Intrathecal Baclofen in Children with Spastic Cerebral Palsy: A Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Study

ERIC Educational Resources Information Center

Hoving, Marjanke A.; van Raak, Elisabeth P. M.; Spincemaille, Geert H. J. J.; Palmans, Liesbeth J.; Sleypen, Frans A. M.; Vles, Johan S. H.

2007-01-01

Intrathecal baclofen (ITB) therapy can be very effective in the treatment of intractable spasticity, but its effectiveness and safety have not yet been thoroughly studied in children with cerebral palsy (CP). The aims of this double-blind, randomized, placebo-controlled, dose-finding study were to select children eligible for continuous ITB…

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

PubMed

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

2018-05-01

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

Dose-volume metrics and their relation to memory performance in pediatric brain tumor patients: A preliminary study.

PubMed

Raghubar, Kimberly P; Lamba, Michael; Cecil, Kim M; Yeates, Keith Owen; Mahone, E Mark; Limke, Christina; Grosshans, David; Beckwith, Travis J; Ris, M Douglas

2018-06-01

Advances in radiation treatment (RT), specifically volumetric planning with detailed dose and volumetric data for specific brain structures, have provided new opportunities to study neurobehavioral outcomes of RT in children treated for brain tumor. The present study examined the relationship between biophysical and physical dose metrics and neurocognitive ability, namely learning and memory, 2 years post-RT in pediatric brain tumor patients. The sample consisted of 26 pediatric patients with brain tumor, 14 of whom completed neuropsychological evaluations on average 24 months post-RT. Prescribed dose and dose-volume metrics for specific brain regions were calculated including physical metrics (i.e., mean dose and maximum dose) and biophysical metrics (i.e., integral biological effective dose and generalized equivalent uniform dose). We examined the associations between dose-volume metrics (whole brain, right and left hippocampus), and performance on measures of learning and memory (Children's Memory Scale). Biophysical dose metrics were highly correlated with the physical metric of mean dose but not with prescribed dose. Biophysical metrics and mean dose, but not prescribed dose, correlated with measures of learning and memory. These preliminary findings call into question the value of prescribed dose for characterizing treatment intensity; they also suggest that biophysical dose has only a limited advantage compared to physical dose when calculated for specific regions of the brain. We discuss the implications of the findings for evaluating and understanding the relation between RT and neurocognitive functioning. © 2018 Wiley Periodicals, Inc.

Obtaining the Optimal Dose in Alcohol Dependence Studies

PubMed Central

Wages, Nolan A.; Liu, Lei; O’Quigley, John; Johnson, Bankole A.

2012-01-01

In alcohol dependence studies, the treatment effect at different dose levels remains to be ascertained. Establishing this effect would aid us in identifying the best dose that has satisfactory efficacy while minimizing the rate of adverse events. We advocate the use of dose-finding methodology that has been successfully implemented in the cancer and HIV settings to identify the optimal dose in a cost-effective way. Specifically, we describe the continual reassessment method (CRM), an adaptive design proposed for cancer trials to reconcile the needs of dose-finding experiments with the ethical demands of established medical practice. We are applying adaptive designs for identifying the optimal dose of medications for the first time in the context of pharmacotherapy research in alcoholism. We provide an example of a topiramate trial as an illustration of how adaptive designs can be used to locate the optimal dose in alcohol treatment trials. It is believed that the introduction of adaptive design methods will enable the development of medications for the treatment of alcohol dependence to be accelerated. PMID:23189064

Embracing model-based designs for dose-finding trials

PubMed Central

Love, Sharon B; Brown, Sarah; Weir, Christopher J; Harbron, Chris; Yap, Christina; Gaschler-Markefski, Birgit; Matcham, James; Caffrey, Louise; McKevitt, Christopher; Clive, Sally; Craddock, Charlie; Spicer, James; Cornelius, Victoria

2017-01-01

Background: Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM). Methods: We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. Results: We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators’ preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. Conclusions: There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia. PMID:28664918

Dose and timing in neurorehabilitation: Prescribing motor therapy after stroke

PubMed Central

Lang, Catherine E.; Lohse, Keith R.; Birkenmeier, Rebecca L.

2015-01-01

Purpose of the review Prescribing the most appropriate dose of motor therapy for individual patients is a challenge because minimal data are available and a large number of factors are unknown. This review explores the concept of dose and reviews the most recent findings in the field of neurorehabilitation, with a focus on relearning motor skills post stroke. Recent findings Appropriate dosing involves the prescription of a specific amount of an active ingredient, at a specific frequency and duration. Dosing parameters, particularly amount, are not well-defined or quantified in most studies. Compiling data across studies indicates a positive, moderate dose-response relationship, indicating that more movement practice results in better outcomes. This relationship is confounded by time post stroke however, where longer durations of scheduled therapy may not be beneficial in the first few hours, days, and/or weeks. Summary These findings suggest that substantially more movement practice may be necessary to achieve better outcomes for people living with the disabling consequences of stroke. Preclinical investigations are needed to elucidate many of the unknowns and allow for a more biologically-driven rehabilitation prescription process. Likewise, clinical investigations are needed to determine the dose-response relationships and examine the potential dose-timing interaction in humans. PMID:26402404

Phase I Design for Completely or Partially Ordered Treatment Schedules

PubMed Central

Wages, Nolan A.; O’Quigley, John; Conaway, Mark R.

2013-01-01

The majority of methods for the design of Phase I trials in oncology are based upon a single course of therapy, yet in actual practice it may be the case that there is more than one treatment schedule for any given dose. Therefore, the probability of observing a dose-limiting toxicity (DLT) may depend upon both the total amount of the dose given, as well as the frequency with which it is administered. The objective of the study then becomes to find an acceptable combination of both dose and schedule. Past literature on designing these trials has entailed the assumption that toxicity increases monotonically with both dose and schedule. In this article, we relax this assumption for schedules and present a dose-schedule finding design that can be generalized to situations in which we know the ordering between all schedules and those in which we do not. We present simulation results that compare our method to other suggested dose-schedule finding methodology. PMID:24114957

An FDA oncology analysis of immune activating products and first-in-human dose selection.

PubMed

Saber, Haleh; Gudi, Ramadevi; Manning, Michael; Wearne, Emily; Leighton, John K

2016-11-01

As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities. For approximately half the antibodies (44%) examined, the FIH doses were at least a hundred-fold lower than the doses safely administered to patients, indicating optimization of FIH dose selection and/or optimization of dose-finding trial design is needed to minimize patient exposure to sub-therapeutic doses. However, selection of the FIH dose for antibodies based on animal toxicology studies using 1/6th the HNSTD or 1/10th the NOAEL resulted in human doses that were unsafe for several antibodies examined. We also concluded that antibodies with Fc-modifications for increased effector function may be less tolerated, resulting in toxicities at lower doses than those without such modifications. There was insufficient information to evaluate CD3 bispecific products. Published by Elsevier Inc.

The FIND-CKD study--a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale.

PubMed

Macdougall, Iain C; Bock, Andreas; Carrera, Fernando; Eckardt, Kai-Uwe; Gaillard, Carlo; Van Wyck, David; Roubert, Bernard; Cushway, Timothy; Roger, Simon D

2014-04-01

Rigorous data are sparse concerning the optimal route of administration and dosing strategy for iron therapy with or without concomitant erythropoiesis-stimulating agent (ESA) therapy for the management of iron deficiency anaemia in patients with non-dialysis dependent chronic kidney disease (ND-CKD). FIND-CKD was a 56-week, open-label, multicentre, prospective, randomized three-arm study (NCT00994318) of 626 patients with ND-CKD and iron deficiency anaemia randomized to (i) intravenous (IV) ferric carboxymaltose (FCM) at an initial dose of 1000 mg iron with subsequent dosing as necessary to target a serum ferritin level of 400-600 µg/L (ii) IV FCM at an initial dose of 200 mg with subsequent dosing as necessary to target serum ferritin 100-200 µg/L or (iii) oral ferrous sulphate 200 mg iron/day. The primary end point was time to initiation of other anaemia management (ESA therapy, iron therapy other than study drug or blood transfusion) or a haemoglobin (Hb) trigger (two consecutive Hb values <10 g/dL without an increase of ≥ 0.5 g/dL). The background, rationale and study design of the trial are presented here. The study has been completed and results are expected in late 2013. FIND-CKD was the longest randomized trial of IV iron therapy to date. Its findings will address several unanswered questions regarding iron therapy to treat iron deficiency anaemia in patients with ND-CKD. It was also the first randomized trial to utilize both a high and low serum ferritin target range to adjust IV iron dosing, and the first not to employ Hb response as its primary end point.

The estimation of galactic cosmic ray penetration and dose rates

NASA Technical Reports Server (NTRS)

Burrell, M. O.; Wright, J. J.

1972-01-01

This study is concerned with approximation methods that can be readily applied to estimate the absorbed dose rate from cosmic rays in rads - tissue or rems inside simple geometries of aluminum. The present work is limited to finding the dose rate at the center of spherical shells or behind plane slabs. The dose rate is calculated at tissue-point detectors or for thin layers of tissue. This study considers cosmic-rays dose rates for both free-space and earth-orbiting missions.

Correlation between radiation dose and histopathological findings in patients with gliblastoma treated with boron neutron capture therapy (BNCT).

PubMed

Kageji, T; Mizobuchi, Y; Nagahiro, S; Nakagawa, Y; Kumada, H

2014-06-01

The purpose of this study was to clarify the correlation between the radiation dose and histopathological findings in patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT). Histopathological studies were performed on specimens from 8 patients, 3 had undergone salvage surgery and 5 were autopsied. For histopathological cure of GBM at the primary site, the optimal minimal dose to the gross tumor volume (GTV) and the clinical target volume (CTV) were 68Gy(w) and 44Gy(w), respectively. Copyright © 2014. Published by Elsevier Ltd.

