging of YFP tumors and independently supported antitumor effects of G4-FA/siVEGFA. Taken together, G4-FA shows high tumor uptake and sustained retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible such as HNSCC. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is difficult to transfect for gene therapy. We developed folate receptor (FR)-targeted polyamidoamine (PAMAM) dendrimer for enhanced delivery of genes to HNSCC and gained in-depth understanding of how gene delivery and transfection in head and neck squamous cancer cells can be enhanced via FR-targeted PAMAM dendrimers. The results we report here are encouraging and present latest advances in using dendrimers for cancer therapies, in particular for HNSCC. Our work has demonstrated that localized delivery of FR-targeted PAMAM dendrimer G4 complexed with siVEGFA resulted in pronounced tumor suppression in an HN12 xenograft tumor model. Tumor suppression was attributed to enhanced tumor uptake of siRNA and prolonged nanoparticle retention in the tumor. Taken together, G4-FA shows high tumor uptake and sustained highly localized retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible such as HNSCC. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Optimizing inpatient glycemic control with basal-bolus insulin therapy.

PubMed

Pollom, R Daniel

2010-11-01

Hyperglycemia is highly prevalent in the acute-care setting and is associated with an increased risk of morbidity and mortality. Evidence suggests that glycemic control in this population is suboptimal, due in part to continued use of nonphysiologic sliding-scale insulin strategies without scheduled basal insulin doses or prandial insulin with concomitant correction doses. Although the ineffectiveness and risks of sliding-scale insulin regimens have been criticized for decades, sliding-scale insulin is still the most commonly prescribed subcutaneous insulin regimen among inpatients. Improving inpatient management requires the use of scheduled basal-bolus insulin therapy that includes basal insulin, nutritional insulin, and supplemental, or correctional, insulin. Insulin analogs are the preferred insulins, as they provide a more physiologic action than human insulin regimens, are associated with a lower risk of hypoglycemia, and are more convenient to administer than human insulins. Standardized insulin protocols and subcutaneous insulin order sets are critical components of effective inpatient glycemic control. Although preliminary data have demonstrated that inpatient diabetes management programs involving basal-bolus insulin therapy are effective and well tolerated, more research is needed.

Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

PubMed

Thomas, David M; Kuhn, Donald M

2005-02-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

Suppression of ovarian activity with a low-dose 21/7-day regimen oral contraceptive containing ethinylestradiol 20 mcg/drospirenone 3 mg in Japanese and Caucasian women.

PubMed

Anzai, Yuzuru; Heger-Mahn, Doris; Schellschmidt, Ilka; Marr, Joachim

2012-07-01

Two studies assessed the effect of a low-estrogen-dose 21/7-day oral contraceptive containing ethinylestradiol and drospirenone (EE 20 mcg/drsp 3 mg) on ovarian activity in Japanese and Caucasian women. Study 1 was conducted in Japanese women (20-35 years), and Study 2 was conducted in Caucasian women (18-35 years). All women received EE 20 mcg/drsp 3 mg in a 21-day active pill regimen. The primary endpoint was the proportion of women with ovulation inhibition (Hoogland score <6; as assessed by transvaginal ultrasonography) during treatment cycle 2. Japanese (n=23) and Caucasian (n=30) women received two cycles of study treatment. During treatment cycle 2, ovulation was inhibited in 100% and 92.9% of Japanese and Caucasian women, respectively. EE 20 mcg/drsp 3 mg in a 21/7-day regimen provides comparable ovarian suppression in Japanese and Caucasian women, with normal ovarian function resuming shortly after treatment end in both populations. Copyright © 2012 Elsevier Inc. All rights reserved.

Drug safety evaluation through biomarker analysis-A toxicity study in the cynomolgus monkey using an antibody-cytotoxic conjugate against ovarian cancer

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

Hsieh, Frank Y.; Tengstrand, Elizabeth; Lee, J.-W.

2007-10-01

Antibody-cytotoxin conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify serum biomarkers that correlate with MLN8866 (an Antibody-Cytotoxic Conjugate, mAb8866-CT) pathological events in monkeys and to predict the maximal tolerated dose (MTD) level using biomarkers. Cynomolgus monkeys were administered a single dose MLN8666 (5, 15 or 30 mg/kg) by intravenous infusion and evaluated over a 7-day period. Exposure levels were determined by quantifying MLN8866 levels (C{sub max} and AUC{sub 0-96h}) in serum. The increase in MLN8866 C{sub max} and AUC{sub 0-96h} was approximately dose proportional. Two biomarkersmore » in serum (m/z 316 and m/z 368) were identified to be correlated with MLN8866 toxicological outcomes. The predicted MTD, 11.4 mg/kg, was within the MTD range set by pathology results (5-15 mg/kg). Administration of MLN8866 at 15 mg/kg and 30 mg/kg dose levels resulted in changes in hematology parameters associated with impaired hematopoiesis and bone marrow toxicity. The projected MLN8866 MTD exposure level was integrated with toxicokinetic analysis and showed C{sub max} = 236 {mu}g/mL and AUC{sub 0-96h} = 7246 h mg/mL. The safety of three different MLN8866 dosing regimens with three dosing schedules was explored with pharmacokinetic modeling.« less

A phase 1 trial of 2 dose schedules of ABT-510, an antiangiogenic, thrombospondin-1-mimetic peptide, in patients with advanced cancer.

PubMed

Gordon, Michael S; Mendelson, David; Carr, Robert; Knight, Raymond A; Humerickhouse, Rod A; Iannone, Maria; Stopeck, Alison T

2008-12-15

ABT-510 is a substituted nonapeptide that mimics the antiangiogenic activity of the endogenous protein thrombospondin-1 (TSP-1). The current study was designed to establish the safety of ABT-510 in the treatment of patients with advanced malignancies on a once-daily (QD) and twice-daily dosing schedule. Patients were randomly assigned to 1 of 6 dosing regimens: 20 mg, 50 mg, or 100 mg QD or 10 mg, 25 mg, or 50 mg twice daily. ABT-510 was administered by subcutaneous bolus injection in cycles of 28 days. Tumor response and disease progression were monitored at 8-week intervals by computed tomography scan or magnetic resonance imaging. Thirty-six patients were randomly assigned in equal numbers to the 6 study regimens, with an additional 13 patients randomized to the 10-mg-twice-daily and 50-mg-twice-daily ABT-510 regimens. The expected pharmacokinetic target was achieved at all dose levels tested. The majority of adverse events were grade 1 or 2 (according to National Cancer Institute Common Toxicity Criteria [version 2]) and were not found to be dose related. The most frequently reported adverse events that were possibly related to ABT-510 included injection site reactions, asthenia, headache, and nausea. Grade 3 events considered to possibly be related included nausea, dyspnea, bone pain, constipation, vomiting, asthenia, and chills and tremors. One partial response was observed in a patient with carcinosarcoma who received 20 mg QD. The 6-month progression-free survival rate was 6%. Approximately 42% of patients (21 of 50 patients) had stable disease for > or =3 months. ABT-510 can be administered at doses of 20 mg/day to 100 mg/day without significant toxicity. In the current study, minimal antitumor activity was observed, which was similar to observations in other single-agent antiangiogenic trials.

Massage Therapy for Osteoarthritis of the Knee: A Randomized Dose-Finding Trial

PubMed Central

Perlman, Adam I.; Ali, Ather; Njike, Valentine Yanchou; Hom, David; Davidi, Anna; Gould-Fogerite, Susan; Milak, Carl; Katz, David L.

2012-01-01

Background In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination. Methods We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks. Results WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3–32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1–12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose. Conclusion Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials. Trial Registration ClinicalTrials.gov NCT00970008 PMID:22347369

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer

PubMed Central

Tezuka, Kenji; Takashima, Tsutomu; Kashiwagi, Shinichiro; Kawajiri, Hidemi; Tokunaga, Shinya; Tei, Seika; Nishimura, Shigehiko; Yamagata, Shigehito; Noda, Satoru; Nishimori, Takeo; Mizuyama, Yoko; Sunami, Takeshi; Ikeda, Katsumi; Ogawa, Yoshinari; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei

2017-01-01

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted. PMID:28413662

Dose and side effects of sublingual misoprostol for treatment of postpartum hemorrhage: what difference do they make?

PubMed Central

2012-01-01

Background Shivering and fever are common side effects of misoprostol. An unexpectedly high rate of fever above 40°C was documented among Ecuadorian women given treatment with 800mcg of sublingual misoprostol to manage postpartum hemorrhage (PPH) (36%). Much lower rates have been reported elsewhere (0-9%). Methods From February to July 2010, an open-label pilot study was conducted in Quito, Ecuador to determine whether a lower dose--600mcg sublingual misoprostol--would result in a lower incidence of high fever (≥40°C). Rates of shivering and fever with 600mcg sublingual regimen were compared to previously documented rates in Ecuador following PPH treatment with 800mcg sublingual misoprostol. Results The 600mcg dose resulted in a 55% lower rate of high fever compared with the 800mcg regimen (8/50; 16% vs. 58/163; 36%; relative risk 0.45 95% CI 0.23-0.88). Only one woman had severe shivering following the 600mcg dose compared with 19 women in the 800mcg cohort (2% vs. 12%; relative risk 0.17 (0.02-1.25)). No cases of delirium/altered sensorium were reported with the 600mcg dose and women’s assessment of severity/tolerability of shivering and fever was better with the lower dose. Conclusions 600mcg sublingual misoprostol was found to decrease the occurrence of high fever among Ecuadorian women when given to treat PPH. This study however was not powered to examine the efficacy of this treatment regimen and cannot be recommended at this time. Future research is needed to confirm whether other populations, outside of Quito, Ecuador, experience unusually high rates of elevated body temperature following sublingual administration of misoprostol for treatment of PPH. If indeed similar trends are found elsewhere, larger trials to confirm the efficacy of lower dosages may be justified. Trial Registration Clinical trials.gov, Registry No. NCT01080846 PMID:22769055

Dose and side effects of sublingual misoprostol for treatment of postpartum hemorrhage: what difference do they make?

PubMed

León, Wilfrido; Durocher, Jill; Barrera, Gustavo; Pinto, Ernesto; Winikoff, Beverly

2012-07-07

Shivering and fever are common side effects of misoprostol. An unexpectedly high rate of fever above 40°C was documented among Ecuadorian women given treatment with 800mcg of sublingual misoprostol to manage postpartum hemorrhage (PPH) (36%). Much lower rates have been reported elsewhere (0-9%). From February to July 2010, an open-label pilot study was conducted in Quito, Ecuador to determine whether a lower dose--600mcg sublingual misoprostol--would result in a lower incidence of high fever (≥40°C). Rates of shivering and fever with 600mcg sublingual regimen were compared to previously documented rates in Ecuador following PPH treatment with 800mcg sublingual misoprostol. The 600mcg dose resulted in a 55% lower rate of high fever compared with the 800mcg regimen (8/50; 16% vs. 58/163; 36%; relative risk 0.45 95% CI 0.23-0.88). Only one woman had severe shivering following the 600mcg dose compared with 19 women in the 800mcg cohort (2% vs. 12%; relative risk 0.17 (0.02-1.25)). No cases of delirium/altered sensorium were reported with the 600mcg dose and women's assessment of severity/tolerability of shivering and fever was better with the lower dose. 600mcg sublingual misoprostol was found to decrease the occurrence of high fever among Ecuadorian women when given to treat PPH. This study however was not powered to examine the efficacy of this treatment regimen and cannot be recommended at this time. Future research is needed to confirm whether other populations, outside of Quito, Ecuador, experience unusually high rates of elevated body temperature following sublingual administration of misoprostol for treatment of PPH. If indeed similar trends are found elsewhere, larger trials to confirm the efficacy of lower dosages may be justified. Clinical trials.gov, Registry No. NCT01080846.

Pulsed electromagnetic fields dosing impacts postoperative pain in breast reduction patients.

PubMed

Taylor, Erin M; Hardy, Krista L; Alonso, Amanda; Pilla, Arthur A; Rohde, Christine H

2015-01-01

Pulsed electromagnetic fields (PEMF) reduce postoperative pain and narcotic requirements in breast augmentation, reduction, and reconstruction patients. PEMF enhances both calmodulin-dependent nitric oxide and/or cyclic guanosine monophosphate signaling and phosphodiesterase activity, which blocks cyclic guanosine monophosphate. The clinical effect of these competing responses on PEMF dosing is not known. Two prospective, nonrandomized, active cohorts of breast reduction patients, with 15 min PEMF per 2 h; "Q2 (active)", and 5 min PEMF per 20 min; "5/20 (active)", dosing regimens were added to a previously reported double-blind clinical study wherein 20 min PEMF per 4 h, "Q4 (active)", dosing significantly accelerated postoperative pain reduction compared with Q4 shams. Postoperative visual analog scale pain scores and narcotic use were compared with results from the previous study. Visual analog scale scores at 24 h were 43% and 35% of pain at 1 h in the Q4 (active) and Q2 (active) cohorts, respectively (P < 0.01). Pain at 24 h in the 5/20 (active) cohort was 87% of pain at 1 h, compared with 74% in the Q4 (sham) cohort (P = 0.451). Concomitantly, narcotic usage in the 5/20 (active) and Q4 (sham) cohorts was not different (P = 0.478), and 2-fold higher than the Q4 (active) and Q2 (active) cohorts (P < 0.02). This prospective study shows Q4/Q2, but not 5/20 PEMF dosing, accelerated postoperative pain reduction compared with historical shams. The 5/20 (active) regimen increases NO 4-fold faster than the Q4 (active) regimen, possibly accelerating phosphodiesterase inhibition of cyclic guanosine monophosphate sufficiently to block the PEMF effect. This study helps define the dosing limits of clinically useful PEMF signals. Copyright © 2015 Elsevier Inc. All rights reserved.

Systematic review and meta-analysis of colon cleansing preparations in patients with inflammatory bowel disease

PubMed Central

Restellini, Sophie; Kherad, Omar; Bessissow, Talat; Ménard, Charles; Martel, Myriam; Taheri Tanjani, Maryam; Lakatos, Peter L; Barkun, Alan N

2017-01-01

AIM To performed a systematic review and meta-analysis to determine any possible differences in terms of effectiveness, safety and tolerability between existing colon-cleansing products in patients with inflammatory bowel disease. METHODS Systematic searches were performed (January 1980-September 2016) using MEDLINE, EMBASE, Scopus, CENTRAL and ISI Web of knowledge for randomized trials assessing preparations with or without adjuvants, given in split and non-split dosing, and in high (> 3 L) or low-volume (2 L or less) regimens. Bowel cleansing quality was the primary outcome. Secondary outcomes included patient willingness-to-repeat the procedure and side effects/complications. RESULTS Out of 439 citations, 4 trials fulfilled our inclusion criteria (n = 449 patients). One trial assessed the impact of adding simethicone to polyethylene glycol (PEG) 4 L with no effect on bowel cleansing quality, but a better tolerance. Another trial compared senna to castor oil, again without any differences in term of bowel cleansing. Two trials compared the efficacy of PEG high-volume vs PEG low-volume associated to an adjuvant in split-dose regimens: PEG low-dose efficacy was not different to PEG high-dose; OR = 0.84 (0.37-1.92). A higher proportion of patients were willing to repeat low-volume preparations vs high-volume; OR = 5.11 (1.31-20.0). CONCLUSION In inflammatory bowel disease population, PEG low-volume regimen seems not inferior to PEG high-volume to clean the colon, and yields improved willingness-to-repeat. Further additional research is urgently required to compare contemporary products in this population. PMID:28932092

Systematic review and meta-analysis of colon cleansing preparations in patients with inflammatory bowel disease.

PubMed

Restellini, Sophie; Kherad, Omar; Bessissow, Talat; Ménard, Charles; Martel, Myriam; Taheri Tanjani, Maryam; Lakatos, Peter L; Barkun, Alan N

2017-08-28

To performed a systematic review and meta-analysis to determine any possible differences in terms of effectiveness, safety and tolerability between existing colon-cleansing products in patients with inflammatory bowel disease. Systematic searches were performed (January 1980-September 2016) using MEDLINE, EMBASE, Scopus, CENTRAL and ISI Web of knowledge for randomized trials assessing preparations with or without adjuvants, given in split and non-split dosing, and in high (> 3 L) or low-volume (2 L or less) regimens. Bowel cleansing quality was the primary outcome. Secondary outcomes included patient willingness-to-repeat the procedure and side effects/complications. Out of 439 citations, 4 trials fulfilled our inclusion criteria ( n = 449 patients). One trial assessed the impact of adding simethicone to polyethylene glycol (PEG) 4 L with no effect on bowel cleansing quality, but a better tolerance. Another trial compared senna to castor oil, again without any differences in term of bowel cleansing. Two trials compared the efficacy of PEG high-volume vs PEG low-volume associated to an adjuvant in split-dose regimens: PEG low-dose efficacy was not different to PEG high-dose; OR = 0.84 (0.37-1.92). A higher proportion of patients were willing to repeat low-volume preparations vs high-volume; OR = 5.11 (1.31-20.0). In inflammatory bowel disease population, PEG low-volume regimen seems not inferior to PEG high-volume to clean the colon, and yields improved willingness-to-repeat. Further additional research is urgently required to compare contemporary products in this population.

Population pharmacokinetics and dosing simulations of imipenem in serious bacteraemia in immunocompromised patients with febrile neutropenia.

PubMed

Jaruratanasirikul, Sutep; Wongpoowarak, Wibul; Jullangkoon, Monchana; Samaeng, Maseetoh

2015-02-01

The aims of this study were to i) reveal the population pharmacokinetics; and ii) assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) (defined as the expected population PTA for a specific drug dose and a specific population of microorganisms) of imipenem in febrile neutropenic patients with bacteraemia. Ten patients were randomised into two groups: Group I received a 0.5-h infusion of 0.5 g of imipenem every 6 h (q6h) for 8 doses; and Group II received a 4-h infusion of 0.5 g q6h for 8 doses. A Monte Carlo simulation was performed to determine the PTA. The volume of distribution and total clearance of imipenem were 20.78 ± 1.35 l and 23.19 ± 1.34 l/h, respectively. Only a 4-h infusion of 1 g q6h regimen achieved a PTA >93% for 80% T>MIC for a MIC of 2 μg/ml. A 4-h infusion of all simulated regimens and a 0.5-h infusion of 0.5 g q6h and 1 g q6h achieved targets (CFR ≥ 90%) against Escherichia coli and Klebsiella spp. However, against Pseudomonas aeruginosa and Acinetobacter spp., no regimens achieved their targets. In conclusion, the results indicate that a higher than manufacturer's dosage recommendation is required to maximize the activity of imipenem. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Intermittent tuberculosis treatment for patients with isoniazid intolerance or drug resistance.

PubMed

Reves, R; Heilig, C M; Tapy, J M; Bozeman, L; Kyle, R P; Hamilton, C D; Bock, N; Narita, M; Wing, D; Hershfield, E; Goldberg, S V

2014-05-01

Twenty tuberculosis (TB) clinics in the United States and Canada. To evaluate the efficacy and safety of a 6-month intermittent regimen of rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB) in human immunodeficiency virus (HIV) negative patients with culture-confirmed pulmonary or extra-pulmonary tuberculosis and either isoniazid (INH) resistance or INH intolerance. Patients were enrolled in a single-arm clinical trial to receive intermittent dosing after at least 14 initial daily doses of RMP+PZA+EMB. Treatment was continued twice (BIW) or thrice weekly (TIW) per physician/patient preference for a total of 6 months, with 2 years of follow-up for relapse after treatment. From 1999 to 2004, 98 patients were enrolled, 78 with reported INH resistance and 20 with INH intolerance. BIW dosing was used in 77 and TIW in 21. Study treatment was completed in 73 (74%). Reasons for discontinuation were hepatic adverse events (n= 12), other adverse effects (n= 3) and other reasons (n= 10). Failure (n= 1) and relapse (n= 2) occurred in 3 (3.5%, 95%CI 1.2-9.8) of 86 patients eligible for efficacy analysis, all occurring in patients with cavitary, acid-fast bacilli smear-positive pulmonary TB. Intermittent RMP+PZA+EMB appears to be effective in HIV-negative patients, but the regimen is poorly tolerated, possibly due to the prolonged use of PZA. Alternative regimens of lower toxicity are needed.

High-dose Carboplatin/Etoposide/Melphalan increases risk of thrombotic microangiopathy and organ injury after autologous stem cell transplantation in patients with neuroblastoma.

PubMed

Jodele, Sonata; Dandoy, Christopher E; Myers, Kasiani; Wallace, Gregory; Lane, Adam; Teusink-Cross, Ashley; Weiss, Brian; Davies, Stella M

2018-04-19

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant that can result in multi-organ failure (MOF). Patients undergoing high-dose chemotherapy with autologous stem cell transplant (aHCT) for neuroblastoma require good organ function to receive post-transplant radiation and immunotherapy. We examined TA-TMA incidence and transplant outcomes in patients with neuroblastoma receiving different transplant preparative regimens. Sixty patients underwent aHCT using high-dose chemotherapy: 41 patients received carboplatin/etoposide/melphalan (CEM), 13 patients busulfan/melphalan (Bu/Mel) and six patients received tandem transplant (cyclophosphamide/thiotepa and CEM). TA-TMA with MOF was diagnosed in 13 patients (21.7%) at a median of 18 days after aHCT. TA-TMA occurred in 12 patients receiving CEM and in 1 after cyclophosphamide/thiotepa. There were no incidences of TA-TMA after Bu/Mel regimen. Six of 13 patients with TA-TMA and MOF received terminal complement blocker eculizumab for therapy. They all recovered organ function and received planned post-transplant therapy. Out of seven patients who did not get eculizumab, two died from TA-TMA complications and four progressed to ESRD. We conclude that the CEM regimen is associated with a high incidence of clinically significant TA-TMA after aHCT and eculizumab can be safe and effective treatment option to remediate TA-TMA associated MOF.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism.

PubMed

Hameed, Shihab; Mendoza-Cruz, Abel C; Neville, Kristen A; Woodhead, Helen J; Walker, Jan L; Verge, Charles F

2012-06-09

Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120-156 on the old regimen. She was discharged home. This practical regimen improved sodium control, parental independence, and allowed discharge home.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism

PubMed Central

2012-01-01

Background/Aims Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. Methods A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. Results After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120–156 on the old regimen. She was discharged home. Conclusion This practical regimen improved sodium control, parental independence, and allowed discharge home. PMID:22682315

Late Effects in Pediatric High-risk Neuroblastoma Survivors After Intensive Induction Chemotherapy Followed by Myeloablative Consolidation Chemotherapy and Triple Autologous Stem Cell Transplants.

PubMed

Armstrong, Amy E; Danner-Koptik, Karina; Golden, Shannon; Schneiderman, Jennifer; Kletzel, Morris; Reichek, Jennifer; Gosiengfiao, Yasmin

2018-01-01

Multimodal treatment in high-risk neuroblastoma has modestly improved survival; limited data exist on the late effects from these regimens. We report the sequelae of treatment incorporating 3 consecutive cycles of high-dose therapy and autologous stem cell transplants (ASCTs) without the use of total body irradiation (TBI). We reviewed the medical records of 61 patients treated on or following the Chicago Pilot 2 protocol between 1991 and 2008. Of the 25 patients who are alive (41%), 19 had near complete data to report. Specific treatment modalities and therapy-related side effects were collected. Fourteen of these 19 patients (74%) received 3 cycles of high-dose therapy with ASCT; follow-up occurred over a median of 13.9 years (range, 5.8 to 18.8 y). The majority of late effects were endocrine-related, including growth failure, hypothyroidism, and hypogonadism. Patients also developed secondary neoplasms and skeletal deformities. The most frequent sequela was hearing loss, seen in 17/19 patients. We found a high prevalence of various late effects in survivors of high-risk neuroblastoma using a non-TBI-based regimen including 3 cycles of high-dose therapy with ASCTs. As current treatment regimens recommend tandem ASCT without TBI, it is imperative that we understand and monitor for the sequelae from these modalities.

A phase 1, multicentre, open-label study to evaluate ovarian follicular activity and hormone levels with an extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation.

PubMed

Kroll, Robin; Seidman, Larry; Ricciotti, Nancy; Howard, Brandon; Weiss, Herman

2015-01-01

To evaluate the effect on ovarian follicular activity of the 91-day extended-regimen combined oral contraceptive (COC), consisting of 84 days of levonorgestrel (LNG)/ethinylestradiol (EE) 150 μg/30 μg tablets plus seven days of EE 10 μg tablets in place of placebo. This was a phase 1, open-label study. Ovarian follicular activity was classified via the Hoogland and Skouby method. Safety and tolerability as well as return to ovulation were assessed. Of the 35 subjects included in the efficacy analysis, luteinized, unruptured follicles, or ovulation were detected in 0 of 35 cycles during the first 28-day interval; 1 of 35 cycles (2.9%) in the second 28-day interval; and 2 of 35 cycles (5.7%) in the final 35-day interval. The ovarian activity rate over the entire 91-day treatment period was 2.9%. There was a low incidence of treatment-emergent adverse events. Ovulation returned in most subjects (77.1%, 27/35) within 32 days following the last dose of COC. The 91-day extended-regimen COC with low-dose EE supplementation was found to be effective in suppressing ovarian activity and inhibiting ovulation and was well tolerated. Return to ovulation was rapid, occurring within approximately one month after discontinuation of COC.

The Effect of a New Sodium Bicarbonate Loading Regimen on Anaerobic Capacity and Wrestling Performance.

PubMed

Durkalec-Michalski, Krzysztof; Zawieja, Emilia Ewa; Podgórski, Tomasz; Zawieja, Bogna Ewa; Michałowska, Patrycja; Łoniewski, Igor; Jeszka, Jan

2018-05-30

Gastrointestinal side effects are the main problem with sodium bicarbonate (SB) use in sports. Therefore, our study assessed the effect of a new SB loading regimen on anaerobic capacity and wrestling performance. Fifty-eight wrestlers were randomized to either a progressive-dose regimen of up to 100 mg∙kg -1 of SB or a placebo for 10 days. Before and after treatment, athletes completed an exercise protocol that comprised, in sequence, the first Wingate, dummy throw, and second Wingate tests. Blood samples were taken pre- and post-exercise. No gastrointestinal side effects were reported during the study. After SB treatment, there were no significant improvements in the outcomes of the Wingate and dummy throw tests. The only index that significantly improved with SB, compared to the placebo ( p = 0.0142), was the time-to-peak power in the second Wingate test, which decreased from 3.44 ± 1.98 to 2.35 ± 1.17 s. There were also no differences in blood lactate or glucose concentrations. In conclusion, although the new loading regimen eliminated gastrointestinal symptoms, the doses could have been too small to elicit additional improvements in anaerobic power and wrestling performance. However, shortening the time-to-peak power during fatigue may be particularly valuable and is one of the variables contributing to the final success of a combat sports athlete.

Etanercept provides an effective, safe and flexible short- and long-term treatment regimen for moderate-to-severe psoriasis: a systematic review of current evidence.