Dose-finding design for multi-drug combinations

PubMed Central

Wages, Nolan A; Conaway, Mark R; O'Quigley, John

2012-01-01

Background Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose–toxicity curve. Purpose Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose-limiting toxicity cannot be known a priori. Methods We describe a new dose-finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known. Results We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design. Limitations A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders. Conclusions The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials. PMID:21652689

Spline-based procedures for dose-finding studies with active control

PubMed Central

Helms, Hans-Joachim; Benda, Norbert; Zinserling, Jörg; Kneib, Thomas; Friede, Tim

2015-01-01

In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose–response relationship and to find the smallest target dose concentration d*, which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose–response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose–response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs. © 2014 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:25319931

Dose and elasticity of demand for self-administered cocaine in rats.

PubMed

Kearns, David N; Silberberg, Alan

2016-04-01

The present experiment tested whether the elasticity of demand for self-administered cocaine in rats is dose-dependent. Subjects lever pressed for three different doses of intravenous cocaine - 0.11, 0.33, and 1.0 mg/kg/infusion - on a demand procedure where the number of lever presses required per infusion increased within a session. The main finding was that demand for the 0.11 mg/kg dose was more elastic than it was for the two larger doses. There was no difference in demand elasticity between the 0.33 and 1.0 mg/kg doses. These results parallel findings previously reported in monkeys. The present study also demonstrated that a within-session procedure can be used to generate reliable demand curves.

Identifying a maximum tolerated contour in two-dimensional dose-finding

PubMed Central

Wages, Nolan A.

2016-01-01

The majority of Phase I methods for multi-agent trials have focused on identifying a single maximum tolerated dose combination (MTDC) among those being investigated. Some published methods in the area have been based on the notion that there is no unique MTDC, and that the set of dose combinations with acceptable toxicity forms an equivalence contour in two dimensions. Therefore, it may be of interest to find multiple MTDC's for further testing for efficacy in a Phase II setting. In this paper, we present a new dose-finding method that extends the continual reassessment method to account for the location of multiple MTDC's. Operating characteristics are demonstrated through simulation studies, and are compared to existing methodology. Some brief discussion of implementation and available software is also provided. PMID:26910586

Systemic fluoroquinolone prescriptions for hospitalized children in Belgium, results of a multicenter retrospective drug utilization study.

PubMed

Meesters, Kevin; Mauel, Reiner; Dhont, Evelyn; Walle, Johan Vande; De Bruyne, Pauline

2018-02-23

Fluoroquinolones (FQ) are increasingly prescribed for children, despite being labeled for only a limited number of labeled pediatric indications. In this multicenter retrospective drug utilization study, we analyzed indications for systemic FQ prescriptions in hospitalized children and the appropriateness of the prescribed dose. Using data obtained from electronic medical files, the study included all children who received a systemic FQ prescription in two Belgian university children's hospitals between 2010 and 2013. Two authors reviewed prescribed daily doses. Univariate and multivariate logistic regression models were used to analyze risk factors for inadequately dosing. Results262 FQ prescriptions for individual patients were included for analysis. 16.8% of these prescriptions were for labeled indications, and 35.1% were guided by bacteriological findings. Prescribed daily dose was considered to be inappropriate in 79 prescriptions (30.2%). Other FQ than ciprofloxacin accounted for 9 prescriptions (3.4%), of which 8 were correctly dosed. Underdosing represented 45 (56.9%) dosing errors. Infants and preschool children were at particular risk for dosing errors, with associated adjusted OR of 0.263 (0.097-0.701) and 0.254 (0.106-0.588) respectively. FQ were often prescribed off-label and not guided by bacteriological findings in our study population. Dosing errors were common, particularly in infants and preschool children. FQ prescriptions for children should be improved by specific pediatric antimicrobial stewardship teams. Furthermore, pharmacokinetic studies should optimise dosing recommendations for children.

Experimental and Monte Carlo evaluation of Eclipse treatment planning system for effects on dose distribution of the hip prostheses

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

Çatlı, Serap, E-mail: serapcatli@hotmail.com; Tanır, Güneş

2013-10-01

The present study aimed to investigate the effects of titanium, titanium alloy, and stainless steel hip prostheses on dose distribution based on the Monte Carlo simulation method, as well as the accuracy of the Eclipse treatment planning system (TPS) at 6 and 18 MV photon energies. In the present study the pencil beam convolution (PBC) method implemented in the Eclipse TPS was compared to the Monte Carlo method and ionization chamber measurements. The present findings show that if high-Z material is used in prosthesis, large dose changes can occur due to scattering. The variance in dose observed in the presentmore » study was dependent on material type, density, and atomic number, as well as photon energy; as photon energy increased back scattering decreased. The dose perturbation effect of hip prostheses was significant and could not be predicted accurately by the PBC method for hip prostheses. The findings show that for accurate dose calculation the Monte Carlo-based TPS should be used in patients with hip prostheses.« less

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4–5 December 2014)

PubMed Central

Manolis, E; Holford, N; Cheung, SYA; Friberg, LE; Ogungbenro, K; Posch, M; Yates, JWT; Berry, S; Thomas, N; Corriol‐Rohou, S; Bornkamp, B; Bretz, F; Hooker, AC; Van der Graaf, PH; Standing, JF; Hay, J; Cole, S; Gigante, V; Karlsson, K; Dumortier, T; Benda, N; Serone, F; Das, S; Brochot, A; Ehmann, F; Hemmings, R; Rusten, I Skottheim

2017-01-01

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late‐stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well‐established and regulatory‐acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4–5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP‐Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)‐based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well‐designed dose‐finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. PMID:28722322

Intradermal Inactivated Poliovirus Vaccine: A Preclinical Dose-Finding Study

PubMed Central

Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

2015-01-01

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. PMID:25391313

A Practical Bayesian Design to Identify the Maximum Tolerated Dose Contour for Drug Combination Trials

PubMed Central

Zhang, Liangcai; Yuan, Ying

2016-01-01

Drug combination therapy has become the mainstream approach to cancer treatment. One fundamental feature that makes combination trials different from single-agent trials is the existence of the maximum tolerated dose (MTD) contour, i.e., multiple MTDs. As a result, unlike single-agent phase I trials, which aim to find a single MTD, it is often of interest to find the MTD contour for combination trials. We propose a new dose-finding design, the waterfall design, to find the MTD contour for drug combination trials. Taking the divide-and-conquer strategy, the waterfall design divides the task of finding the MTD contour into a sequence of one-dimensional dose-finding processes, known as subtrials. The subtrials are conducted sequentially in a certain order, such that the results of each subtrial will be used to inform the design of subsequent subtrials. Such information borrowing allows the waterfall design to explore the two-dimensional dose space efficiently using a limited sample size, and decreases the chance of overdosing and underdosing patients. To accommodate the consideration that doses on the MTD contour may have very different efficacy or synergistic effects due to drug-drug interaction, we further extend our approach to a phase I/II design with the goal of finding the MTD with the highest efficacy. Simulation studies show that the waterfall design is safer and has higher probability of identifying the true MTD contour than some existing designs. The R package “BOIN” to implement the waterfall design is freely available from CRAN. PMID:27580928

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

PubMed

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

2016-06-01

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

Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

DTIC Science & Technology

2008-05-01

in non-human primates. a. Study behavioral effects of ultra- low doses of intrathecal N/OFQ over a wide dose range using a warm water tail...threshold of monkeys. Figure 1 compares the effects of ultra- low doses of intrathecal N/OFQ (i.e., 1 fmol and 1 pmol) with those of a mu opioid...findings indicate that ultra- low doses of intrathecal N/OFQ did not change the monkey’s thermal nociceptive threshold (Figure 1, middle panels

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels

PubMed Central

Hyun, Seung Won; Wong, Weng Kee

2016-01-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels.

PubMed

Hyun, Seung Won; Wong, Weng Kee

2015-11-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs.

Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

PubMed

Lenz, Robert A; Pritchett, Yili L; Berry, Scott M; Llano, Daniel A; Han, Shu; Berry, Donald A; Sadowsky, Carl H; Abi-Saab, Walid M; Saltarelli, Mario D

2015-01-01

ABT-089, an α4β2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014).

PubMed

Musuamba, F T; Manolis, E; Holford, N; Cheung, Sya; Friberg, L E; Ogungbenro, K; Posch, M; Yates, Jwt; Berry, S; Thomas, N; Corriol-Rohou, S; Bornkamp, B; Bretz, F; Hooker, A C; Van der Graaf, P H; Standing, J F; Hay, J; Cole, S; Gigante, V; Karlsson, K; Dumortier, T; Benda, N; Serone, F; Das, S; Brochot, A; Ehmann, F; Hemmings, R; Rusten, I Skottheim

2017-07-01

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. © 2017 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose–toxicity and dose–efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID:24470329

Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor

PubMed Central

Chang, Jane C.F.; Ciaccio, Paul; Schroeder, Patricia; Wright, Lindsay; Westwood, Russell; Berg, Anna-Lena

2014-01-01

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology. PMID:24791065

Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies.

PubMed

Paranjpe, Madhav G; Belich, Jessica; Vidmar, Tom J; Elbekai, Reem H; McKeon, Marie; Brown, Caren

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

Nandrolone decanoate as anabolic therapy in chronic kidney disease: a randomized phase II dose-finding study.