PubMed

Strohal, Robert; Chimenti, Sergio; Vena, Gino Antonio; Girolomoni, Giampiero

2013-06-01

The treatment of psoriasis requires long-lasting intervention. Conventional treatments for psoriasis comprise topical, phototherapeutic and systemic modalities, such as methotrexate or cyclosporine. Biological therapies are advocated by treatment guidelines for the use in moderate-to-severe psoriasis, when conventional treatments have failed, are contraindicated or are associated with severe adverse events. Etanercept is an anti-TNF recombinant fusion protein that has emerged as a standard biologic treatment option for moderate-to-severe psoriasis. The present review summarizes data from pivotal and post-marketing randomized controlled etanercept trials to treat moderate-to-severe psoriasis for 24 weeks and longer. During the first 12 weeks, etanercept can be administered in different dosing regimens: 50 mg twice weekly (BIW) and 50 mg once weekly. Although both regimens are effective, it has been shown that the 50 mg BIW dosage leads to higher response rates at week 24. In addition, after 24 weeks' treatment etanercept provides the unique possibility of continuous or intermittent long-term treatment programmes. The medium- to long-term efficacy of etanercept was consistent, regardless of whether etanercept therapy was interrupted or continuous. Taking the chronic nature of psoriasis into account, this flexibility in dosing regimen bestows a key advantage in facilitating individualisation of long-term treatment according to patient needs.

In vivo prostacyclin biosynthesis and effects of different aspirin regimens in patients with essential thrombocythaemia.

PubMed

Cavalca, V; Rocca, B; Squellerio, I; Dragani, A; Veglia, F; Pagliaccia, F; Porro, B; Barbieri, S S; Tremoli, E; Patrono, C

2014-07-03

Essential thrombocythaemia (ET) is characterised by enhanced platelet generation and thrombosis. Once daily (od) aspirin incompletely inhibits platelet thromboxane (TX)A2 production in ET. A twice daily (bid) dosing is necessary to fully inhibit TXA2. Whether this dosing regimen affects in vivo prostacyclin (PGI2) biosynthesis is unknown. PGI2 biosynthesis was characterised in 50 ET patients on enteric-coated (EC) aspirin 100 mg od, by measuring its urinary metabolite, 2,3-dinor-6-keto-PGF1α (PGI-M). Moreover, in a crossover study 22 patients poorly responsive to standard aspirin based on serum TXB2 levels (≥4 ng/ml) were randomised to different seven-day aspirin regimens: EC aspirin 100 mg od, 100 mg bid, 200 mg od, or plain aspirin 100 mg od. PGI-M measured 24 hours after the last aspirin intake (EC, 100 mg od) was similar in patients and healthy subjects both on (n=10) and off (n=30) aspirin. PGI-M was unrelated to in vivo TXA2 biosynthesis, and not affected by EC aspirin 100 mg bid or 200 mg od as compared to EC 100 mg od. PGI2 biosynthesis in aspirin-treated ET patients appears unrelated to TXA2 biosynthesis, and not affected by an improved aspirin regimen, demonstrating its vascular safety for future trials.

Capecitabine treatment patterns in patients with gastroesophageal cancer in the United States

PubMed Central

Saif, Muhammad Wasif; Shi, Nianwen; Zelt, Susan

2009-01-01

AIM: To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer (GEC) in a real-world treatment setting. METHODS: Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan® databases. Capecitabine regimens were compared with 5-fluorouracil (5-FU) and other chemotherapy regimens, and were stratified by treatment setting. RESULTS: We identified 1013 patients with GEC: approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treatment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% (95% CI: 26%-81%) lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU. CONCLUSION: Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC. PMID:19764093

Immunogenicity, safety and antibody persistence of a purified vero cell cultured rabies vaccine (Speeda) administered by the Zagreb regimen or Essen regimen in post-exposure subjects

PubMed Central

Shi, Nianmin; Zhang, Yibin; Zheng, Huizhen; Zhu, Zhenggang; Wang, Dingming; Li, Sihai; Li, Yuhua; Yang, Liqing; Zhang, Junnan; Bai, Yunhua; Lu, Qiang; Zhang, Zheng; Luo, Fengji; Yu, Chun; Li, Li

2017-01-01

ABSTRACT Aim: To compare the safety, immunogenicity and long-term effect of a purified vero cell cultured rabies vaccine in post-exposure subjects following 2 intramuscular regimens, Zagreb or Essen regimen. Methods: Serum samples were collected before vaccination and on days 7, 14, 42, 180 and 365 post vaccination. Solicited adverse events were recorded for 7 d following each vaccine dose, and unsolicited adverse events throughout the entire study period. This study was registered with ClinicalTrials.gov (NCT01821911 and NCT01827917). Results: No serious adverse events were reported. Although Zagreb regimen had a higher incidence of adverse reactions than Essen regimen at the first and second injection, the incidence was similar at the third and fourth injection between these 2 groups as well. At day 42, 100% subjects developed adequate rabies virus neutralizing antibody concentrations (≥ 0.5IU/ml) for both regimens. At days 180 and 365, the antibody level decreased dramatically, however, the percentage of subjects with adequate antibody concentrations still remained high (above 75% and 50% respectively). None of confirmed rabies virus exposured subjects had rabies one year later, and percentage of subjects with adequate antibody concentrations reached 100% at days 14 and 42. Conclusions: Rabies post-exposure prophylaxis vaccination with PVRV following a Zagreb regimen had a similar safety, immunogenicity and long-term effect to the Essen regimen in China. PMID:28121231

Safety and metabolic impact of Ramadan fasting in children and adolescents with type 1 diabetes.

PubMed

El-Hawary, Amany; Salem, Nanees; Elsharkawy, Ashraf; Metwali, Abdelhameed; Wafa, Alaa; Chalaby, Nehad; El-Gilany, Abelhady; Abo-Elmagd, Megahed; El-Ziny, Magdy

2016-05-01

Annually, many children and adolescents with type 1 diabetes mellitus (T1DM) insist on fasting for Ramadan despite being exempted and despite knowing all the risks. We aimed to assess the safety and metabolic impact of Ramadan fasting in children with T1DM using different insulin regimens. Children with T1DM who choose to fast during Ramadan 1434/2013 (29 days) were recruited 3 months before Ramadan. They received pre-Ramadan intensive education. Three insulin regimens were included; Regimen-I (regular insulin/NPH); Regimen-II (regular insulin/insulin glargine) and Regimen-III (premixed insulin). Changes in weight, insulin dose, HbA1c, fructosamine and lipid profile were evaluated. Out of total 53 patients (24 male), 28 patients (52.8%) completed Ramadan fasting (fasting group). The remaining 25 patients were included in (broke-fasting group). Positive correlation between fructosamine changes and number of days fasted during Ramadan. Significant decrease in post-Ramadan fructosamine (<0.001) and increase in post-Ramadan total cholesterol and low density lipoprotein (LDL) levels were detected within fasting, broke-fasting and insulin regimen groups. Significant higher blood glucose at three time points, pre-Iftar, pre-Sohur and midday in Regimen-I compared to Regimen-II and Regimen-III (p=0.004). Fasting during Ramadan is feasible and is associated with significant improvement in fructosamine level in children with T1DM using different insulin regimens. Mandatory consideration to the quality and quantity of food offered to patients with T1DM during Ramadan to guard against adverse changes in lipid profile.

Doxycycline in Eradication Therapy of Helicobacter pylori--a Systematic Review and Meta-Analysis.

PubMed

Niv, Yaron

2016-01-01

Since resistance of Helicobacter pylori is developing very fast all over the world, new treatment regimens for eradication are urgently needed. To compare eradication success rate of H. pylori treatment regimens with and without doxycycline. English medical literature searches were conducted for regimens including doxycycline for eradication of H. pylori. Searches were performed up to August 31, 2015, using MEDLINE, PubMed, EMBASE, Scopus and CENTRAL. Meta-analysis was performed by using comprehensive meta-analysis software. Pooled ORs and 95% CIs were calculated comparing treatment regimens for eradication of H. pylori infection with and without doxycycline. The OR for eradication success rate in a fixed model was in favor for treatment regimens with doxycycline: 1.292, 95% CI 1.048-1.594, p = 0.016. There was no significant heterogeneity in the included studies: Q = 15.130, d.f. (Q) = 8, I2 = 47.126, p > 0.10. When treatment regimens with doxycycline were compared only with treatment regimens with tetracycline, no significant difference was found in eradication success rate: OR 0.95, 95% CI 0.68-1.32, p = 0.77. But when treatment regimens with doxycycline were compared with treatment regimens without tetracycline, the OR in favor of doxycycline was even higher: OR 1.59, 95% CI 1.21-2.09, p < 0.001. In this meta-analysis, we confirmed doxycycline efficiency in the eradication of H. pylori. Thus, triple, quadruple or even high dose dual therapy with regimens containing doxycycline should be considered. © 2016 S. Karger AG, Basel.

Efficacy and safety of a flexible extended regimen of ethinylestradiol/drospirenone for the treatment of dysmenorrhea: a multicenter, randomized, open-label, active-controlled study.

PubMed

Momoeda, Mikio; Kondo, Masami; Elliesen, Joerg; Yasuda, Masanobu; Yamamoto, Shigetomo; Harada, Tasuku

2017-01-01

Dysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen) is approved for this indication in Japan. The aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen) in Japanese women with dysmenorrhea. This multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 μg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24-120 days followed by a 4-day tablet-free interval) or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles). The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed. A total of 216 women (mean age 29.7 years) were randomized to the flexible regimen (n=108) or 28d regimen (n=108) and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107). Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in disease severity reported in both treatment groups. According to the investigators, 64.8% and 59.4% of women in the flexible-regimen and 28d-regimen treatment groups had "very much improved" or "much improved" disease, while 54.3% and 50.9% of patients reported being "very much satisfied" or "much satisfied" with their treatment, respectively. In Japanese women with dysmenorrhea, a flexible extended regimen of ethinylestradiol/drospirenone decreased the number of days with dysmenorrheic pain versus the traditional 28d regimen.

Efficacy and safety of a flexible extended regimen of ethinylestradiol/drospirenone for the treatment of dysmenorrhea: a multicenter, randomized, open-label, active-controlled study

PubMed Central

Momoeda, Mikio; Kondo, Masami; Elliesen, Joerg; Yasuda, Masanobu; Yamamoto, Shigetomo; Harada, Tasuku

2017-01-01

Background Dysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen) is approved for this indication in Japan. Aim The aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen) in Japanese women with dysmenorrhea. Methods This multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 μg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24–120 days followed by a 4-day tablet-free interval) or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles). The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed. Results A total of 216 women (mean age 29.7 years) were randomized to the flexible regimen (n=108) or 28d regimen (n=108) and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107). Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in disease severity reported in both treatment groups. According to the investigators, 64.8% and 59.4% of women in the flexible-regimen and 28d-regimen treatment groups had “very much improved” or “much improved” disease, while 54.3% and 50.9% of patients reported being “very much satisfied” or “much satisfied” with their treatment, respectively. Conclusion In Japanese women with dysmenorrhea, a flexible extended regimen of ethinylestradiol/drospirenone decreased the number of days with dysmenorrheic pain versus the traditional 28d regimen. PMID:28496369

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.

Dual Therapeutic Effects of C-10068, a Dextromethorphan Derivative, Against Post-Traumatic Nonconvulsive Seizures and Neuroinflammation in a Rat Model of Penetrating Ballistic-Like Brain Injury.

PubMed

Lu, Xi-Chun May; Shear, Deborah A; Graham, Philip B; Bridson, Gary W; Uttamsingh, Vinita; Chen, Zhiyong; Leung, Lai Yee; Tortella, Frank C

2015-10-15

Post-traumatic seizures can exacerbate injurious outcomes of severe brain trauma, yet effective treatments are limited owing to the complexity of the pathology underlying the concomitant occurrence of both events. In this study, we tested C-10068, a novel deuterium-containing analog of (+)-N-methyl-3-ethoxymorphinan, in a rat model of penetrating ballistic-like brain injury (PBBI) and evaluated the effects of C-10068 on PBBI-induced nonconvulsive seizures (NCS), acute neuroinflammation, and neurofunctional outcomes. NCS were detected by electroencephalographic monitoring. Neuroinflammation was evaluated by immunohistochemical markers, for example, glial fibrillary acidic protein and major histocompatibility complex class I, for activation of astrocytes and microglia, respectively. Neurofunction was tested using rotarod and Morris water maze tasks. Three infusion doses of C-10068 (1.0, 2.5, and 5.0 mg/kg/h × 72 h) were tested in the antiseizure study. Neuroinflammation and neurofunction were evaluated in animals treated with 5.0 mg/kg/h × 72 h C-10068. Compared to vehicle treatment, C-10068 dose dependently reduced PBBI-induced NCS incidence (40-50%), frequency (20-70%), and duration (30-82%). The most effective antiseizure dose of C-10068 (5.0 mg/kg/h × 72 h) also significantly attenuated hippocampal astrocyte activation and perilesional microglial reactivity post-PBBI. Within C-10068-treated animals, a positive correlation was observed in reduction in NCS frequency and reduction in hippocampal astrocyte activation. Further, C-10068 treatment significantly attenuated astrocyte activation in seizure-free animals. However, C-10068 failed to improve PBBI-induced motor and cognitive functions with the dosing regimen used in this study. Overall, the results indicating that C-10068 exerts both potent antiseizure and antiinflammatory effects are promising and warrant further investigation.

Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin combination chemotherapy.

PubMed

Barişta, I; Tekuzman, G; Yalçin, S; Güllü, I; Güler, N; Ozişik, Y; Kars, A; Celik, I; Türker, A; Altundağ, K; Zengin, N; Uner, A; Baltali, E; Firat, D

2000-01-01

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas. Copyright 2000 Wiley-Liss, Inc.

Salicylic acid plasma levels following multiple doses of Norgesic Forte and aspirin.

PubMed

Harrison, L I; Kehe, C R; Goldlust, M B; Kvam, D C; Bianchine, J R

1983-01-01

Plasma salicyclic acid levels from the recommended multiple dose regimen of Norgesic Forte (orphenadrine citrate, aspirin, and caffeine) were compared to those from an equivalent multiple dose regimen of aspirin alone in 24 volunteers. The drugs were administered double-blind so that side effects could also be compared. No statistically significant differences were found between Norgesic Forte and aspirin in peak or trough levels, time to peak level, area under the curve, or mean steady-state level of salicylic acid. Mean steady-state levels averaged 154 +/- 46 (+/- SD) and 152 +/- 49 micrograms/ml on days 5 and 10 following Norgesic Forte versus 161 +/- 49 and 154 +/- 47 micrograms/ml following aspirin. Thus, the aspirin in Norgesic Forte provides an anti-inflammatory amount of salicylic acid equivalent to that of plain aspirin. There was no evidence that the combination of orphenadrine citrate, caffeine, and aspirin in Norgesic Forte caused increased or unusual side effects compared with aspirin alone.

Palonosetron as an anti-emetic and anti-nausea agent in oncology.

PubMed

Aapro, Matti S

2007-12-01

Palonosetron (Aloxi(®), Onicit(®), Paloxi(®)) is a second-generation 5-HT(3) receptor antagonist (RA) with an extended half-life of ~40 hours and high binding affinity for the 5-HT₃ receptor that is markedly different from other 5-HT(3) RAs. Phase III trials demonstrate that a single dose of palonosetron compared with traditional 5-HT₃ RAs is more effective in preventing chemotherapy-induced nausea and vomiting (CINV) during the first 24 hours following chemotherapy (acute CINV), and also exhibits prolonged efficacy to provide significantly better protection from CINV in the delayed and overall phases. This superior and extended protection from CINV conferred by palonosetron following a single intravenous dose before chemotherapy simplifies dosing schedules. Recent research has focused on optimization of palonosetron-based antiemetic regimens, particularly in combination with steroids and neurokinin-1 RAs. The available clinical data indicate high control rates for palonosetron, suggesting a synergistic potential for protection in patients scheduled to receive emetogenic drug regimens.

DOSIMETRIC CHARACTERISTICS OF GAMMA-TRON-2 (in Russian)

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

Krongauz, A.N.; Pavlova, T.G.; Frolova, A.V.

1963-01-01

Dosimetric characteristics of the Gammatron-2 during operation in a static regimen are presented. The air dose and the distribution of doses along the central ray of the beam and on the sides were determined. The protective properties of Gammatron-2 were studied. On the basis of the measurements, charts of isodoses were elaborated. (P.C.H.)

Pharmacoeconomic analysis of recombinant factor VIIa versus APCC in the treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors.

PubMed

Joshi, Ashish V; Stephens, Jennifer M; Munro, Vicki; Mathew, Prasad; Botteman, Marc F

2006-01-01

To compare the cost-effectiveness of three treatment regimens using recombinant activated Factor VII (rFVIIa), NovoSeven, and activated prothrombin-complex concentrate (APCC), FEIBA VH, for home treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors. A literature-based, decision-analytic model was developed to compare three treatment regimens. The regimens consisting of first-, second-, and third-line treatments were: rFVIIa-rFVIIa-rFVIIa; APCC-rFVIIa-rFVIIa; and APCC-APCC-rFVIIa. Patients not responding to first-line treatment were administered second-line treatment, and those failing second-line received third-line treatment. Using literature and expert opinion, the model structure and base-case inputs were adapted to the US from a previously published analysis. The percentage of evaluable bleeds controlled with rFVIIa and APCC were obtained from published literature. Drug costs (2005 US$) based on average wholesale price were included in the base-case model. Univariate and probabilistic sensitivity analyses (second-order Monte Carlo simulation) were conducted by varying the efficacy, re-bleeding rates, patient weight, and dosing to ascertain robustness of the model. In the base-case analysis, the average cost per resolved bleed using rFVIIa as first-, second-, and third-line treatment was $28 076. Using APCC as first-line and rFVIIa as second- and third-line treatment resulted in an average cost per resolved bleed of $30 883, whereas the regimen using APCC as first- and second-line, and rFVIIa as third-line treatment was the most expensive, with an average cost per resolved bleed of $32 150. Cost offsets occurred for the rFVIIa-only regimen through avoidance of second and third lines of treatment. In probabilistic sensitivity analyses, the rFVIIa-only strategy was the least expensive strategy more than 68% of the time. The management of minor-to-moderate bleeds extends beyond the initial line of treatment, and should include the economic impact of re-bleeding and failures over multiple lines of treatment. In the majority of cases, the rFVIIa-only regimen appears to be a less expensive treatment option in inhibitor patients with minor-to-moderate bleeds over three lines of treatment.

High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group.

PubMed

Pritchard, Jon; Cotterill, Simon J; Germond, Shirley M; Imeson, John; de Kraker, Jan; Jones, David R

2005-04-01

High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative "megatherapy" was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment. Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21-54%) in the melphalan-treated group and 27% (95% CI 12-42%) in the "no-melphalan" group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test). In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified. Because they are more toxic, complex, and costly these combination megatherapy regimens should be compared with single agent melphalan in randomised clinical trials.

Antitumor activity of cryptophycins: effect of infusion time and combination studies.

PubMed

Menon, K; Alvarez, E; Forler, P; Phares, V; Amsrud, T; Shih, C; Al-Awar, R; Teicher, B A

2000-01-01

Cryptophycins are a family of antitubulin antitumor agents. A synthetic cryptophycin derivative (LY355703, CRYPTO 52) is in early clinical evaluation. The effect of infusion time on the antitumor activity of four cryptophycins was assessed in rats bearing the 13762 mammary carcinoma and combination treatment regimens were assessed in nude mice bearing human tumor xenografts. The cryptophycins were prepared in 2% PEG300/8% cremophor/90% normal saline and delivered by jugular vein catheter on days 7, 9 and 11 post tumor implant to 13762 tumor-bearing rats. The cryptophycins prepared in the same formulation were administered by intravenous bolus injection on an alternate day schedule for five doses to human tumor xenograft bearing nude mice. An infusion time of 2 h in the rats increased the tumor growth delay produced by CRYPTO 52 and CRYPTO 55, while increasing the infusion time to 6 h continued to increase the tumor growth delay for CRYPTO 292 and CRYPTO 296. Administering CRYPTO 292 at a higher dose two times was more effective than administering it at a lower dose three times. The tumor growth delays produced by the cryptophycins in the rat 13762 mammary carcinoma were greater than those with cisplatin, doxorubicin, 5-fluorouracil and 5 x 3 Gray and comparable with cyclophosphamide and gemcitabine. Combination studies were carried out in human tumor xenografts including the MX-1 breast carcinoma, the Calu-6 non-small cell lung carcinoma, the H82 small cell lung carcinoma and the SW-2 small cell lung carcinoma. CRYPTO 52 and CRYPTO 55 combined with doxorubicin, paclitaxel and 5-fluorouracil to form highly effective regimens against the human MX-1 breast carcinoma. CRYPTO 52 and CRYPTO 55 were also highly effective against the three lung carcinoma xenografts when combined with the antitumor platinum complexes, cisplatin, carboplatin or oxaliplatin. Cryptophycins represent a promising new class of antitumor agents that may be optimally administered by intravenous infusion and in combination with doxorubicin, paclitaxel and 5-fluorouracil.

A short 2 week dose titration regimen reduces the severity of flu-like symptoms with initial interferon gamma-1b treatment.

PubMed

Devane, John G; Martin, Mary L; Matson, Mark A

2014-06-01

Flu-like symptoms (FLS) are commonly experienced by patients receiving interferon gamma-1b which may cause discontinuation or disruption of dosing during initial therapy or on re-initiation following a break in therapy. In contrast to Type I interferons, the impact of dose-titration on FLS has not been reported and is not a practice described or included in the approved prescribing information for interferon gamma-1b.The objective of this study was to assess the effect of a 2 week titration regimen on the severity of FLS during the initial 3 weeks of therapy with three times weekly subcutaneous injections of interferon gamma-1b. Healthy men and women were randomized into a double-blind, two-period, crossover study. Each study period was 3 weeks in duration and there was a minimum 15 day washout between treatment periods. Two treatment regimens were compared: No Titration dosing (full 50 mcg/m(2) subcutaneously [s.c.] three times weekly for 3 weeks) and Titration (15 mcg/m(2) s.c. three times weekly during week 1, 30 mcg/m(2) s.c. three times weekly during week 2 followed by the full dose of 50 mcg/m(2) s.c. three times weekly during week 3). Subjects remained in the clinic for at least 12 hours following each injection. FLS was based on a composite score for fever, chills, tiredness and muscle aches assessed at baseline and 4, 8 and 12 hours following each injection. Acetaminophen was allowed at the discretion of the PI. The primary endpoint was the change from baseline in FLS severity at 8 hours averaged over the 3 weeks of treatment. Additional endpoints included FLS at 4 and 12 hours, individual flu-like symptoms, rates of discontinuation, incidence of FLS and acetaminophen use. NCT 01929382. Of the 40 subjects randomized, there were 15 (37.5%) discontinuations. Titration resulted in a significant reduction in FLS severity at 8 hours (p = 0.023) averaged over the 3 week treatment period. The difference in 3 week FLS severity reflects differences during week 1 treatment, indicating an early peak in FLS severity during the No Titration treatment and subsequent development of tolerance. In contrast, titration results in near baseline severity scores throughout the treatment period. Similar trends were seen for 4 and 12 hour FLS severity scores. Of the individual FLS, difference in fever severity was most marked. Safety profiles for both regimens were consistent with the approved prescribing information for interferon gamma-1b. Study limitations included the use of healthy subjects rather than disease subjects, the lack of a validated assessment tool for evaluating FLS and the relatively high discontinuation rate. A short 2 week, dose-titration regimen reduces FLS severity following interferon gamma-1b treatment initiation in normal subjects.

Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.

PubMed

Hézode, Christophe; Asselah, Tarik; Reddy, K Rajender; Hassanein, Tarek; Berenguer, Marina; Fleischer-Stepniewska, Katarzyna; Marcellin, Patrick; Hall, Coleen; Schnell, Gretja; Pilot-Matias, Tami; Mobashery, Niloufar; Redman, Rebecca; Vilchez, Regis A; Pol, Stanislas

2015-06-20

Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. AbbVie. Copyright © 2015 Elsevier Ltd. All rights reserved.

A phase II study of V-BEAM as conditioning regimen before second auto-SCT for multiple myeloma.

PubMed

Wang, T-F; Fiala, M A; Cashen, A F; Uy, G L; Abboud, C N; Fletcher, T; Wu, N; Westervelt, P; DiPersio, J F; Stockerl-Goldstein, K E; Vij, R

2014-11-01

High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.

Omeprazole does not change the oral bioavailability or pharmacokinetics of vinpocetine in rats.

PubMed

Sozański, Tomasz; Magdalan, Jan; Trocha, Małgorzata; Szumny, Antoni; Merwid-Ląd, Anna; Słupski, Wojciech; Karaźniewicz-Łada, Marta; Kiełbowicz, Grzegorz; Ksiądzyna, Dorota; Szeląg, Adam

2011-01-01

Previous studies proved that food strongly enhanced the bioavailability of vinpocetine. Food may change the pharmacokinetics of a drug by affecting various factors, including gastrointestinal pH. However, the influence of proton pump inhibitor-induced pH alterations on vinpocetine pharmacokinetics is not known. The aim was to evaluate the influence of omeprazole on the pharmacokinetics of oral vinpocetine. One group of male Wistar rats received single oral doses of vinpocetine (2 mg/kg - regimen V). In the second group, omeprazole (10 mg/kg) was administered intraperitoneally for 5 days before vinpocetine administration (regimen OV). For analysis of vinpocetine pharmacokinetics, blood samples were obtained before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h after vinpocetine administration. Vinpocetine concentrations were measured by high performance liquid chromatography (HPLC). The mean values of AUC(0-t), AUC(0-inf) and C(max) in regimen V were very similar to respective values in regimen OV. The mean T(max) in both regimens was estimated for 1.5 h. There were no statistically significant differences between both regimens. In conclusion, omeprazole did not affect the pharmacokinetic profile of vinpocetine.

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

Perko, Z; Bortfeld, T; Hong, T

Purpose: The safe use of radiotherapy requires the knowledge of tolerable organ doses. For experimental fractionation schemes (e.g. hypofractionation) these are typically extrapolated from traditional fractionation schedules using the Biologically Effective Dose (BED) model. This work demonstrates that using the mean dose in the standard BED equation may overestimate tolerances, potentially leading to unsafe treatments. Instead, extrapolation of mean dose tolerances should take the spatial dose distribution into account. Methods: A formula has been derived to extrapolate mean physical dose constraints such that they are mean BED equivalent. This formula constitutes a modified BED equation where the influence of themore » spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 14 liver cancer patients previously treated with proton therapy in 5 or 15 fractions, for whom also photon IMRT plans were available. Results: Our work has two main implications. First, in typical clinical plans the dose distribution can have significant effects. When mean dose tolerances are extrapolated from standard fractionation towards hypofractionation they can be overestimated by 10–15%. Second, the shape difference between photon and proton dose distributions can cause 30–40% differences in mean physical dose for plans having the same mean BED. The combined effect when extrapolating proton doses to mean BED equivalent photon doses in traditional 35 fraction regimens resulted in up to 7–8 Gy higher doses than when applying the standard BED formula. This can potentially lead to unsafe treatments (in 1 of the 14 analyzed plans the liver mean dose was above its 32 Gy tolerance). Conclusion: The shape effect should be accounted for to avoid unsafe overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. In addition, tolerances established for a given treatment modality cannot necessarily be applied to other modalities with drastically different dose distributions.« less

Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa.