PubMed

Macdonald, Jamie H; Marcora, Samuele M; Jibani, Mahdi M; Kumwenda, Mick J; Ahmed, Wasim; Lemmey, Andrew B

2007-01-01

In patients with chronic kidney disease (CKD) receiving adequate erythropoietin therapy, the ideal dose of nandrolone decanoate (ND) to enhance muscle mass is not known. In this phase II dose-finding study, 54 patients with CKD stage 5 were randomized to either low, medium or high doses of ND (50, 100 or 200 mg/week for 24 weeks, respectively, in males; doses halved in females), while 7 patients acted as non-randomized controls. The primary outcome measure was appendicular lean mass (ALM) by dual-energy X-ray absorptiometry. Fluid overload (hydration of the fat-free mass) and indicators of physical functioning were secondary measures. Harms were also recorded. Data were analysed using Quade's (1967) non-parametric analysis of covariance. ND increased ALM in a dose-responsive manner (change scores = 0.3 +/- 0.3 vs. 0.8 +/- 0.3 vs. 1.5 +/- 0.5 vs. 2.1 +/- 0.4 kg, control vs. low vs. medium vs. high dose groups, respectively, p < 0.001) with no increases in fluid overload but no consistent effect on physical functioning. The highest dose of ND (100 mg/week) was intolerable in females because of virilizing effects. If goals of future studies are to improve body composition, dosing of ND up to 200 mg/week in males and 50 mg/week in females should be investigated. However, to realize improvements in physical functioning, future phase III trials of ND may require additional interventions such as exercise training. Copyright 2007 S. Karger AG, Basel.

Accelerated heavy particles and the lens. VII: The cataractogenic potential of 450 MeV/amu iron ions

NASA Technical Reports Server (NTRS)

Worgul, B. V.; Brenner, D. J.; Medvedovsky, C.; Merriam, G. R. Jr; Huang, Y.

1993-01-01

PURPOSE. To determine the cataractogenic potential dose of high velocity iron ions as a fixation of dose administered singly or fractionated. The dose is critical to risk assessment and to theories of radiation action and cataractogenesis. METHODS. Twenty-eight-day-old rats were examined by slit-lamp biomicroscopy on a weekly-bi-weekly basis for more than 2 yr after radiation exposure. For the acute exposure study doses of 1, 2, 5, 25, and 50 cGy were evaluated. The fractionated regimens involved total doses of 2, 25, and 50 cGy. The reference radiation consisted of 50, 100, 200, or 700 cGy of 250 kilovolt (peak) x-rays. RESULTS. In accordance with previous findings in the rat using 570 MeV/amu 40Ar ions, the relative biologic effectiveness increased rapidly with decreasing dose, reaching values as high as 100. Unlike 40Ar ions, fractionation of the 56Fe doses did not produce a consistent enhancement at any of the doses examined. CONCLUSIONS. The data support the previous findings of a high cataractogenic potential for high linear energy transfer (LET) radiation. The effectiveness for the production of cataracts increases with decreasing dose relative to x-rays and is independent of dose protraction. Although the present study did not reveal a consistent enhancement of effect when the ions were applied in fractions, the results are consistent with at least one theory of the inverse dose-rate effect observed for high-LET radiation.

Safety of coronary CT angiography and functional testing for stable chest pain in the PROMISE trial: A randomized comparison of test complications, incidental findings, and radiation dose.

PubMed

Lu, Michael T; Douglas, Pamela S; Udelson, James E; Adami, Elizabeth; Ghoshhajra, Brian B; Picard, Michael H; Roberts, Rhonda; Lee, Kerry L; Einstein, Andrew J; Mark, Daniel B; Velazquez, Eric J; Carter, William; Ridner, Michael; Al-Khalidi, Hussein R; Hoffmann, Udo

Coronary computed tomography angiography (CTA) and functional testing strategies for stable chest pain yield similar outcomes; one aspect that may guide test choice is safety. We compared test safety (test complications, incidental findings, and effective radiation dose) between CTA and functional testing as-tested in PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain). In the subgroup whose physicians intended nuclear stress over other functional tests if randomized to the functional arm, we compared radiation dose of CTA versus nuclear stress and identified characteristics associated with dose. Of 9470 patients, none had major and <1% had minor complications (CTA: 0.8% [37/4633] vs. functional: 0.6% [27/4837]). CTA identified more incidental findings (11.6% [539/4633] vs. 0.7% [34/4837], p < 0.001), most commonly pulmonary nodules (9.4%, 437/4633). CTA had similar 90-day cumulative radiation dose to functional testing. However, in the subgroup whose physicians intended nuclear stress (CTA 3147; nuclear 3203), CTA had lower median index test (8.8 vs. 12.6 mSv, p < 0.001) and 90-day cumulative (11.6 vs. 13.1 mSv, p < 0.001) dose, independent of patient characteristics. The lowest nuclear doses employed 1-day Tc-99m protocols (12.2 mSv). The lowest CTA doses were at sites performing ≥500 CTAs/year (6.9 mSv) and with advanced (latest available) CT scanners (5.5 mSv). Complications were negligibly rare for both CTA and functional testing. CTA detects more incidental findings. Compared to nuclear stress testing, CTA's lower radiation dose, independent of patient characteristics, makes it an attractive test choice. Radiation dose varies with imaging protocol, indicating opportunities to further reduce dose. (ClinicalTrials.gov number, NCT01174550). Copyright © 2017 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.

Dose-finding designs for trials of molecularly targeted agents and immunotherapies

PubMed Central

Chiuzan, Cody; Shtaynberger, Jonathan; Manji, Gulam A.; Duong, Jimmy K.; Schwartz, Gary K.; Ivanova, Anastasia; Lee, Shing M.

2017-01-01

Recently, there has been a surge of early phase trials of molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from new trial designs that allow inclusion of low-grade toxicities, late-onset toxicities, addition of an efficacy endpoint, and flexibility in the specification of a target toxicity probability. To study the degree of adoption of these methods, we conducted a Web of Science search of articles published between 2008 and 2014 that describe phase 1 oncology trials. Trials were categorized based on the dose-finding design used and the type of drug studied. Out of 1,712 dose-finding trials that met our criteria, 1,591 (92.9%) utilized a rule-based design, and 92 (5.4%; range 2.3% in 2009 to 9.7% in 2014) utilized a model-based or novel design. Over half of the trials tested an MTA or immunotherapy. Among the MTA and immunotherapy trials, 5.8% used model-based methods, compared to 3.9% and 8.3% of the chemotherapy or radiotherapy trials, respectively. While the percentage of trials using novel dose-finding designs has tripled since 2007, only 7.1% of trials use novel designs. PMID:28166468

Icons improve older and younger adults' comprehension of medication information.

PubMed

Morrow, D G; Hier, C M; Menard, W E; Leirer, V O

1998-07-01

We examined whether timeline icons improved older and younger adults' comprehension of medication information. In Experiment 1, comprehension of instructions with the icon (icon/text format) and without the icon (text-only format) was assessed by questions about information that was (a) implicit in the text but depicted explicitly by the icon (total dose in a 24 hour period), (b) stated and depicted in the icon/text condition (medication dose and times), and (c) stated but not depicted by the icon (e.g., side effects). In a separate task, participants also recalled medication instructions (with or without the icon) after a study period. We found that questions about dose and time information were answered more quickly and accurately when the icon was present in the instructions. Notably, icon benefits were greater for information that was implicit rather than stated in the text. This finding suggests that icons can improve older and younger adults' comprehension by reducing the need to draw some inferences. The icon also reduced effective study time (study time per item recalled). In Experiment 2, icon benefits did not occur for a less integrated version of the timeline icon that, like the text, required participants to integrate dose and time information in order to identify the total daily dose. The integrated version of the icon again improved comprehension, as in Experiment 1, as well as drawing inferences from memory. These findings show that integrated timeline icons improved comprehension primarily by aiding the integration of dose and time information. These findings are discussed in terms of a situation model approach to comprehension.

A dose ranging study of ibuprofen suspension as an antipyretic.

PubMed Central

Marriott, S C; Stephenson, T J; Hull, D; Pownall, R; Smith, C M; Butler, A

1991-01-01

A double blind trial was conducted to determine the dose of ibuprofen suspension, which is effective in reducing the body temperature. The principal measure of efficacy was a reduction in axillary temperature of 1 degree C or more three hours after dosing. A second objective of the trial was to compare the incidence and severity of side effects and the palatability of a range of ibuprofen doses. Ninety three children were included in the analysis. All four doses of ibuprofen studied (0.625 mg/kg-5 mg/kg) were associated with temperature reduction and only the lowest dose failed to satisfy the principal measure of efficacy. The influence of dose on the magnitude of the body temperature reduction was significant and the 5 mg/kg dose achieved the largest mean reduction in body temperature (2 degrees C). The tolerability and palatability of all doses studied were excellent. These findings suggest that ibuprofen is a good alternative to paracetamol as an antipyretic. PMID:1929509

Improved Overall Survival with Aggressive Primary Tumor Radiotherapy for Patients with Metastatic Esophageal Cancer.

PubMed

Guttmann, David M; Mitra, Nandita; Bekelman, Justin; Metz, James M; Plastaras, John; Feng, Weiwei; Swisher-McClure, Samuel

2017-07-01

The aim of this study was to characterize utilization and survival outcomes associated with primary tumor-directed radiotherapy (PTDRT) in patients with newly diagnosed metastatic esophageal cancer. We conducted an observational cohort study using the National Cancer Data Base to evaluate patients with newly diagnosed metastatic esophageal cancer between 2004 and 2012. Overall survival outcomes after treatment with chemotherapy plus conventional palliative dose radiotherapy (<5040 cGy), chemotherapy plus definitive dose radiotherapy (≥5040 cGy), or chemotherapy alone were compared by using Cox proportional hazards models with inverse probability of treatment weighting using the propensity score. Potential unmeasured confounding was assessed through sensitivity analyses. The final cohort consisted of 12,683 patients: 57% were treated with chemotherapy alone, 24% were treated with chemotherapy plus palliative dose radiotherapy, and 19% were treated with chemotherapy plus definitive dose radiotherapy. Compared with chemotherapy alone, chemotherapy plus definitive dose radiotherapy was associated with improved survival (median overall survival of 8.3 versus 11.3 months [hazard ratio = 0.72, 95% confidence interval: 0.70-0.74, p ≤ 0.001]), whereas chemotherapy plus palliative dose radiotherapy was associated with slightly inferior outcomes (median overall survival of 8.3 months versus 7.5 months (hazard ratio = 1.10, 95% confidence interval 1.07-1.13, p ≤ 0.001). These findings were robust to potential unmeasured confounding in sensitivity analyses. Additionally, landmark analyses confirmed these findings in patients surviving 12 months or longer. Definitive dose, but not conventional palliative dose, PTDRT is associated with improved overall survival in metastatic esophageal cancer, suggesting that local control may be important to prognosis. These findings support integrating PTDRT into future clinical trials aimed at refining personalized treatment for patients with metastatic esophageal cancer. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

The dose-response ratio in electroconvulsive therapy a preliminary study.