PubMed

Taylor, W Robert; Naw, Htee Khu; Maitland, Kathryn; Williams, Thomas N; Kapulu, Melissa; D'Alessandro, Umberto; Berkley, James A; Bejon, Philip; Okebe, Joseph; Achan, Jane; Amambua, Alfred Ngwa; Affara, Muna; Nwakanma, Davis; van Geertruyden, Jean-Pierre; Mavoko, Muhindo; Lutumba, Pascal; Matangila, Junior; Brasseur, Philipe; Piola, Patrice; Randremanana, Rindra; Lasry, Estrella; Fanello, Caterina; Onyamboko, Marie; Schramm, Birgit; Yah, Zolia; Jones, Joel; Fairhurst, Rick M; Diakite, Mahamadou; Malenga, Grace; Molyneux, Malcolm; Rwagacondo, Claude; Obonyo, Charles; Gadisa, Endalamaw; Aseffa, Abraham; Loolpapit, Mores; Henry, Marie-Claire; Dorsey, Grant; John, Chandy; Sirima, Sodiomon B; Barnes, Karen I; Kremsner, Peter; Day, Nicholas P; White, Nicholas J; Mukaka, Mavuto

2018-01-18

In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

Cycle control with an extended-regimen oral contraceptive combining levonorgestrel and ethinyl estradiol that includes continuous low-dose ethinyl estradiol instead of the traditional hormone-free interval.

PubMed

Nappi, Rossella E; Lobo Abascal, Paloma; Hsieh, Jennifer; Micheletti, Marie-Christine

2017-01-01

To evaluate scheduled and unscheduled bleeding and spotting over 1 year of treatment with 91-day extended-regimen combined oral contraception (COC) providing continuous low-dose ethinyl estradiol (EE) in place of the traditional 7-day hormone-free interval (HFI). This post hoc analysis of a multicenter, open-label, 1-year, Phase 3 study of extended-regimen COC with 30 µg EE/150 µg levonorgestrel (LNG) for 84 days and EE 10 µg for 7 days included 799 sexually active, adult women who completed at least one 91-day cycle of therapy. Subjects recorded bleeding and spotting episodes daily using electronic diaries. Logistic regression analyses are reported as ORs with 95% CIs. There was a 10% increase (OR =1.102; 95% CI: 1.006-1.206) in the likelihood of reporting no scheduled bleeding for each additional 91-day cycle completed. From the third 91-day cycle, more than one fifth of women reported no scheduled bleeding (third cycle =23% [121/533]; fourth cycle =22% [97/446]). Among women who reported no scheduled bleeding at Cycle 1 (136/758 [18%]), ≥45% showed sustained lack of scheduled bleeding in later cycles. There were increases of 53% (OR =1.531; 95% CI: 1.393-1.683) and 31% (OR =1.307; 95% CI: 1.205-1.418) in the likelihood of reporting 0 to ≤6 days vs >6 days of unscheduled bleeding and spotting, respectively, for each additional 91-day cycle. By Cycle 2, more than 80% of women reported no unscheduled bleeding or ≤6 days of unscheduled bleeding during each 91-day cycle. Improved cycle control with decreased bleeding over time was shown during extended-regimen COC with 30 µg EE/150 µg LNG for 84 days and continuous low-dose EE instead of the traditional 7-day HFI. Women considering this regimen should be informed that those who complete at least one 91-day COC cycle will likely experience less bleeding/spotting in future cycles.

Cycle control with an extended-regimen oral contraceptive combining levonorgestrel and ethinyl estradiol that includes continuous low-dose ethinyl estradiol instead of the traditional hormone-free interval

PubMed Central

Nappi, Rossella E; Lobo Abascal, Paloma; Hsieh, Jennifer; Micheletti, Marie-Christine

2017-01-01

Purpose To evaluate scheduled and unscheduled bleeding and spotting over 1 year of treatment with 91-day extended-regimen combined oral contraception (COC) providing continuous low-dose ethinyl estradiol (EE) in place of the traditional 7-day hormone-free interval (HFI). Patients and methods This post hoc analysis of a multicenter, open-label, 1-year, Phase 3 study of extended-regimen COC with 30 µg EE/150 µg levonorgestrel (LNG) for 84 days and EE 10 µg for 7 days included 799 sexually active, adult women who completed at least one 91-day cycle of therapy. Subjects recorded bleeding and spotting episodes daily using electronic diaries. Logistic regression analyses are reported as ORs with 95% CIs. Results There was a 10% increase (OR =1.102; 95% CI: 1.006–1.206) in the likelihood of reporting no scheduled bleeding for each additional 91-day cycle completed. From the third 91-day cycle, more than one fifth of women reported no scheduled bleeding (third cycle =23% [121/533]; fourth cycle =22% [97/446]). Among women who reported no scheduled bleeding at Cycle 1 (136/758 [18%]), ≥45% showed sustained lack of scheduled bleeding in later cycles. There were increases of 53% (OR =1.531; 95% CI: 1.393–1.683) and 31% (OR =1.307; 95% CI: 1.205–1.418) in the likelihood of reporting 0 to ≤6 days vs >6 days of unscheduled bleeding and spotting, respectively, for each additional 91-day cycle. By Cycle 2, more than 80% of women reported no unscheduled bleeding or ≤6 days of unscheduled bleeding during each 91-day cycle. Conclusion Improved cycle control with decreased bleeding over time was shown during extended-regimen COC with 30 µg EE/150 µg LNG for 84 days and continuous low-dose EE instead of the traditional 7-day HFI. Women considering this regimen should be informed that those who complete at least one 91-day COC cycle will likely experience less bleeding/spotting in future cycles. PMID:29042818

Levofloxacin dosing regimen in severely morbidly obese patients (BMI ≥40 kg/m(2)) should be guided by creatinine clearance estimates based on ideal body weight and optimized by therapeutic drug monitoring.

PubMed

Pai, Manjunath P; Cojutti, Piergiorgio; Pea, Federico

2014-08-01

Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses. The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24 h (AUC24). A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18 years of age with a body mass index ≥40 kg/m(2). A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24. A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250 kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg·h/L, respectively. Levofloxacin CL was significantly (p < 0.05) related to height but not weight. As a result, levofloxacin CL was best related (R (2) = 0.57) to creatinine CL (CLcr) estimated by the Cockcroft-Gault (CG) equation and ideal body weight (IBW) because IBW is a height transformation. An empiric four-category daily-dose regimen (500, 750, 1,000, 1,250 mg) stratified by CLcr (CG-IBW) is expected to have >90 % probability of achieving an AUC24 of 50-150 mg·h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen. The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese.

Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

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

Westover, Kenneth D.; Loo, Billy W.; Gerber, David E.

2015-09-01

Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiationmore » therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59). Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.« less

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 Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.

PubMed

Biran, Noa; Rowley, Scott D; Vesole, David H; Zhang, Shijia; Donato, Michele L; Richter, Joshua; Skarbnik, Alan P; Pecora, Andrew; Siegel, David S

2016-12-01

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m 2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m 2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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.

Case profile, volume analysis, and dropout rate of antirabies vaccination regimens among animal bite victims in Gujarat.

PubMed

Dhaduk, Kishor M; Unadkat, Sumit V; Katharotiya, Pooja R; Mer, Ankit R; Chaudhary, Monika C; Prajapati, Mrudul M

2016-01-01

Rabies is a preventable neglected public health problem and associated with multiple cultural, religious, and social practices, myths in our country. There is a lack of organized surveillance system to measure the incidence of animal bite and human rabies as well as to evaluate cost-saving of different routes, regimen, and types of antirabies vaccines (ARV)/immunoglobulin available in India. The objective of this study is to know dropout rate in intradermal (i.d.) ARV regimen among animal bite and to analyze the utilized volume of ARV by a different route of vaccine administration. A total of 250 animal bite victims were followed up at ARV Clinic (ARVC). Volume utilization of i.d. route over intramuscular (i.m.) route was analyzed among the patients who attended ARVC during the past 2 years. Total dropout and delayed compliance rates of ARV regimen among different group were compared by Chi-square test. The i.d. route was about five times more volume and cost-saving than i.m. route. The majority of victims belonged to 15-30 years (27.60%) and children <15 years (26.40%) and had wound at their lower limbs (85%) mainly bitten by dogs (98%). Thirty-four percent total dropout and 31.5% delayed compliance observed particularly during the last dose of i.d. regimen. There was no significant difference in dropout rates among different demographic groups. Half of the victims practiced wound toilet on the same day of bite. Only 68% received the first dose of ARV within 24 h of the exposure. Children and young adults are at higher risk of having dog bite. I.d. ARV regimen is more volume and cost-saving than i.m. one and proper counseling and follow-up should be arranged to complete the vaccination schedule.

Treatment outcomes of fixed-dose combination versus separate tablet regimens in pulmonary tuberculosis patients with or without diabetes in Qatar.

PubMed

Al-Shaer, Mohammad H; Mansour, Hanine; Elewa, Hazem; Salameh, Pascale; Iqbal, Fatima

2017-02-02

Tuberculosis is considered the second most common cause of death due to infectious agent. The currently preferred regimen for treatment of pulmonary tuberculosis (PTB) is isoniazid, rifampin, pyrazinamide, and ethambutol, which has been used either as separate tablets (ST) or as fixed-dose combination (FDC). To date, no studies have compared both regimens in Qatar. We aim to evaluate the safety and effectiveness of FDC and ST regimen for treating PTB, in addition to comparing safety and efficacy of FDC and ST regimens in patients with diabetes treated for TB. A retrospective observational study was conducted in two general hospitals in Qatar. Patients diagnosed with PTB received anti-tuberculosis medications (either as FDC or ST) administered by the nurse. Sputum smears were tested weekly. We assessed the time to negative sputum smear and incidence of adverse events among FDC and ST groups. The study included 148 patients. FDC was used in 90 patients (61%). Effectiveness was not different between FDC and ST regimens as shown by mean time to sputum conversion (29.9 ± 18.3 vs. 35.6 ± 23 days, p = 0.12). Similarly, there was no difference in the incidence of adverse events, except for visual one that was higher in ST group. Among the 33 diabetic patients, 19 received the FDC and had faster sputum conversion compared to those who received ST (31 ± 12 vs. 49.4 ± 30.9 days, p = 0.05). Overall, diabetic patients needed longer time for sputum conversion and had more hepatotoxic and gastric adverse events compared to non-diabetics. ST group had higher visual side effects compared to FDC. FDC may be more effective in diabetic patients; however, further studies are required to confirm such finding.

Can BuCyE conditioning regimen be an alternative treatment to BEAM at autologous transplantation in malignant lymphoma patients?: a single center experience

PubMed Central

Berber, Ilhami; Erkurt, Mehmet Ali; Nizam, Ilknur; Koroglu, Mustafa; Kaya, Emin; Kuku, Irfan; Bag, Harika Gozukara

2015-01-01

High-dose chemotherapy (HDC) applied together with autologous stem cell transplantation (ASCT) is a commonly used treatment modality in patients with malignant lymphoma. At present, there is a limited number of studies which compare toxicity and efficacy of various high-dose regimens applied in the treatment of malignant lymphoma. For this reason, the aim of this study was to investigate the efficacy and toxicity of BuCyE (busulfan, cyclophosphamide and etoposide) and BEAM (carmustine, etoposide, cytarabine and melphalan) preparative regimens in the patients with malignant lymphoma scheduled for autologous stem cell transplantation. Between November, 2010 and April, 2015, 42 patients with relapsed or refractory malignant lymphoma who underwent autologous stem cell transplantation following BEAM (n=11) and BuCyE (n=31) preparative regimens were analyzed at Bone Marrow Transplantation Unit of TurgutOzal Medicine Center in Turkey. The groups were compared in terms of patient characteristics, hematopoietic engraftment time, toxicity profiles and survival. No significant differences were detected between the groups with regard to age, gender distribution, international prognostic index, ASCT indications, disease status at the time of ASCT and type of lymphoma (P>0.05). Median number of infused CD34+ cells/kg, neutrophil and platelet engraftment statuses of BuCyE and BEAM groups were found to be similar (P>0.05). More patients in BuCyE group developed mucositis and nausea, but this difference was not statistically significant (P>0.05). A similar statistically insignificant difference was seen in that infectious complications occurred more commonly in BEAM group (P>0.05). Overall survival and event-free survival rates were not significantly different between the groups (P>0.05). BuCyE is a conditioning regimen which can be effectively used as an alternative to BEAM in the patients with malignant lymphoma undergoing ASCT. Moreover, toxicity rates of both regimens are similar. In order to comprehend the effect of each HDC regimen, further evidence-based data obtained from the studies involving larger sample sizes are required. PMID:26629149

Can BuCyE conditioning regimen be an alternative treatment to BEAM at autologous transplantation in malignant lymphoma patients?: a single center experience.

PubMed

Berber, Ilhami; Erkurt, Mehmet Ali; Nizam, Ilknur; Koroglu, Mustafa; Kaya, Emin; Kuku, Irfan; Bag, Harika Gozukara

2015-01-01

High-dose chemotherapy (HDC) applied together with autologous stem cell transplantation (ASCT) is a commonly used treatment modality in patients with malignant lymphoma. At present, there is a limited number of studies which compare toxicity and efficacy of various high-dose regimens applied in the treatment of malignant lymphoma. For this reason, the aim of this study was to investigate the efficacy and toxicity of BuCyE (busulfan, cyclophosphamide and etoposide) and BEAM (carmustine, etoposide, cytarabine and melphalan) preparative regimens in the patients with malignant lymphoma scheduled for autologous stem cell transplantation. Between November, 2010 and April, 2015, 42 patients with relapsed or refractory malignant lymphoma who underwent autologous stem cell transplantation following BEAM (n=11) and BuCyE (n=31) preparative regimens were analyzed at Bone Marrow Transplantation Unit of TurgutOzal Medicine Center in Turkey. The groups were compared in terms of patient characteristics, hematopoietic engraftment time, toxicity profiles and survival. No significant differences were detected between the groups with regard to age, gender distribution, international prognostic index, ASCT indications, disease status at the time of ASCT and type of lymphoma (P>0.05). Median number of infused CD34+ cells/kg, neutrophil and platelet engraftment statuses of BuCyE and BEAM groups were found to be similar (P>0.05). More patients in BuCyE group developed mucositis and nausea, but this difference was not statistically significant (P>0.05). A similar statistically insignificant difference was seen in that infectious complications occurred more commonly in BEAM group (P>0.05). Overall survival and event-free survival rates were not significantly different between the groups (P>0.05). BuCyE is a conditioning regimen which can be effectively used as an alternative to BEAM in the patients with malignant lymphoma undergoing ASCT. Moreover, toxicity rates of both regimens are similar. In order to comprehend the effect of each HDC regimen, further evidence-based data obtained from the studies involving larger sample sizes are required.

A randomized, Phase IIb study investigating oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (μ-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty.

PubMed

Singla, Neil; Minkowitz, Harold S; Soergel, David G; Burt, David A; Subach, Ruth Ann; Salamea, Monica Y; Fossler, Michael J; Skobieranda, Franck

2017-01-01

Oliceridine (TRV130), a novel μ-receptor G-protein pathway selective (μ-GPS) modulator, was designed to improve the therapeutic window of conventional opioids by activating G-protein signaling while causing low β-arrestin recruitment to the μ receptor. This randomized, double-blind, patient-controlled analgesia Phase IIb study was conducted to investigate the efficacy, safety, and tolerability of oliceridine compared with morphine and placebo in patients with moderate to severe pain following abdominoplasty (NCT02335294; oliceridine is an investigational agent not yet approved by the US Food and Drug Administration). Patients were randomized to receive postoperative regimens of intravenous oliceridine (loading/patient-controlled demand doses [mg/mg]: 1.5/0.10 [regimen A]; 1.5/0.35 [regimen B]), morphine (4.0/1.0), or placebo with treatment initiated within 4 hours of surgery and continued as needed for 24 hours. Two hundred patients were treated (n=39, n=39, n=83, and n=39 in the oliceridine regimen A, oliceridine regimen B, morphine, and placebo groups, respectively). Patients were predominantly female (n=198 [99%]) and had a mean age of 38.2 years, weight of 71.2 kg, and baseline pain score of 7.7 (on 11-point numeric pain rating scale). Patients receiving the oliceridine regimens had reductions in average pain scores (model-based change in time-weighted average versus placebo over 24 hours) of 2.3 and 2.1 points, respectively ( P =0.0001 and P =0.0005 versus placebo); patients receiving morphine had a similar reduction (2.1 points; P <0.0001 versus placebo). A lower prevalence of adverse events (AEs) related to nausea, vomiting, and respiratory function was observed with the oliceridine regimens than with morphine ( P <0.05). Other AEs with oliceridine were generally dose-related and similar in nature to those observed with conventional opioids; no serious AEs were reported with oliceridine. These results suggest that oliceridine may provide effective, rapid analgesia in patients with moderate to severe postoperative pain, with an acceptable safety/tolerability profile and potentially wider therapeutic window than morphine.

Evolving Role of Local Anesthetics in Managing Postsurgical Analgesia.

PubMed

Golembiewski, Julie; Dasta, Joseph

2015-06-01

Opioid analgesics, the cornerstone of effective postsurgical pain management, may be associated with risk of opioid-related adverse drug events (ADEs) that may complicate the postsurgical experience. Perioperative multimodal analgesic regimens have the potential to improve postsurgical pain control and may permit use of lower analgesic doses and reduce the incidence of opioid-related ADEs. Utility of traditional local anesthetic formulations to provide analgesia over the entire postsurgical period is limited by their short duration of action. Liposome bupivacaine, a liposomal formulation of bupivacaine indicated for single-dose administration into the surgical site to produce postsurgical analgesia, was evaluated in multiple surgical models as part of multimodal analgesic regimens and was found in clinical trials to provide postsurgical analgesia for up to 72 hours. Here, we provide an overview of the available multimodal analgesic options and recent recommendations for optimal postsurgical pain management. A review of the literature was conducted, and results from recent clinical trials are included. The use of a multimodal analgesic regimen, including liposome bupivacaine, can extend the time to first postsurgical opioid use, may reduce postsurgical opioid consumption, and reduce hospital length of stay and costs compared with an opioid-only analgesic regimen. Use of multimodal analgesic regimens is a practical way to achieve good postsurgical analgesia while minimizing reliance on opioids and associated adverse events. Taken as a whole, evidence from the clinical studies of liposome bupivacaine suggests this local anesthetic formulation may be a useful component of multimodal analgesic regimens for managing postsurgical pain in select patients, with the potential to reduce opioid use and opioid-related ADEs in the postsurgical setting. As with bupivacaine, appropriate use of liposome bupivacaine to optimize clinical effects, economic implications, and patient tolerability will depend on appropriate patient selection, practitioner training, and institutional protocols. As a component of a multimodal analgesic regimen, liposome bupivacaine represents a new approach to extending the duration of postsurgical analgesia. Further studies across a range of surgical settings should help clarify the most appropriate roles for this prolonged-release formulation of bupivacaine. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Immunogenicity and Safety of Four Different Dosing Regimens of Anthrax Vaccine Adsorbed for Post-Exposure Prophylaxis for Anthrax in Adults

PubMed Central

Bernstein, David I.; Jackson, Lisa; Patel, Shital M.; El Sahly, Hana M.; Spearman, Paul; Rouphael, Nadine; Rudge, Thomas L.; Hill, Heather; Goll, Johannes B.

2014-01-01

Background Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. Methods Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: A) days 0, 14; B) days 0 and 28; C) days 0, 14, and 28; or D) 0.25 ml at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. Results Almost all subjects developed some local reactions with 46% to 64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥4 fold antibody rise in more subjects on days 21, 28 and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. Conclusion Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages. PMID:25239484

Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics.

PubMed

Rocha, José-Francisco; Sicard, Éric; Fauchoux, Nicolas; Falcão, Amílcar; Santos, Ana; Loureiro, Ana I; Pinto, Roberto; Bonifácio, Maria João; Nunes, Teresa; Almeida, Luís; Soares-da-Silva, Patrício

2017-03-01

To compare the levodopa/carbidopa (LC) and levodopa/benserazide (LB) pharmacokinetic profiles following repeated doses of opicapone (OPC) administered apart from levodopa. Two randomized, double blind, sex-balanced, placebo-controlled studies in four groups of 12 or 18 healthy subjects each. In each group, enrolled subjects received a once-daily morning (5, 15 and 30 mg) or evening (5, 15 and 50 mg) administration of OPC or placebo for up to 28 days. On the morning of Day 11, 12 h after the OPC or placebo evening dose, or the morning of Day 21, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LC was administered. Similarly, on Day 18 morning, 12 h after the OPC or placebo evening dose, or Day 28 morning, 1 h after the OPC or placebo dose, a single dose of immediate-release 100/25 mg LB was administered. All OPC treatments, in relation to the placebo group, presented a higher extent of exposure (AUC) to levodopa following either LC or LB doses. A relevant but not dose-dependent increase in the levodopa AUC occurred with all OPC dose groups in relation to placebo. All active treatments significantly inhibited both peak (E max ) and extent (AUEC) of the catechol-O-methyltransferase activity in relation to placebo. The tolerability profile was favourable. Opicapone, as once-daily oral evening regimen and/or 1 h apart from levodopa therapy, increases the bioavailability of levodopa associated with its pronounced, long-lasting and sustained catechol-O-methyltransferase inhibition. The tolerability profile was favourable and similar between OPC and placebo. © 2016 The British Pharmacological Society.

Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults.

PubMed

Bernstein, David I; Jackson, Lisa; Patel, Shital M; El Sahly, Hana M; Spearman, Paul; Rouphael, Nadine; Rudge, Thomas L; Hill, Heather; Goll, Johannes B

2014-10-29

Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: (A) days 0, 14; (B) days 0 and 28; (C) days 0, 14, and 28; or (D) 0.25 mL at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. Almost all subjects developed some local reactions with 46-64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥ 4 fold antibody rise in more subjects on days 21, 28, and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model.

PubMed

Brange, Charlotte; Smailagic, Amir; Jansson, Anne-Helene; Middleton, Brian; Miller-Larsson, Anna; Taylor, John D; Silberstein, David S; Lal, Harbans

2009-02-01

Clinical studies show that flexible dosing (maintenance and symptom-driven dose adjustments) of budesonide and formoterol (BUD/FORM) improves control of asthma exacerbations as compared to fixed maintenance dosing protocols (maintenance therapy) even when the latter utilize higher BUD/FORM doses. This suggests that dose-response relationships for certain pathobiologic mechanisms in asthma shift over time. Here, we have conducted animal studies to address this issue. (1) To test in an animal asthma-like model whether it is possible to achieve the same or greater pharmacological control over bronchoconstriction and airway/lung inflammation, and with less total drug used, by flexible BUD/FORM dosing (upward adjustment of doses) in association with allergen challenges. (2) To determine whether the benefit requires adjustment of both drug components. Rats sensitized on days 0 and 7 were challenged intratracheally with ovalbumin on days 14 and 21. On days 13-21, rats were treated intratracheally with fixed maintenance or flexible BUD/FORM combinations. On day 22, rats were challenged with methacholine and lungs were harvested for analysis. A flexible BUD/FORM dosing regimen (using 3.3 times less total drug than the fixed maintenance high dose regimen), delivered the same or greater reductions of excised lung gas volume (a measure of gas trapped in lung by bronchoconstriction) and lung weight (a measure of inflammatory oedema). When either BUD or FORM alone was increased on days of challenge, the benefit of the flexible dose upward adjustment was lost. Flexible dosing of the BUD/FORM combination improves the pharmacological inhibition of allergen-induced bronchoconstriction and an inflammatory oedema in an allergic asthma-like rat model.

Medication regimen complexity in ambulatory older adults with heart failure.

PubMed

Cobretti, Michael R; Page, Robert L; Linnebur, Sunny A; Deininger, Kimberly M; Ambardekar, Amrut V; Lindenfeld, JoAnn; Aquilante, Christina L

2017-01-01

Heart failure prevalence is increasing in older adults, and polypharmacy is a major problem in this population. We compared medication regimen complexity using the validated patient-level Medication Regimen Complexity Index (pMRCI) tool in "young-old" (60-74 years) versus "old-old" (75-89 years) patients with heart failure. We also compared pMRCI between patients with ischemic cardiomyopathy (ISCM) versus nonischemic cardiomyopathy (NISCM). Medication lists were retrospectively abstracted from the electronic medical records of ambulatory patients aged 60-89 years with heart failure. Medications were categorized into three types - heart failure prescription medications, other prescription medications, and over-the-counter (OTC) medications - and scored using the pMRCI tool. The study evaluated 145 patients (n=80 young-old, n=65 old-old, n=85 ISCM, n=60 NISCM, mean age 73±7 years, 64% men, 81% Caucasian). Mean total pMRCI scores (32.1±14.4, range 3-84) and total medication counts (13.3±4.8, range 2-30) were high for the entire cohort, of which 72% of patients were taking eleven or more total medications. Total and subtype pMRCI scores and medication counts did not differ significantly between the young-old and old-old groups, with the exception of OTC medication pMRCI score (6.2±4 young-old versus 7.8±5.8 old-old, P =0.04). With regard to heart failure etiology, total pMRCI scores and medication counts were significantly higher in patients with ISCM versus NISCM (pMRCI score 34.5±15.2 versus 28.8±12.7, P =0.009; medication count 14.1±4.9 versus 12.2±4.5, P =0.008), which was largely driven by other prescription medications. Medication regimen complexity is high in older adults with heart failure, and differs based on heart failure etiology. Additional work is needed to address polypharmacy and to determine if medication regimen complexity influences adherence and clinical outcomes in this population.

Drospirenone/ethinyl estradiol.

PubMed

Rapkin, Andrea J; Sorger, Shelley N; Winer, Sharon A

2008-02-01

Drospirenone 3 mg/ethinyl estradiol 20 microg (24/4) is a new unique oral contraceptive formulation that combines in a novel dosing regimen the lowest dosage of ethinyl estradiol commonly used today with drospirenone, an innovative progestin. Drospirenone is a compound closely resembling progesterone, but with the antimineralocorticoid and antiandrogenic properties of a related therapeutic agent, the diuretic, antihypertensive and androgen receptor antagonist, 17alpha-spironolactone. The prolongation of hormonally active pills in the monthly drospirenone/ethinyl estradiol cycle from 21 days to 24 days, followed by 4 days of inactive pills, is an interesting variant of the recently developed extended pill regimens (1). Recent contraceptive research has focused on improving side effect profiles and providing noncontraceptive health and lifestyle advantages. Many of these benefits are now supported with evidence-based medicine (2). Most available oral contraceptives improve cycle regularity, menstrual pain, excessive menstrual flow and acne. However, weight gain, bloating, food cravings, breast tenderness and mood alterations (especially irritability and depression and the complex of affective, behavioral and somatic symptoms of premenstrual syndrome [PMS] and the severe form of PMS, premenstrual dysphoric disorder [PMDD]) are not generally improved with the traditional oral contraceptive formulations (3). Drospirenone/ethinyl estradiol 24/4 is currently the only hormonally based contraceptive regimen with large, randomized, controlled trials demonstrating efficacy for PMDD. It has received U.S. Food and Drug Administration (FDA) indications not only for the prevention of pregnancy but also for PMDD and for moderate acne vulgaris in women who choose oral contraception for birth control (4, 5). Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

A strategy for reaching therapeutic salicylate levels in patients with rheumatoid arthritis using standardized dosing regimens.

PubMed

Furst, D E; Blocka, K; Cassell, S; Dromgoole, S; Harris, E R; Hirschberg, J M; Josephson, N; Rupp, P A; Paulus, H E; Trimble, R B

1987-04-01

After one to 2 weeks of 45 mg/kg/day choline magnesium trisalicylate (CMT) in 2 divided doses, 51 of 71 patients with rheumatoid arthritis (72%) had observed steady state serum salicylate concentrations between 150 and 300 mg/l (mean salicylate: 213 +/- 10 mg/l), although 17 later required dose adjustment. CMT dosing was changed in 37 cases by using the formula: dosing rate = total clearance X concentration. The expected and observed concentrations were not different (p = 0.31); thus, this formula can help calculate salicylate dosing changes to bring the serum salicylate level to within the therapeutic range.