PubMed

Price, T R; Mackenzie, T B; Tucker, G J; Culver, C

1978-09-01

To investigate pretreatment patient variables that might correlate with dose-response characteristics of electroconvulsive therapy (ECT) and treatment outcomes, 14 patients were assessed on a daily basis, before and during treatment, using self-report affective scales, three simple paper-and-pencil tests of cognitive function,and finger-tapping speed. From these data, dose-response ratios and treatment outcome measures were derived. The dose-response ratio of ECT was found to correlate with age--the younger the patient, the more favorable the ratio. This finding is discussed in terms of the known relationships between brain monoamine oxidase levels and age, and the established relationship between seizure duration and treatment efficacy. The dose-response ratio over the first two electroconvulsive treatments as well as lesser degrees of initial congnitive and greater degrees of initial affective impairment correlated strongly with greater overall affective improvement. Some clinical and research implications of these findings are discussed.

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

ERIC Educational Resources Information Center

Tolbert, Lelland; And Others

1993-01-01

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

Relationship of glucose values to sliding scale insulin (correctional insulin) dose delivery and meal time in acute care patients with diabetes mellitus.

PubMed

Trotter, Barbara; Conaway, Mark R; Burns, Suzanne M

2013-01-01

Findings of this study suggest the traditional sliding scale insulin (SSI) method does not improve target glucose values among adult medical inpatients. Timing of blood glucose (BC) measurement does affect the required SSI dose. BC measurement and insulin dose administration should be accomplished immediately prior to mealtime.

Hemopoietic Response to Low Dose-Rates of Ionizing Radiation Shows Stem Cell Tolerance and Adaptation

PubMed Central

Fliedner, Theodor M.; Graessle, Dieter H.; Meineke, Viktor; Feinendegen, Ludwig E.

2012-01-01

Chronic exposure of mammals to low dose-rates of ionizing radiation affects proliferating cell systems as a function of both dose-rate and the total dose accumulated. The lower the dose-rate the higher needs to be the total dose for a deterministic effect, i.e., tissue reaction to appear. Stem cells provide for proliferating, maturing and functional cells. Stem cells usually are particularly radiosensitive and damage to them may propagate to cause failure of functional cells. The paper revisits 1) medical histories with emphasis on the hemopoietic system of the victims of ten accidental chronic radiation exposures, 2) published hematological findings of long-term chronically gamma-irradiated rodents, and 3) such findings in dogs chronically exposed in large life-span studies. The data are consistent with the hypothesis that hemopoietic stem and early progenitor cells have the capacity to tolerate and adapt to being repetitively hit by energy deposition events. The data are compatible with the “injured stem cell hypothesis”, stating that radiation–injured stem cells, depending on dose-rate, may continue to deliver clones of functional cells that maintain homeostasis of hemopoiesis throughout life. Further studies perhaps on separated hemopoietic stem cells may unravel the molecular-biology mechanisms causing radiation tolerance and adaptation. PMID:23304110

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.

PubMed

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2015-07-01

High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies. © 2014 by The Author(s).

Dose-response plasma appearance of coffee chlorogenic and phenolic acids in adults.

PubMed

Renouf, Mathieu; Marmet, Cynthia; Giuffrida, Francesca; Lepage, Mélissa; Barron, Denis; Beaumont, Maurice; Williamson, Gary; Dionisi, Fabiola

2014-02-01

Coffee contains phenolic compounds, mainly chlorogenic acids (CGAs). Even though coffee intake has been associated with some health benefits in epidemiological studies, the bioavailability of coffee phenolics is not fully understood. We performed a dose-response study measuring plasma bioavailability of phenolics after drinking three increasing, but still nutritionally relevant doses of instant pure soluble coffee. The study design was a one treatment (coffee) three-dose randomized cross-over design, with a washout period of 2 wks between visits. CGAs, phenolic acids, and late-appearing metabolites all increased with increasing ingested dose. Hence, the sum of area under the curve was significantly higher for the medium to low dose, and high to medium dose, by 2.23- and 2.38-fold, respectively. CGAs were not well absorbed in their intact form, regardless of the dose. CGA and phenolic acids appeared rapidly in plasma, indicating an early absorption in the gastrointestinal tract. Late-appearing metabolites were the most abundant, regardless of the dose. This study confirmed previous findings about coffee bioavailability but also showed that coffee phenolics appear in a positive dose-response manner in plasma when drank at nutritionally relevant doses. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma.

PubMed

Kumar, Shaji K; Laubach, Jacob P; Giove, Thomas J; Quick, Maureen; Neuwirth, Rachel; Yung, Godwin; Rajkumar, S Vincent; Richardson, Paul G

2017-09-01

Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. © 2017 John Wiley & Sons Ltd.

Student's music exposure: Full-day personal dose measurements.

PubMed

Washnik, Nilesh Jeevandas; Phillips, Susan L; Teglas, Sandra

2016-01-01

Previous studies have shown that collegiate level music students are exposed to potentially hazardous sound levels. Compared to professional musicians, collegiate level music students typically do not perform as frequently, but they are exposed to intense sounds during practice and rehearsal sessions. The purpose of the study was to determine the full-day exposure dose including individual practice and ensemble rehearsals for collegiate student musicians. Sixty-seven college students of classical music were recruited representing 17 primary instruments. Of these students, 57 completed 2 days of noise dose measurements using Cirrus doseBadge programed according to the National Institute for Occupational Safety and Health criterion. Sound exposure was measured for 2 days from morning to evening, ranging from 7 to 9 h. Twenty-eight out of 57 (49%) student musicians exceeded a 100% daily noise dose on at least 1 day of the two measurement days. Eleven student musicians (19%) exceeded 100% daily noise dose on both days. Fourteen students exceeded 100% dose during large ensemble rehearsals and eight students exceeded 100% dose during individual practice sessions. Approximately, half of the student musicians exceeded 100% noise dose on a typical college schedule. This finding indicates that a large proportion of collegiate student musicians are at risk of developing noise-induced hearing loss due to hazardous sound levels. Considering the current finding, there is a need to conduct hearing conservation programs in all music schools, and to educate student musicians about the use and importance of hearing protection devices for their hearing.

Student's music exposure: Full-day personal dose measurements

PubMed Central

Washnik, Nilesh Jeevandas; Phillips, Susan L.; Teglas, Sandra

2016-01-01

Previous studies have shown that collegiate level music students are exposed to potentially hazardous sound levels. Compared to professional musicians, collegiate level music students typically do not perform as frequently, but they are exposed to intense sounds during practice and rehearsal sessions. The purpose of the study was to determine the full-day exposure dose including individual practice and ensemble rehearsals for collegiate student musicians. Sixty-seven college students of classical music were recruited representing 17 primary instruments. Of these students, 57 completed 2 days of noise dose measurements using Cirrus doseBadge programed according to the National Institute for Occupational Safety and Health criterion. Sound exposure was measured for 2 days from morning to evening, ranging from 7 to 9 h. Twenty-eight out of 57 (49%) student musicians exceeded a 100% daily noise dose on at least 1 day of the two measurement days. Eleven student musicians (19%) exceeded 100% daily noise dose on both days. Fourteen students exceeded 100% dose during large ensemble rehearsals and eight students exceeded 100% dose during individual practice sessions. Approximately, half of the student musicians exceeded 100% noise dose on a typical college schedule. This finding indicates that a large proportion of collegiate student musicians are at risk of developing noise-induced hearing loss due to hazardous sound levels. Considering the current finding, there is a need to conduct hearing conservation programs in all music schools, and to educate student musicians about the use and importance of hearing protection devices for their hearing. PMID:26960787

Experimental design and statistical analysis for three-drug combination studies.

PubMed

Fang, Hong-Bin; Chen, Xuerong; Pei, Xin-Yan; Grant, Steven; Tan, Ming

2017-06-01

Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value of multidrug combinations has been well recognized in the cancer research community, to our best knowledge, all existing experimental studies rely on fixing the dose of one drug to reduce the dimensionality, e.g. looking at pairwise two-drug combinations, a suboptimal design. Hence, there is an urgent need to develop experimental design and analysis methods for studying multidrug combinations directly. Because the complexity of the problem increases exponentially with the number of constituent drugs, there has been little progress in the development of methods for the design and analysis of high-dimensional drug combinations. In fact, contrary to common mathematical reasoning, the case of three-drug combinations is fundamentally more difficult than two-drug combinations. Apparently, finding doses of the combination, number of combinations, and replicates needed to detect departures from additivity depends on dose-response shapes of individual constituent drugs. Thus, different classes of drugs of different dose-response shapes need to be treated as a separate case. Our application and case studies develop dose finding and sample size method for detecting departures from additivity with several common (linear and log-linear) classes of single dose-response curves. Furthermore, utilizing the geometric features of the interaction index, we propose a nonparametric model to estimate the interaction index surface by B-spine approximation and derive its asymptotic properties. Utilizing the method, we designed and analyzed a combination study of three anticancer drugs, PD184, HA14-1, and CEP3891 inhibiting myeloma H929 cell line. To our best knowledge, this is the first ever three drug combinations study performed based on the original 4D dose-response surface formed by dose ranges of three drugs.

Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.

PubMed

Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

2015-05-01

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

PubMed

Atkins, Michael B; Plimack, Elizabeth R; Puzanov, Igor; Fishman, Mayer N; McDermott, David F; Cho, Daniel C; Vaishampayan, Ulka; George, Saby; Olencki, Thomas E; Tarazi, Jamal C; Rosbrook, Brad; Fernandez, Kathrine C; Lechuga, Mariajose; Choueiri, Toni K

2018-03-01

Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). Pfizer Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

Controlling Mitochondrial Dynamics to Mitigate Noise-Induced Hearing Loss

DTIC Science & Technology

2017-10-01

protection against outer hair cell loss at the high frequency responsive region of the organ of Corti was observed. Importantly, these findings demonstrated...a high dose would be detrimental to hearing sensitivity or to outer hair cell viability. The 25 and 100 µM doses were similar to the 50 µM dose in...Completion of outer hair cell counts on the 200 µM study group revealed that this higher dose did not reduce OHC survival in the treated ear

Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

PubMed

Land, Charles E; Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M; Simon, Steven L

2015-02-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response.

Duration of post-vaccination immunity to yellow fever in volunteers eight years after a dose-response study.

PubMed

de Menezes Martins, Reinaldo; Maia, Maria de Lourdes S; de Lima, Sheila Maria Barbosa; de Noronha, Tatiana Guimarães; Xavier, Janaina Reis; Camacho, Luiz Antonio Bastos; de Albuquerque, Elizabeth Maciel; Farias, Roberto Henrique Guedes; da Matta de Castro, Thalita; Homma, Akira

2018-06-27

In 2009, Bio-Manguinhos conducted a dose-response study with the yellow fever vaccine, administering the vaccine in the usual mean dose of 27,476 IU (full dose, reference) and in tapered doses (10,447 IU, 3013 IU, 587 IU, 158 IU, and 31 IU) by the usual subcutaneous route and usual volume (0.5 mL). Tapered doses were obtained by dilution in the manufacturer's laboratory, and the test batches presented industrial quality. Doses down to 587 IU showed similar immunogenicity to the full dose (27,476, reference), while the 158 IU and 31 IU doses displayed lower immunogenicity. Seropositivity was maintained at 10 months, except in the group that received the 31 IU dose. The current study aims to determine whether yellow fever seropositivity was maintained eight years after YF vaccination in non-revaccinated individuals. According to the current study's results, seropositivity was maintained in 85% of 318 participants and was similar across groups. The findings support the use of the yellow fever vaccine in fractional doses during outbreaks, but each fractional dose should have at least 587 IU. This study also supports the minimum dose required by WHO, 1000 IU. Clinicaltrials.gov NCT 03338231. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Combined effects of alpha particles and depleted uranium on Zebrafish (Danio rerio) embryos

PubMed Central

Ng, Candy Y.P.; Pereira, Sandrine; Cheng, Shuk Han; Adam-Guillermin, Christelle; Garnier-Laplace, Jacqueline; Yu, Kwan Ngok

2016-01-01

The combined effects of low-dose or high-dose alpha particles and depleted uranium (DU) in Zebrafish (Danio rerio) embryos were studied. Three schemes were examined—(i) [ILUL]: 0.44 mGy alpha-particle dose + 10 µg/l DU exposure, (ii) [IHUH]: 4.4 mGy alpha-particle dose + 100 µg/l DU exposure and (iii) [IHUL]: 4.4 mGy alpha-particle dose + 10 µg/l DU exposure—in which Zebrafish embryos were irradiated with alpha particles at 5 h post fertilization (hpf) and/or exposed to uranium at 5–6 hpf. The results were also compared with our previous work, which studied the effects of [ILUH]: 0.44 mGy alpha-particle dose + 100 µg/l DU exposure. When the Zebrafish embryos developed to 24 hpf, the apoptotic signals in the entire embryos, used as the biological endpoint for this study, were quantified. Our results showed that [ILUL] and [IHUL] led to antagonistic effects, whereas [IHUH] led to an additive effect. The effect found for the previously studied case of [ILUH] was difficult to define because it was synergistic with reference to the 100 µg/l DU exposure, but it was antagonistic with reference to the 0.44 mGy alpha-particle dose. All the findings regarding the four different schemes showed that the combined effects critically depended on the dose response to each individual stressor. We also qualitatively explained these findings in terms of promotion of early death of cells predisposed to spontaneous transformation by alpha particles, interacting with the delay in cell death resulting from various concentrations of DU exposure. PMID:26937024

A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors.

PubMed

Wakui, Hiroshi; Yamamoto, Noboru; Kitazono, Satoru; Mizugaki, Hidenori; Nakamichi, Shinji; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamada, Yasuhide; Suzuki, Kohei; Kanda, Hironori; Akinaga, Shiro; Tamura, Tomohide

2014-07-01

Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors. LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m²/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia. Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m²/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/μl within 7 days. All patients at 4 and 5 mg/m²/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m²/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed. The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m²/day in Japanese patients with advanced solid tumors.

Single visit rabies pre-exposure priming induces a robust anamnestic antibody response after simulated post-exposure vaccination: results of a dose-finding study.

PubMed

Jonker, Emile F F; Visser, Leonardus G

2017-09-01

The current standard 3-dose intramuscular rabies PrEP schedule suffers from a number of disadvantages that severely limit accessibility and availability. The cost of is often prohibitive, it requires 3 visits to the clinic, and there are regular vaccine shortages. Volunteers ( N  = 30) were randomly assigned to 4 study arms: 1 standard dose intramuscular (IM) dose of PVRV (purified Vero cell rabies vaccine, Verorab), and 1/5th, 2/5th or 3/5th- fractional intradermal (ID) dose of PVRV in a single visit. All subjects received a simulated rabies post-exposure prophylaxis (D0, D3) 1 year later. Rabies virus neutralizing antibodies (RVNA) were determined by virus neutralization microtest (FAVN) on D0, D7, D28, Y1 and Y1 + D7. 28 out of 30 subjects (93%) seroconverted 1 month after primary vaccination; 1 subject in the 1-dose IM arm and 1 in the 1/5th-fractional dose ID arm did not. After 1 year, 22 out of 30 subjects (73%) no longer had RVNA above 0.5 IU/ml, with no discernible difference between study groups. After 1 year, all 30 subjects mounted a booster response within 7 days after simulated PEP, with the highest titers found in the single dose IM group ( P  < 0.03). This dose finding study demonstrates that priming with a single dose of rabies vaccine was sufficient to induce an adequate anamnestic antibody response to rabies PEP in all subjects 1 year later, even in those in whom the RVNA threshold of 0.5 IU/ml was not reached after priming. © International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

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

PubMed Central

Koopmeiners, Joseph S.; Wey, Andrew

2017-01-01

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

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

PubMed

Koopmeiners, Joseph S; Wey, Andrew

2017-01-01

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

Do all patients in the phase I oncology trials need to be hospitalized? Domestic but outstanding issues for globalization of drug development in Japan.

PubMed

Shimomura, Akihiko; Kondo, Shunsuke; Kobayashi, Noriko; Iwasa, Satoru; Kitano, Shigehisa; Tamura, Kenji; Fujiwara, Yutaka; Yamamoto, Noboru

2017-08-01

Most trials investigating new drugs around the world, including phase I trials, are conducted in outpatient clinics. However, in Japan, regulatory authority requirements and traditional domestic guidelines often require hospitalization of phase I study participants. Patients participating in single-agent phase I clinical trials at National Cancer Center Hospital between December 1996 and August 2014 were monitored. Toxicity requiring hospitalization is defined as toxicity that needs intensive treatment. Study designs were classified into three types: first-in-human (FIH) study, dose-escalation study (conventional dose-escalation study to determine maximum tolerated dose (MTD) in Japanese patients), and dose-finding study (to assess safety and pharmacokinetic profiles up to the MTD previously determined in the West). A total of 945 patients who participated in a variety of single-agent phase I clinical trials between December 1996 and August 2014 were included in this study. Patients participated in one of three study types: dose-escalation (n = 582, 62%), first-in-human (n = 129, 14%), or dose-finding (n = 234, 25%). A total of 76 study drugs were evaluated as part of this pool of phase I studies. Subdivided by mechanism of action, 20 (26%) were cytotoxic, 50 (66%) were molecularly targeted, and 6 (8%) were immune checkpoint inhibitor. Thirty-six patients (3.8%) had severe toxicities requiring hospitalization during the first cycle. The overall number of toxicities requiring hospitalization and/or grade 4 toxicities during any cycle was 5.0%. The frequency of severe toxicity that needs to be hospitalized was unexpectedly low. The data did not demonstrate the need for hospitalization in the phase I trials, suggesting that phase I trials in Japan could be conducted in outpatient settings.

Optimizing adaptive design for Phase 2 dose-finding trials incorporating long-term success and financial considerations: A case study for neuropathic pain.

PubMed

Gao, Jingjing; Nangia, Narinder; Jia, Jia; Bolognese, James; Bhattacharyya, Jaydeep; Patel, Nitin

2017-06-01

In this paper, we propose an adaptive randomization design for Phase 2 dose-finding trials to optimize Net Present Value (NPV) for an experimental drug. We replace the traditional fixed sample size design (Patel, et al., 2012) by this new design to see if NPV from the original paper can be improved. Comparison of the proposed design to the previous design is made via simulations using a hypothetical example based on a Diabetic Neuropathic Pain Study. Copyright © 2017 Elsevier Inc. All rights reserved.

Switching From Age-Based Stimulus Dosing to Dose Titration Protocols in Electroconvulsive Therapy: Empirical Evidence for Better Patient Outcomes With Lower Peak and Cumulative Energy Doses.