A Pivotal Field Study to Support the Registration of Levothyroxine Sodium Tablets for Canine Hypothyroidism.

PubMed

Lewis, Victoria A; Morrow, Carla M K; Jacobsen, Johnny A; Lloyd, W Eugene

2018-05-14

A prospective, pivotal, multicenter field study to evaluate the dose regimen, effectiveness, and safety of levothyroxine sodium tablets, USP for the treatment of hypothyroidism and hypothyroidism-associated clinical signs in dogs was conducted. Ninety-two dogs diagnosed with primary hypothyroidism met the entrance criteria and were enrolled into the study. Levothyroxine sodium was administered to each dog on a daily basis either as the whole dose q 24 hr or as half the dose q 12 hr. Dosing started at 0.1 mg/10 lb (0.022 mg/kg) and continued for approximately 6 mo to Day 182. During this time, the thyroid status of each dog was evaluated at monthly intervals. For the determination of effectiveness, dogs classified as euthyroid at Day 182, based on their thyroid hormone values, were considered treatment successes. Results of the statistical analysis showed that there was no difference between the two dosing regimens (P = .11) and that when the data from both groups were pooled, the overall success rate was 75.64% (95% confidence interval = 66.34%). By Day 182, improvement and/or resolution of hypothyroidism-associated clinical signs was observed in all categories. No abnormal trends in the reported adverse events were observed.

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer.

PubMed

Uwagawa, Tadashi; Sakamoto, Taro; Abe, Kyohei; Okui, Norimitsu; Hata, Daigo; Shiba, Hiroaki; Futagawa, Yasuro; Aiba, Keisuke; Yanaga, Katsuhiko

2015-01-01

To date, gemcitabine-based or fluoropyrimidine-based regimens are recommended for unresectable advanced biliary tract cancer. Then, we conducted a phase I study of gemcitabine/cisplatin and S-1 that is an oral fluoropyrimidine. The aim of this study was to determine the dose-limiting toxicity (DLT), maximum-tolerated dose, and a recommended phase II dose of S-1. Response was assessed as a secondary endpoint. Patients who have been diagnosed with unresectable or postoperative recurrent biliary tract cancer received cisplatin (25 mg/m² i.v. for 120 min) followed by gemcitabine (1,000 mg/m² i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days; this regimen was repeated at 21-day intervals. A standard '3 + 3' phase I dose-escalation design was adopted. This study was registered with University hospital Medical Information Network (UMIN) Center in Japan, number UMIN000008415. Twelve patients were evaluable in this study. No patients developed DLTs. Recommended dose of S-1 was 80 (<1.25 m²), 100 (1.25 ≤ 1.5 m²), and 120 mg (1.5 m²≥) per day. One patient could achieve conversion to curative surgery. This phase I study was performed safely and demonstrated encouraging response.

Three day oral course of Augmentin to treat chancroid.

PubMed Central

Ndinya-Achola, J O; Nsanze, H; Karasira, P; Fransen, L; D'Costa, L J; Piot, P; Ronald, A R

1986-01-01

Amoxycillin and clavulanic acid (Augmentin; Beecham Research Laboratories) was used to treat patients with bacteriologically proved chancroid in three different dose regimens. A single dose of Augmentin (amoxycillin 3 g, clavulanic acid 350 mg) was found to be ineffective. A similar dose repeated after 24 hours was equally ineffective, but a dose (amoxycillin 500 mg, clavulanic acid 250 mg) given every 8 hours for three days was found to be effective. The drug was well tolerated and no side effects were noted in any of the patients treated. PMID:3733082

Comparison of anti-retroviral therapy treatment strategies in prevention of mother-to-child transmission in a teaching hospital in Ethiopia.

PubMed

Kumela, Kabaye; Amenu, Demisew; Chelkeba, Legese

2015-01-01

More than 90% of Human immunodeficiency virus (HIV) infection in children is acquired due to mother-to-child transmission, which is spreading during pregnancy, delivery or breastfeeding. To determine the effectiveness of highly active antiretroviral and short course antiretroviral regimens in prevention of mother-to-child transmission of HIV and associated factors Jimma University Specialized Hospital (JUSH). A hospital based retrospective cohort study was conducted on HIV infected pregnant mothers who gave birth and had follow up at anti-retroviral therapy (ART) clinic for at least 6 months during a time period paired with their infants. The primary and secondary outcomes were rate of infant infection by HIV at 6 weeks and 6 months respectively. The Chi-square was used for the comparison of categorical data multivariate logistic regression model was used to identify the determinants of early mother-to-child transmission of HIV at 6 weeks. Cox proportional hazard model was used to analyze factors that affect the 6 month HIV free survival of infants born to HIV infected mothers. A total of 180 mother infant pairs were considered for the final analysis, 90(50%) mothers received single dose nevirapine (sdNVP) designated as regimen-3, 67 (37.2%) mothers were on different types of ARV regimens commonly AZT + 3TC + NVP (regimen-1), while the rest 23 (12.8%) mothers were on short course dual regimen AZT + 3TC + sdNVP (regimen-2). Early mother-to-child transmission rate at 6 weeks for regimens 1, 2 and 3 were 5.9% (4/67), 8.6% (2/23), and 15.5% (14/90) respectively. The late cumulative mother-to-child transmission rate of HIV at 6 months regardless of regimen type was 15.5% (28/180). Postnatal transmission at 6 months was 28.5% (8/28) of infected children. Factors that were found to be associated with high risk of early mother-to-child transmission of HIV include duration of ARV regimen shorter than 2 months during pregnancy (OR=4.3, 95%CI =1.38-13.46), base line CD4 less than 350 cells/cubic mm (OR=6.98, 95%CI=0.91-53.76), early infant infection (OR=5.4, 95%CI=2.04-14.4), infants delivered home (OR=13.1, 95%CI=2.69-63.7), infant with birth weight less than 2500 g (OR=6.41, 95%CI=2.21-18.61), and mixed infant feeding (OR=6.7, 95%CI=2.2-20.4). Antiretroviral regimen duration less than 2 months, maternal base line CD4 less than 350 cells/cubic mm and mixed infant feeding were also important risk factors for late infant infection or death. The effectiveness of multiple antiretroviral drugs in prevention of early mother-to-child transmission of HIV was found to be more effective than that of single dose nevirapine, although, the difference was not statistically significant. But in late transmission, a significant difference was observed in which infants born to mother who received multiple antiretroviral drugs were less likely to progress to infection or death than infants born to mothers who received single dose nevirapine.

Platinum and high-dose cytarabine-based regimens are efficient in ultra high/high-risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study.

PubMed

Durot, Eric; Michallet, Anne-Sophie; Leprêtre, Stéphane; Le, Quoc-Hung; Leblond, Véronique; Delmer, Alain

2015-08-01

Ultra high-risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine-based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty-seven patients had R/R CLL (including 36 ultra high-risk CLL) and 28 had RS. Median age was 62 years (range, 18-79 years). Median number of previous therapies was 3 (range, 1-7), including fludarabine-based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression-free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥ 2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high-dose cytarabine-based regimens provide high response rates in high-risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non-transformed CLL. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Patterns of use and appropriateness of antibiotics prescribed to patients receiving haemodialysis: an observational study.

PubMed

Hui, Katrina; Nalder, Michelle; Buising, Kirsty; Pefanis, Aspasia; Ooi, Khai Y; Pedagogos, Eugenie; Nelson, Craig; Kirkpatrick, Carl M J; Kong, David C M

2017-05-12

There are limited published data on the types and appropriateness of oral and intravenous (IV) antibiotics prescribed to patients receiving haemodialysis. This information is critical to optimise antibiotic prescribing. Therefore this study aims to describe the patterns of use and the appropriateness of oral and IV antibiotics prescribed to patients receiving haemodialysis. This was a prospective, observational study across four community and two hospital inpatient haemodialysis units in Melbourne, Australia. Data were collected from July 2014 to January 2015 from participants. Antibiotic regimens prescribed were compared with nationally available antibiotic guidelines and then classified as being either appropriate, inappropriate or not assessable by an expert multidisciplinary team using the National Antimicrobial Prescribing Survey tool. Overall, 114 participants consented to this study where 55.3% (63/114) received antibiotics and 235 antibiotic regimens were prescribed at a rate of 69.1 antibiotic regimens/100 patient-months. The most common oral antibiotics prescribed were amoxycillin/clavulanic acid and cephalexin. The most common IV antibiotics prescribed were vancomycin, piperacillin/tazobactam, cephazolin and ceftriaxone. The percentage of inappropriate antibiotic regimens prescribed were 34.9% (15/43) in the community setting and 22.1% (40/181) in the hospital setting. Furthermore, 29.4% (30/102) of oral and 20.5% (25/122) of IV antibiotic regimens were inappropriate with incorrect dosing as the primary reason. Although this study is limited by the sample size, it describes the high antibiotic exposure that patients receiving haemodialysis experience. Of concern is inappropriate dose and frequency being a major issue. This requires interventions focused on the quality use of medicines and antimicrobial stewardship aspects of prescribing in this population.

Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir.

PubMed

Sebbag, Lionel; Thomasy, Sara M; Woodward, Andrew P; Knych, Heather K; Maggs, David J

2016-08-01

OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS 7 male domestic shorthair cats. PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for penciclovir and compared among all dosage regimens. RESULTS Compared with penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus.

Pilot study of a pediatric metronomic 4-drug regimen.

PubMed

André, Nicolas; Abed, Sylvie; Orbach, Daniel; Alla, Corinne Armari; Padovani, Laetitia; Pasquier, Eddy; Gentet, Jean Claude; Verschuur, Arnauld

2011-12-01

Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC is gaining interest as an alternative strategy to fight resistant cancer. to assess the safety of 4 drug MC regimen in paediatric patients with refractory or relapsing various tumour types. From November 2008 to December 2010, in three academic paediatric oncology centers, 16 children (median age 12 years old; range 5.5-20) were included in this pilot study. This treatment was proposed to children with refractory disease for whom no further effective treatments were available. Most frequent diagnosis were medulloblastoma/cerebral PNET (5) osteosarcoma (5), and one case each of nephroblastoma, high grade glioma, Hodgkin lymphoma, rhabdomyosarcoma, neuroblastoma and kidney rhabdoid tumour. The MC regimen consisted in cycles of 56 days (8 weeks) with weekly vinblastine 3 mg/m2 (week 1-7), daily cyclophosphamide 30 mg/m2 (days 1-21), and twice weekly methotrexate 10 mg/m² (days 21-42), and daily celecoxib 100 mg to 400 mg twice daily (days 1-56) followed by a 2-weeks chemotherapy break. Adverse events were determined through laboratory analysis and investigator observations. One objective response was observed in a patient with Hodgkin lymphoma, and 4 patients experienced disease stabilization and continued their treatment for 3 cycles (24 weeks) or more. At last follow-up, 7 patients (43%) are alive including 1 still undergoing treatment. During the overall 36 cycles of treatments received by patients, 4 grade IV toxicities and 24 grade III toxicities were observed in 11 cycles in only 10 different patients. The metronomic regimen we report here was well tolerated and associated with disease stabilization. This regimen is currently being evaluated in a national multicenter phase II study.

Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.

PubMed

Maloney, J Michael; Dietze, Peter; Watson, David; Niknian, Minoo; Lee-Rugh, Sooji; Sampson-Landers, Carole; Korner, Paul

2008-10-01

To assess the efficacy of the combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol (3-mg drospirenone/20-microgram ethinyl estradiol) administered as 24 consecutive days of active treatment after a 4-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris. Healthy females aged 14-45 years with moderate acne were randomized in this double-blind study to 3-mg drospirenone/20-microgram ethinyl estradiol (n=270) or placebo (n=268) for six cycles of 28 days. The primary outcome measures of acne lesion counts and Investigator Static Global Assessment scale ratings were assessed at baseline and during cycles 1, 3, and 6. The percentage reduction from baseline to endpoint for total lesions is 46.3% for 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 combination oral contraceptive group and 30.6% for placebo group (P<.001). The likelihood of participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen group having "clear" or "almost clear" skin as rated by the investigators at endpoint was about threefold (odds ratio 3.13, 95% confidence interval 1.69-5.81; P=.001) greater than in the placebo group. The 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen was well tolerated. The low-dose combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol administered in a 24/4 regimen significantly reduced acne lesion counts more effectively than placebo and demonstrated greater improvement in the Investigator Static Global Assessment rating of acne. The safety profile was consistent with low-dose combined oral contraceptive use.

Elucidation of the pharmacokinetic/pharmacodynamic determinants of fosfomycin activity against Pseudomonas aeruginosa using a dynamic in vitro model.

PubMed

Bilal, Hajira; Peleg, Anton Y; McIntosh, Michelle P; Styles, Ian K; Hirsch, Elizabeth B; Landersdorfer, Cornelia B; Bergen, Phillip J

2018-06-01

To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT>MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance. Dose fractionation was conducted over 24 h in a dynamic one-compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7). In total, 35 different dosing regimens were examined across the three strains. Microbiological response was examined by log changes and population analysis profiles. A Hill-type Emax model was fitted to the killing effect data (expressed as the log10 ratio of the area under the cfu/mL curve for treated regimens versus controls). Bacterial killing of no more than ∼3 log10 cfu/mL was achieved irrespective of regimen. The fAUC/MIC was the PK/PD index most closely correlated with efficacy (R2 = 0.80). The fAUC/MIC targets required to achieve 1 and 2 log10 reductions in the area under the cfu/mL curve relative to growth control were 489 and 1024, respectively. No regimen was able to suppress the emergence of resistance, and near-complete replacement of susceptible with resistant subpopulations occurred with virtually all regimens. Bacterial killing for fosfomycin against P. aeruginosa was most closely associated with the fAUC/MIC. Suppression of fosfomycin-resistant subpopulations could not be achieved even with fosfomycin exposures well above those that can be safely achieved clinically.