PubMed

O'Neill-Kerr, Alex; Yassin, Anhar; Rogers, Stephen; Cornish, Janie

2017-09-01

The aim of this study was to test the proposition that adoption of a dose titration protocol may be associated with better patient outcomes, at lower treatment dose, and with comparable cumulative dose to that in patients treated using an age-based stimulus dosing protocol. This was an analysis of data assembled from archived records and based on cohorts of patients treated respectively on an age-based stimulus dosing protocol and on a dose titration protocol in the National Health Service in England. We demonstrated a significantly better response in the patient cohort treated with dose titration than with age-based stimulus dosing. Peak doses were less and the total cumulative dose was less in the dose titration group than in the age-based stimulus dosing group. Our findings are consistent with superior outcomes in patients treated using a dose titration protocol when compared with age-based stimulus dosing in a similar cohort of patients.

Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles.

PubMed

Warheit, D B; Brown, S C; Donner, E M

2015-10-01

Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm - 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies - each with different TiO2 particulate-types, demonstrated an absence of adverse toxicological effects. Apart from reporting the findings of these three studies, this publication also focuses on additional critical issues associated with particle and nanotoxicology studies. First, describing the detailed methodology requirements and rigor upon which the standardized OECD 408 guideline subchronic oral toxicity studies are conducted. Moreover, an attempt is made to reconcile the complex issue of particle size distribution as it relates to measurements of nanoscale and pigment-grade TiO2 particles. Clearly this has been a confusing issue and often misrepresented in the media and the scientific literature. It is clear that the particle-size distribution for pigment-grade TiO2, contains a small ("tail") component of nanoscale particles (i.e., 21% by particle number and <1% by weight in the test material used in the 90-day study). However, this robust particle characterization finding should not be confused with mislabeling the test materials as exclusively in the nanoscale range. Moreover, based upon the findings presented herein, there appears to be no significant oral toxicity impact contributed by the nanoscale component of the TiO2 Test Material sample in the 90-day study. Finally, it seems reasonable to conclude that the study findings should be considered for read-across purposes to food-grade TiO2 particles (e.g., E171), as the physicochemical characteristics are quite similar. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety of orally administered, USP-compliant levothyroxine sodium tablets in dogs.

PubMed

Hare, J E; Morrow, C M K; Caldwell, J; Lloyd, W E

2018-04-01

The safety of synthetic levothyroxine sodium tablets (Thyro-Tabs® Canine; LLOYD, Inc.) in dogs was evaluated in a randomized, sham-dose controlled, parallel-group study. Young, healthy, euthyroid Beagle dogs were randomized into four groups (four females and four males per group) and received single daily doses of 0×, 2× (0.044 mg/kg), 6× (0.132 mg/kg), or 10× (0.22 mg/kg) the labeled starting dose of 0.022 mg kg -1  day -1 for 182 days. Every 2 weeks, physical examinations, electrocardiology examinations, and sample collections for thyroid panel, hematology, serum biochemistry, coagulation panel, and urinalysis were performed. At the end of the study, the dogs were euthanized and full necropsies performed. The most overt finding was the expected dose-dependent increase in serum concentrations of total and free thyroxine with dose-dependent suppression of the hypothalamic-pituitary-thyroid axis as evidenced by decreased serum thyroid-stimulating hormone concentrations, decreased thyroid+parathyroid/body weight ratios, and a trend for decreased pituitary weight/brain weight ratios. Clinical signs of thyrotoxicosis (excitation, tachypnea, tachycardia) in the treated dogs were sporadic with no dose-response relationship. Other findings statistically associated with levothyroxine treatment were generally mild and not clinically important. In summary, doses of levothyroxine sodium up to 10× the labeled starting dose were well tolerated in healthy dogs. © 2017 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Low-Dose Aspirin Reduces Breast Cancer Risk in Women with Diabetes: A Nationwide Retrospective Cohort Study in Taiwan.

PubMed

Yang, Yi-Sun; Kornelius, Edy; Chiou, Jeng-Yuan; Lai, Yung-Rung; Lo, Shih-Chang; Peng, Chiung-Huei; Huang, Chien-Ning

2017-12-01

Low-dose aspirin is commonly used for preventing cardiovascular disease in people with diabetes, but its association with cancer remains controversial. This study used a nationwide population-based reimbursement database to investigate the relationship between low-dose aspirin use and breast cancer incidence in women with diabetes. This retrospective cohort study was conducted using data retrieved from the National Health Insurance Research Database in Taiwan from January 1, 1998 to December 31, 2011. Women diagnosed as having diabetes with low-dose aspirin use (75-165 mg daily) were identified as the study population, whereas those without low-dose aspirin use were selected as the comparison group. We analyzed 148,739 patients with diabetes. Their mean age (standard deviation) was 63.3 (12.8) years. A total of 27,378 patients were taking aspirin. Overall, the use of aspirin in patients with diabetes reduced the risk of breast cancer by 18% (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.94) after adjustment for potential confounders, namely age and comorbidities. Specifically, a cumulative dose of aspirin exceeding 88,900 mg was observed to reduce the risk of breast cancer by 47% (HR, 0.53, 95% CI, 0.43-0.67); however, low (<8,600 mg) and medium (8,600-88,900 mg) cumulative doses of aspirin did not reduce the risk of breast cancer. Our findings suggest that a cumulative aspirin dosage of more than 88,900 mg daily was associated with a reduced risk of breast cancer in women with diabetes. However, additional studies are necessary to confirm these findings.

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.

Cytogenetic effect of low dose gamma-radiation in Hordeum vulgare seedlings: non-linear dose-effect relationship.

PubMed

Geras'kin, Stanislav A; Oudalova, Alla A; Kim, Jin Kyu; Dikarev, Vladimir G; Dikareva, Nina S

2007-03-01

The induction of chromosome aberrations in Hordeum vulgare germinated seeds was studied after ionizing irradiation with doses in the range of 10-1,000 mGy. The relationship between the frequency of aberrant cells and the absorbed dose was found to be nonlinear. A dose-independent plateau in the dose range from about 50 to 500 mGy was observed, where the level of cytogenetic damage was significantly different from the spontaneous level. The comparison of the goodness of the experimental data fitting with mathematical models of different complexity, using the most common quantitative criteria, demonstrated the advantage of a piecewise linear model over linear and polynomial models in approximating the frequency of cytogenetical disturbances. The results of the study support the hypothesis of indirect mechanisms of mutagenesis induced by low doses. Fundamental and applied implications of these findings are discussed.

Maternal and developmental toxicity of ayahuasca in Wistar rats.

PubMed

Oliveira, Carolina Dizioli Rodrigues; Moreira, Camila Queiroz; de Sá, Lilian Rose Marques; Spinosa, Helenice de Souza; Yonamine, Mauricio

2010-06-01

Ayahuasca is a psychotropic plant beverage initially used by shamans throughout the Amazon region during traditional religious cult. In recent years, ayahuasca has also been used in ceremonies of a number of modern syncretic religious groups, including pregnant women. However, no documented study has been performed to evaluate the risk of developmental toxicity of ayahuasca. In the present work, maternal and developmental toxicity was evaluated in Wistar rats. Ayahuasca was administered to pregnant rats in three different doses [the equivalent typical dose (TD) administered to humans, five-fold TD and 10-fold TD] during the gestational period (6-20 days). Dams treated with the highest ayahuasca dose showed maternal toxicity with decrease of weight gain and food intake. Visceral fetal findings were observed in all treatment groups. Skeletal findings were observed in the intermediate- and high-dose groups. The fetuses deriving from the highest dose group also presented a decrease in body weight. From these results, it is possible to conclude that there is a risk of maternal and developmental toxicity following ayahuasca exposure and that the level of toxicity appears to be dose-dependent.

Lateral topography for reducing effective dose in low-dose chest CT.

PubMed

Bang, Dong-Ho; Lim, Daekeon; Hwang, Wi-Sub; Park, Seong-Hoon; Jeong, Ok-man; Kang, Kyung Wook; Kang, Hohyung

2013-06-01

The purposes of this study were to assess radiation exposure during low-dose chest CT by using lateral topography and to compare the lateral topographic findings with findings obtained with anteroposterior topography alone and anteroposterior and lateral topography combined. From November 2011 to February 2012, 210 male subjects were enrolled in the study. Age, weight, and height of the men were recorded. All subjects were placed into one of three subgroups based on the type of topographic image obtained: anteroposterior topography, lateral topography, and both anteroposterior and lateral topography. Imaging was performed with a 128-MDCT scanner. CT, except for topography, was the same for all subjects. A radiologist analyzed each image, recorded scan length, checked for any insufficiencies in the FOV, and calculated the effective radiation dose. One-way analysis of variance and multiple comparisons were used to compare the effective radiation exposure and scan length between groups. The mean scan length in the anteroposterior topography group was significantly greater than that of the lateral topography group and the combined anteroposterior and lateral topography group (p < 0.001). The mean effective radiation dose for the lateral topography group (0.735 ± 0.033 mSv) was significantly lower than that for the anteroposterior topography group (0.763 ± 0.038 mSv) and the combined anteroposterior and lateral topography group (0.773 ± 0.038) (p < 0.001). Lateral topographic low-dose CT was associated with a lower effective radiation dose and scan length than either anteroposterior topographic low-dose chest CT or low-dose chest CT with both anteroposterior and lateral topograms.

Lack of association between dopaminergic antagonism and negative symptoms in schizophrenia: a positron emission tomography dopamine D2/3 receptor occupancy study

PubMed Central

Fervaha, Gagan; Caravaggio, Fernando; Mamo, David C.; Mulsant, Benoit H.; Pollock, Bruce G.; Nakajima, Shinichiro; Gerretsen, Philip; Rajji, Tarek K.; Mar, Wanna; Iwata, Yusuke; Plitman, Eric; Chung, Jun Ku; Remington, Gary; Graff-Guerrero, Ariel

2016-01-01

Rationale Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial. Objective The objective of this study was to examine the relationship between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptoms in patients with schizophrenia. Methods Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [11C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40% from the baseline dose. Results No significant relationship was found between antipsychotic-related dopamine D2/3 receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship. Conclusions Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioural effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined. PMID:27557949

Ultrasound-Detected Thyroid Nodule Prevalence and Radiation Dose from Fallout

PubMed Central

Land, C. E.; Zhumadilov, Z.; Gusev, B. I.; Hartshorne, M. H.; Wiest, P. W.; Woodward, P. W.; Crooks, L. A.; Luckyanov, N. K.; Fillmore, C. M.; Carr, Z.; Abisheva, G.; Beck, H. L.; Bouville, A.; Langer, J.; Weinstock, R.; Gordeev, K. I.; Shinkarev, S.; Simon, S. L.

2014-01-01

Settlements near the Semipalatinsk Test Site (SNTS) in northeastern Kazakhstan were exposed to radioactive fallout during 1949–1962. Thyroid disease prevalence among 2994 residents of eight villages was ascertained by ultrasound screening. Malignancy was determined by cytopathology. Individual thyroid doses from external and internal radiation sources were reconstructed from fallout deposition patterns, residential histories and diet, including childhood milk consumption. Point estimates of individual external and internal dose averaged 0.04 Gy (range 0–0.65) and 0.31 Gy (0–9.6), respectively, with a Pearson correlation coefficient of 0.46. Ultrasound-detected thyroid nodule prevalence was 18% and 39% among males and females, respectively. It was significantly and independently associated with both external and internal dose, the main study finding. The estimated relative biological effectiveness of internal compared to external radiation dose was 0.33, with 95% confidence bounds of 0.09–3.11. Prevalence of papillary cancer was 0.9% and was not significantly associated with radiation dose. In terms of excess relative risk per unit dose, our dose–response findings for nodule prevalence are comparable to those from populations exposed to medical X rays and to acute radiation from the Hiroshima and Nagasaki atomic bombings. PMID:18363427

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.

Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication.

PubMed

Lewis, Roger J; Connor, Jason T; Teerlink, John R; Murphy, James R; Cooper, Leslie T; Hiatt, William R; Brass, Eric P

2011-05-25

Claudication secondary to peripheral artery disease (PAD) is associated with substantial functional impairment. Phosphodiesterase (PDE) inhibitors have been shown to increase walking performance in these patients. K-134 is a selective PDE 3 inhibitor being developed as a potential treatment for claudication. The use of K-134, as with other PDE 3 inhibitors, in patients with PAD raises important safety and tolerability concerns, including the induction of cardiac ischemia, tachycardia, and hypotension. We describe the design, oversight, and implementation of an adaptive, phase II, dose-finding trial evaluating K-134 for the treatment of stable, intermittent claudication. The study design was a double-blind, multi-dose (25 mg, 50 mg, and 100 mg of K-134), randomized trial with both placebo and active comparator arms conducted in the United States and Russia. The primary objective of the study was to compare the highest tolerable dose of K-134 versus placebo using peak walking time after 26 weeks of therapy as the primary outcome. Study visits with intensive safety assessments were included early in the study period to provide data for adaptive decision making. The trial used an adaptive, dose-finding strategy to efficiently identify the highest dose(s) most likely to be safe and well tolerated, based on the side effect profiles observed within the trial, so that less promising doses could be abandoned. Protocol specified criteria for safety and tolerability endpoints were used and modeled prior to the adaptive decision making. The maximum target sample size was 85 subjects in each of the retained treatment arms. When 199 subjects had been randomized and 28-day data were available from 143, the Data Monitoring Committee (DMC) recommended termination of the lowest dose (25 mg) treatment arm. Safety evaluations performed during 14- and 28-day visits which included in-clinic dosing and assessments at peak drug concentrations provided core data for the DMC review. At the time of review, no subject in any of the five treatment arms (placebo, three K-134-containing arms, and cilostazol) had met pre-specified definitions for resting tachycardia or ischemic changes on exercise ECG. If, instead of dropping the 25-mg K-134 treatment arm, all arms had been continued to full enrollment, then approximately 43 additional research subjects would have been required to complete the trial. In this phase II, dose-finding trial of K-134 in the treatment of stable intermittent claudication, no concerning safety signals were seen at interim analysis, allowing the discontinuation of the lowest-dose-containing arm and the retention of the two highest-dose-containing arms. The adaptive design facilitated safe and efficient evaluation of K-134 in this high-risk cardiovascular population. ClinicalTrials.gov: NCT00783081.

Low-dose radiation attenuates chemical mutagenesis in vivo.

PubMed

Kakinuma, Shizuko; Yamauchi, Kazumi; Amasaki, Yoshiko; Nishimura, Mayumi; Shimada, Yoshiya

2009-09-01

The biological effects of low-dose radiation are not only of social concern but also of scientific interest. The radioadaptive response, which is defined as an increased radioresistance by prior exposure to low-dose radiation, has been extensively studied both in vitro and in vivo. Here we briefly review the radioadaptive response with respect to mutagenesis, survival rate, and carcinogenesis in vivo, and introduce our recent findings of cross adaptation in mouse thymic cells, that is, the suppressive effect of repeated low-dose radiation on mutation induction by the alkylating agent N-ethyl-N-nitrosourea.

Dose-Dependent Associations between Wine Drinking and Breast Cancer Risk - Meta-Analysis Findings.

PubMed

Chen, Jia-Yan; Zhu, Hong-Cheng; Guo, Qing; Shu, Zheng; Bao, Xu-Hui; Sun, Feng; Qin, Qin; Yang, Xi; Zhang, Chi; Cheng, Hong-Yan; Sun, Xin-Chen

2016-01-01

To investigate any potential association between wine and breast cancer risk. We quantitatively assessed associations by conducting a meta-analysis based on evidence from observational studies. In May 2014, we performed electronic searches in PubMed, EmBase and the Cochrane Library to identify studies examining the effect of wine drinking on breast cancer incidence. The relative risk (RR) or odds ratio (OR) were used to measure any such association. The analysis was further stratified by confounding factors that could influence the results. A total of twenty-six studies (eight case-control and eighteen cohort studies) involving 21,149 cases were included in our meta-analysis. Our study demonstrated that wine drinking was associated with breast cancer risk. A 36% increase in breast cancer risk was observed across overall studies based on the highest versus lowest model, with a combined RR of 1.0059 (95%CI 0.97-1.05) in dose-response analysis. However, 5 g/d ethanol from wine seemed to have protective value from our non-linear model. Our findings indicate that wine drinking is associated with breast cancer risk in a dose-dependent manner. High consumption of wine contributes to breast cancer risk with protection exerted by low doses. Further investigations are needed for clarification.

Accounting for Shared and Unshared Dosimetric Uncertainties in the Dose Response for Ultrasound-Detected Thyroid Nodules after Exposure to Radioactive Fallout

PubMed Central

Hoffman, F. Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M.; Simon, Steven L.

2015-01-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semi-palatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point “best estimates”. In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response. PMID:25574587

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

PubMed

Dropkin, Greg

2016-11-24

Analyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour. GAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 - 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy. For all solid cancer incidence, RR estimated from 0 - 100 mGy and 0 - 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 - 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort. Non-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

PubMed Central

Sherry, Nicole; Hagopian, William; Ludvigsson, Johnny; Jain, Sunil M; Wahlen, Jack; Ferry, Robert J; Bode, Bruce; Aronoff, Stephen; Holland, Christopher; Carlin, David; King, Karen L; Wilder, Ronald L; Pillemer, Stanley; Bonvini, Ezio; Johnson, Syd; Stein, Kathryn E; Koenig, Scott; Herold, Kevan C; Daifotis, Anastasia G

2011-01-01

Summary Background Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. Methods In this 2-year trial, patients aged 8–35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0.5 U/kg per day and glycated haemoglobin A1c (HbA1C) of less than 6.5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. Findings 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). Interpretation Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. PMID:21719095

Dysthymic disorder: treatment with citalopram.

PubMed

Dunner, David L; Hendricksen, Helen E; Bea, Carolyn; Budech, Chris B; Friedman, S D

2002-01-01

We studied 15 patients with dysthymic disorder with open-label citalopram. The purpose of this study was to determine the dose range and safety of citalopram necessary for treatment of patients with dysthymic disorder and to attempt to increase doses in order to enhance remission of patients with dysthymic disorder when treated. Citalopram was well tolerated. The mean dose used in this 10-week study was 37.3 mg and the majority of patients responded to treatment. Various criteria for response and remission were employed. These findings are intended to give guidelines for a subsequent treatment study of dysthymic patients with citalopram using a double-blind placebo-controlled strategy. Copyright 2002 Wiley-Liss, Inc.

Long-Acting C-Terminal Peptide-Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children.

PubMed

Zelinska, Nataliya; Iotova, Violeta; Skorodok, Julia; Malievsky, Oleg; Peterkova, Valentina; Samsonova, Lubov; Rosenfeld, Ron G; Zadik, Zvi; Jaron-Mendelson, Michal; Koren, Ronit; Amitzi, Leanne; Raduk, Dmitri; Hershkovitz, Oren; Hart, Gili

2017-05-01

Daily injections are required for growth hormone (GH) replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients. C-terminal peptide-modified human GH (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children. A multicenter, open-label, randomized, controlled phase 2 study in children with GHD, evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of three different weekly MOD-4023 doses, compared with daily recombinant human GH (r-hGH). The trial was conducted in 14 endocrinology centers in Europe. Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 (N = 42) or r-hGH (N = 11). C-terminal peptide-modified hGH (MOD-4023) was administered weekly at a dose of either 0.25, 0.48, or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk. MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH. Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment. IGF-I standard deviation score for MOD-4023 did not exceed +2. All MOD-4023 cohorts demonstrated adequate catch-up growth. The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH. No serious adverse events were observed during MOD-4023 treatment, and its tolerability was consistent with known properties of r-hGH. This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile. This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023. Copyright © 2017 by the Endocrine Society

An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection.