Economic evaluation of intensive chemotherapy with prophylactic granulocyte colony-stimulating factor for patients with high-risk early breast cancer in Japan.

PubMed

Ishiguro, Hiroshi; Kondo, Masahide; Hoshi, Shu-Ling; Takada, Masahiro; Nakamura, Seigo; Teramukai, Satoshi; Yanagihara, Kazuhiro; Toi, Masakazu

2010-02-01

This study assessed the cost-effectiveness and budget impact of third-generation chemotherapy regimens with prophylactic granulocyte colony-stimulating factor (G-CSF) relative to second-generation regimens without prophylactic G-CSF for patients with high-risk early breast cancer in Japan. We conducted a cost-effectiveness analysis with Markov modeling and calculated incremental cost-effectiveness ratios (ICERs) for the comparison between second-generation regimens without prophylactic G-CSF and third-generation regimens with prophylactic G-CSF. The comparisons consisted of fluorouracil, doxorubicin, and cyclophosphamide, a second-generation regimen, versus docetaxel, doxorubicin, and cyclophosphamide (TAC) with G-CSF, a third-generation regimen; and doxorubicin, cyclophosphamide, and paclitaxel (AC-T) q3wk, a second-generation regimen, versus dose-dense (DD) AC-T q2wk with G-CSF, a third-generation regimen. Patients were stratified by the age at which chemotherapy was started into cohorts aged 35, 45, and 55 years. Outcomes were estimated in terms of life-years (LYs) and quality-adjusted LYs (QALYs). ICER calculations were done from a societal perspective. We also estimated the budget impact, which included the additional public medical expenditures that would cover all subsequent changes after the additional cost of choosing third-generation regimens if G-CSF were approved for use in third-generation regimens for breast cancer. Costs were calculated using prescription drug prices as of 2006. Estimated ICER values for TAC with prophylactic G-CSF were yen956,471/LY and yen919,443/ QALY for age 35 years, yen1,125,540/LY and yen1,078,967/QALY for age 45 years, and yen1,302,746/LY and yen1,224,896/QALY for age 55 years. Values for DD AC-T q2wk with prophylactic G-CSF were yen291,931/LY and yen311,232/QALY for age 35 years, yen357,354/LY and yen380,148/QALY for age 45 years, and yen377,011/LY and yen399,761/QALY for age 55 years. TAC or DD AC-T q2wk with prophylactic G-CSF would yield cost savings compared with the respective second-generation regimens if the per-dose cost of G-CSF decreased from yen31,355 to yen15,700 (TAC) or to yen24,300 (DD AC-T). The estimated budget impact is yen9.5 to yen11.0 billion per year for the next 5 years. According to a Markov model for patients with high-risk early breast cancer in Japan, third-generation regimens with prophylactic G-CSF will yield improved outcomes at a greater cost, but estimated ICER values are still less than the suggested cost-effectiveness threshold value of yen6 million (US $60,000, assuming US $1 = yen100) for a gain of 1 QALY. Copyright 2010. Published by EM Inc USA.

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia.

PubMed

Elefritz, Jessica L; Bauer, Karri A; Jones, Christian; Mangino, Julie E; Porter, Kyle; Murphy, Claire V

2017-09-01

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Management of rivaroxaban in relation to bodyweight and body mass index

PubMed Central

Uprichard, James

2016-01-01

Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery. In addition, there is evidence that obesity represents a significant driving factor for the current and projected prevalence of atrial fibrillation. Rivaroxaban and other direct oral anticoagulants offer fixed-dose regimens for these indications. They do not require therapeutic drug monitoring or dose adjustment according to the weight of the patient. However, primary care physicians seem to be hesitant to accept the concept of a fixed-dose regimen for patients at extremes of weight, perhaps because of familiarity with weight-based dosing of other drugs including low molecular weight heparins. The main concerns related to unadjusted dosing are increased exposure in underweight patients leading to a risk of excessive bleeding and conversely to underanticoagulation of overweight patients. Rivaroxaban has shown similar efficacy and a similar or better safety profile compared with standard treatment for several venous and arterial indications, including venous thromboembolism, nonvalvular atrial fibrillation, and acute coronary syndrome. Prespecified subgroup analyses of patients stratified by weight or body mass index demonstrated outcomes that were consistent with the overall analysis and within each weight and body mass index group. The results suggest that standard-dose rivaroxaban can be safely prescribed in adult patients of all weights. PMID:27090286

Single dose filgastrim in cytotoxic-induced neutropaenia in children.

PubMed

Abdallah, F K

2008-01-01

To document the impact of fixed dose weight adjusted filgastrim (G-CSF) in cytotoxic-induced neutropaenia. A descriptive cross-sectional study. Paediatric Oncology Unit at Kenyatta National Hospital, Nairobi, Kenya. All paediatric oncology patients who had developed cytotoxic-induced neutropaenia. The following were documented for every tissue proven case of malignancy; age, sex, type of malignancy, treatment regimen and schedule, initial blood count at the time of neutropaenia; subsequent blood counts daily for five days from day one of single dose filgastrim, and the calculated neutrophil incremental count. Initially eight patients with solid tumours previously treated with filgastrim revealed that cytotoxic induced neutropaenia could be ameliorated by a single dose of filgastrim. Subsequently, the study listed thirty patients. This cohort consisted of; 37% rhabdomyosarcoma, 30% Burkitts, 27% acute lymphoblastic leukaemia and 6% Hodgkin's lymphoma. Increased neutrophil count after 48 hours was documented in 26 (87%) patients, with absolute neutrophil counts range of 0.5 to 31.5 x 10(9)/L. This response was significantly influenced by gender (p>0.0001), malignancy type and chemotherapy regimen (p>0.001). The study shows that chemotherapy induced neutropaenia can be alleviated by a single dose of filgastrim without adverse effects on lymphoblastic leukaemia. This study suggests that a single dose of filgastrim should be first tried in cytotoxic induced neutropaenia in the paediatric age group.

An update and review of antiretroviral therapy.

PubMed

Piacenti, Frank J

2006-08-01

The human immunodeficiency virus (HIV) was discovered in 1982, but treatment strategies were not introduced until 5 years later. Early regimens consisted of one or two drugs and often led to treatment failure. Since the advent in 1995 of highly active antiretroviral therapy (HAART), which consists of at least three agents, a dramatic improvement has been seen in the number of patients attaining undetectable viral loads, improved CD4 counts, and improved survival. However, early HAART often consisted of drugs with complex dosing schedules, strict food requirements, treatment-limiting adverse effects, and the need to take 16-20 pills/day. These treatment barriers often led to patient nonadherence, with subsequent treatment failure and development of resistant strains. The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated. Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome-defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm(3) or below. In patients with CD4 counts above 350 cells/mm(3) and viral loads above 100,000 copies/ml, some clinicians prefer to defer treatment, whereas others will consider starting therapy; treatment is deferred in patients with CD4 counts above 350 cells/mm(3) and viral load s below 100,000 copies/ml. If therapy is started, the selection of appropriate agents is based on comorbidities (liver disease, depression, cardiovascular disease), pregnancy status, adherence potential (dosage regimen, pill burden, dosing frequency), food restrictions (dosing with regard to meals), adverse drug effects, and potential drug-drug interactions. Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir. This review focuses on the concepts of antiretroviral therapy, barriers to successful antiretroviral treatment, developments to limit treatment barriers, and new drug entities for the treatment of HIV.

Four-times-daily Dosing of Rabeprazole with Sitafloxacin, High-Dose Amoxicillin, or Both for Metronidazole-Resistant Infection with Helicobacter pylori in Japan.

PubMed

Sugimoto, Mitsushige; Sahara, Shu; Ichikawa, Hitomi; Kagami, Takuma; Ban, Hiromitsu; Otsuka, Taketo; Andoh, Akira; Furuta, Takahisa

2017-02-01

The bacterial resistance of Helicobacter pylori to antimicrobial agents such as clarithromycin and metronidazole has been increasing worldwide, leading to the failure of eradication treatment. Here, we present an eradication regimen consisting of four-times-daily dosing (q.i.d.) of rabeprazole with potent acid inhibition. To investigate the efficacy of eradication therapy with rabeprazole q.i.d. and amoxicillin or sitafloxacin in Japanese infected with a metronidazole-resistant strain. We retrospectively investigated the efficacy of eradication regimens with rabeprazole q.i.d. for 7 days in 111 Japanese pooled patients infected with a metronidazole-resistant strain of H. pylori at Hamamatsu University School of Medicine Hospital or the Shiga University of Medical Science Hospital: 1, with sitafloxacin 100 mg twice daily (b.i.d.) (n = 82); 2, with amoxicillin 500 mg q.i.d. (n = 15); and 3, with amoxicillin q.i.d. and sitafloxacin b.i.d.-combined regimen (n = 14). Eradication status was assessed at 8 weeks via a 13 C-urea breath test. Eradication rate on intention-to-treat analysis was 93.7% (95% confidence interval: 87.4-97.4%, 104/111), irrespective of the high prevalence of strains resistant to clarithromycin (81.1%, 90/111) and levofloxacin (42.3%, 47/111). No significant differences in eradication rates were observed among the different treatment regimens (p = .408), eradication history (p = .096) and different CYP2C19 genotypes (p = .789). On multivariate analysis, no significant risk factor for eradication failure by therapy with potent acid inhibition was seen. In Japanese patients infected with metronidazole-resistant strains of H. pylori, eradication rates exceeding 90% can be achieved using appropriate dosing of antibiotic agents with strain susceptibility (amoxicillin q.i.d. and/or sitafloxacin b.i.d.) together with acid inhibition for a full 24 h and rabeprazole 10 mg q.i.d. These findings may be further evidence for dual therapy with rabeprazole q.i.d. and an antibiotic agent (amoxicillin q.i.d. or sitafloxacin b.i.d.) in Japanese patients with metronidazole-resistant strains. © 2016 John Wiley & Sons Ltd.

Evidence-Based Nursing of the 3C Therapeutic Regimen for Type 1 Diabetes.

PubMed

Wu, Jianya; Zou, Ling

2015-05-01

The aim of this study is to explore the efficacy of the 3C therapeutic regimen for type 1 diabetes. Thirty-nine patients with type 1 diabetes, who were hospitalized from January 2013 to April 2014, were included to receive 3C therapeutic regimen. Evidence-based nursing was performed in the treatment period and the efficacy was observed 6 days after therapy. Six days after the administration of the 3C therapeutic regimen, the fasting glucose levels in all 39 patients were controlled to be 4.4-6.0 mmol/L and 2h-postprandial glucose levels to be 4.4-7.8 mmol/L. Three patients had a glucose level <3.9 mmol/L, which was corrected after adjusting the dose of insulin infusion. Evidence-based nursing was provided in the treatment period and no nursing-associated complication occurred. All patients were satisfied with the nursing service. The efficacy of the 3C therapeutic regimen for type 1 diabetes is satisfactory. The evidence-based nursing can help to ensure the efficacy and improve the quality of nursing service.

“One pill, once daily”: what clinicians need to know about Atripla™

PubMed Central

Clay, Patrick G; Taylor, Tracey AH; Glaros, Alan G; McRae, MaryPeace; Williams, Charlott; McCandless, Don; Oelklaus, Maurice

2008-01-01

As the number of persons chronically prescribed antiretrovirals has grown and the realization that antiretrovirals are required to be continued for life, pharmaceutical manufacturers have developed new classes of agents, improved the pharmacokinetics of marketed products through dosing reformulations, and in an effort to maximize success with respect to adherence, compiled into a single dosing unit all necessary elements for an antiretroviral regimen. Atripla™ represents the first ever fixed-dose combination antiretroviral available. This article reviews currently available data on this agent, the impact of resistance on clinical use and implementation, as well as extensive descriptions of the pharmacokinetics, adverse effects and drug-interactions warranting consideration. Whether beginning in a naïve patient or switching from other regimens for tolerability issues, Atripla™ represents a viable option. Its demonstrated advantages with respect to lipid and hematologic parameters and equivalent incidence of renal toxicity are tempered by the findings of bone mineral density decreases, however. Combining multiple mechanisms of action in a single dosing unit appears to improve efficacy, increase the likelihood for adherence and maintain viral suppression compared to administering these agents independently. It is suggested other pharmaceutical companies assess the potential to replicate this for the remaining antiretrovirals. PMID:18728842

A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor.

PubMed

Abbas, Richat; Hug, Bruce A; Leister, Cathie; Sonnichsen, Daryl

2012-07-01

Neratinib, a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB receptor tyrosine kinase inhibitor has antitumor activity in ErbB2 + breast cancer. The objective of this study was to characterize the onset, severity, and duration of diarrhea after administration of neratinib 240 mg once daily (QD) and 120 mg twice daily (BID) for ≤14 days in healthy subjects. A randomized, double-blind, parallel-group, inpatient study was conducted in 50 subjects given oral neratinib either 240 mg QD or 120 mg BID with food for ≤14 days. The primary endpoint was the proportion of subjects with diarrhea of at least moderate severity (grade 2; 5-7 loose stools/day). In subjects with grade 2 diarrhea, fecal analytes were determined. Pharmacokinetic profiles were characterized for neratinib on Days 1 and 7. No severe (grade 3) diarrhea was reported. By Day 4, all subjects had grade 1 diarrhea. Grade 2 diarrhea occurred in 11/22 evaluable subjects (50 % [90 % confidence interval (CI): 28-72 %]) in the QD group and 17/23 evaluable subjects (74 % [90 % CI: 52-90 %]) in the BID group (P = 0.130). In fecal analyses, 18 % tested positive for hemoglobin and 46 % revealed fecal lactoferrin. Specimen pH was neutral to slightly alkaline. In pharmacokinetic analyses, Day 1 peak plasma concentration and Day 7 steady-state exposure were higher with the QD regimen than the BID regimen. In an exploratory analysis, ABCG2 genotype showed no correlation with severity or onset of diarrhea. Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.