PubMed

Saber, Haleh; Del Valle, Pedro; Ricks, Tiffany K; Leighton, John K

2017-11-01

We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe. Published by Elsevier Inc.

Factors Associated With Antidepressant Dosing in Asia: Findings From the Research on Asian Psychotropic Prescription Study.

PubMed

Rajaratnam, Kamini; Xiang, Yu-Tao; Tripathi, Adarsh; Chiu, Helen Fung Kum; Si, Tian-Mei; Chee, Kok-Yoon; Avasthi, Ajit; Grover, Sandeep; Chong, Mian-Yoon; Kuga, Hironori; Kanba, Shigenobu; He, Yan-Ling; Lee, Min-Soo; Yang, Shu-Yu; Udomratn, Pichet; Kallivayalil, Roy Abraham; Tanra, Andi J; Maramis, Margarita; Shen, Winston Wu-Dien; Sartorius, Norman; Kua, Ee-Heok; Tan, Chay-Hoon; Mahendran, Rathi; Shinfuku, Naotaka; Sum, Min Yi; Baldessarini, Ross J; Sim, Kang

2016-12-01

In this study, we sought to examine factors associated with dosing of antidepressants (ADs) in Asia. Based on reported data and clinical experience, we hypothesized that doses of ADs would be associated with demographic and clinical factors and would increase over time. This cross-sectional, pharmacoepidemiological study analyzed data collected within the Research Study on Asian Psychotropic Prescription Pattern for Antidepressants from 4164 participants in 10 Asian countries, using univariate and multivariate methods. The AD doses varied by twofold among countries (highest in PR China and RO Korea, lowest in Singapore and Indonesia), and averaged 124 (120-129) mg/d imipramine-equivalents. Average daily doses increased by 12% between 2004 and 2013. Doses were significantly higher among hospitalized patients and ranked by diagnosis: major depression > anxiety disorders > bipolar disorder, but were not associated with private/public or psychiatric/general-medical settings, nor with age, sex, or cotreatment with a mood stabilizer. In multivariate modeling, AD-dose remained significantly associated with major depressive disorder and being hospitalized. Doses of ADs have increased somewhat in Asia and were higher when used for major depression or anxiety disorders than for bipolar depression and for hospitalized psychiatric patients.

A comparative study for image quality and radiation dose of a cone beam computed tomography scanner and a multislice computed tomography scanner for paranasal sinus imaging.

PubMed

De Cock, Jens; Zanca, Federica; Canning, John; Pauwels, Ruben; Hermans, Robert

2015-07-01

To evaluate image quality and radiation dose of a state of the art cone beam computed tomography (CBCT) system and a multislice computed tomography (MSCT) system in patients with sinonasal poliposis. In this retrospective study two radiologists evaluated 57 patients with sinonasal poliposis who underwent a CBCT or MSCT sinus examination, along with a control group of 90 patients with normal radiological findings. Tissue doses were measured using a phantom model with thermoluminescent dosimeters (TLD). Overall image quality in CBCT was scored significantly higher than in MSCT in patients with normal radiologic findings (p-value: 0.00001). In patients with sinonasal poliposis, MSCT scored significantly higher than CBCT (p-value: 0.00001). The average effective dose for MSCT was 42% higher compared to CBCT (108 μSv vs 63 μSv). CBCT and MSCT are both suited for the evaluation of sinonasal poliposis. In patients with sinonasal poliposis, clinically important structures of the paranasal sinuses can be better delineated with MSCT, whereas in patients without sinonasal poliposis, CBCT turns out to define the important structures of the sinonasal region better. However, given the lower radiation dose, CBCT can be considered for the evaluation of the sinonasal structures in patients with sinonasal poliposis. • CBCT and MSCT are both suited for evaluation of sinonasal poliposis. • Effective dose for MSCT was 42% higher compared to CBCT. • In patients with sinonasal poliposis, clinically important anatomical structures are better delineated with MSCT. • In patients with normal radiological findings, clinically important anatomical structures are better delineated with CBCT.

A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction.

PubMed

Dording, Christina M; Fisher, Lauren; Papakostas, George; Farabaugh, Amy; Sonawalla, Shamsah; Fava, Maurizio; Mischoulon, David

2008-01-01

We sought to determine whether maca, a Peruvian plant, is effective for selective-serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction. We conducted a double-blind, randomized, parallel group dose-finding pilot study comparing a low-dose (1.5 g/day) to a high-dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36+/-13 years; 17 women) with SSRI-induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent-to-treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8+/-3.8 to 16.9+/-6.2; z=-2.20, P=0.028) and in MGH-SFQ scores (from 24.1+/-1.9 to 17.0+/-5.7; z=-2.39, P=0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (P<0.05) for the ITT and completer groups based on ASEX item #1, but not by dosing groups. Maca was well tolerated. Maca root may alleviate SSRI-induced sexual dysfunction, and there may be a dose-related effect. Maca may also have a beneficial effect on libido.

Somatic health effects of Chernobyl: 30 years on.

PubMed

Hatch, Maureen; Cardis, Elisabeth

2017-12-01

2016 marked the 30th anniversary of the Chernobyl Nuclear Power Plant accident. We and others wrote reviews for the 25th anniversary. Since then, additional papers have appeared and it seems timely to highlight lessons learned. To present, not a systematic review, but a commentary drawing attention to notable findings. We include not only recent reports and updates on previous results, but key findings from prior Chernobyl studies. The dose-dependent increase in Papillary Thyroid Cancer (PTC) following childhood I-131 exposure in Ukraine and Belarus has now been shown to persist for decades. Studies of post-Chernobyl PTCs have produced novel information on chromosomal rearrangements and gene fusions, critical to understanding molecular mechanisms. Studies of clean-up workers/liquidators suggest dose-related increases of thyroid cancer and hematological malignancies in adults. They also report increases in cardiovascular and cerebrovascular disease. If confirmed, these would have significant public health and radiation protection implications. The lens opacities following low to moderate doses found earlier are also a concern, particularly among interventional radiologists who may receive substantial lens doses. Finally, there is some, inconsistent, evidence for genetic effects among offspring of exposed persons. Further efforts, including improved dosimetry, collection of information on other risk factors, and continued follow-up/monitoring of established cohorts, could contribute importantly to further understand effects of low doses and dose-rates of radiation, particularly in young people, and ensure that appropriate public health and radiation protection systems are in place. This will require multinational collaborations and long-term funding.

Using machine learning to model dose-response relationships.

PubMed

Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K

2016-12-01

Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.

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.

Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer.

PubMed

Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo; Shi, Yuankai

2015-06-01

To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Duration of Exposure and the Dose-Response Model of PTSD

ERIC Educational Resources Information Center

Kaysen, Debra; Rosen, Gerald; Bowman, Marilyn; Resick, Patricia A.

2010-01-01

A dose-response model underlies posttraumatic stress disorder (PTSD) and posits a relationship between event magnitude and clinical outcome. The present study examines whether one index of event magnitude--duration of exposure--contributes to risk of PTSD among female victims of sexual assault. Findings support a small but significant contribution…

Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis.

PubMed

Zhao, Yan; Guo, Chenyang; Hu, Hongtao; Zheng, Lin; Ma, Junli; Jiang, Li; Zhao, Erjiang; Li, Hailiang

2017-02-07

Previously reported findings on the association between folate intake or serum folate levels and esophageal cancer risk have been inconsistent. This study aims to summarize the evidence regarding these relationships using a dose-response meta-analysis approach. We performed electronic searches of the Pubmed, Medline and Cochrane Library electronic databases to identify studies examining the effect of folate on the risk of esophageal cancer. Ultimately, 19 studies were included in the meta-analysis. Summary odds ratios (ORs) were estimated using a random effects model. A linear regression analysis of the natural logarithm of the OR was carried out to assess the possible dose-response relationship between folate intake and esophageal cancer risk. The pooled ORs for esophageal cancer in the highest vs. lowest levels of dietary folate intake and serum folate were 0.63 (95% CI: 0.56-0.71) and 0.71 (95% CI: 0.55-0.92), respectively. The dose-response meta-analysis indicated that a 100 μg/day increment in dietary folate intake reduced the estimate risk of esophageal cancer by 12%. These findings suggest that dietary and serum folate exert a protective effect against esophageal carcinogenesis.

Study of pharmacological activities of methanol extract of Jatropha gossypifolia fruits

PubMed Central

Apu, Apurba Sarker; Hossain, Faruq; Rizwan, Farhana; Bhuyan, Shakhawat Hossan; Matin, Maima; Jamaluddin, A.T.M

2012-01-01

Objective: The present study was carried out to investigate the possible in vivo analgesic, neuropharmacological and anti-diarrheal activities of the methanol extract of Jatropha gossypifolia fruits. Materials and Methods: The analgesic activity was measured by acetic acid induced writhing inhibition test. The neuropharmacological activities were evaluated by hole cross, hole-board, and elevated plus-maze (EPM) tests and the anti-diarrheal activity was assessed by castor oil induced diarrhea inhibition method. Findings: The extract showed highly significant (P < 0.001) analgesic activity with % inhibitions of writhing response at doses 200 and 400 mg/kg body weight were 77.86% and 71.25%, respectively. The extract at both doses showed significant (P < 0.05) sedative effect in-hole cross test. In-hole board test, the extract showed highly significant (P < 0.001) anxiolytic activity at lower dose whereas this activity was observed at higher dose in EPM test. The extract also showed highly significant (P < 0.001) anti-diarrheal activity. Conclusion: The findings of the study clearly indicate the presence of significant analgesic, neuropharmacological and anti-diarrheal properties of the plant, which demands further investigation including, compound isolation. PMID:24808665

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour-bearing dogs: A phase I dose finding study.

PubMed

Wouda, R M; Hocker, S E; Higginbotham, M L

2018-03-01

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low-dose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an open-label 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg -1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m -2 . A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m -2 . AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m -2 IV every 21 days and approximately 2.75 mg kg -1 PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials. © 2017 John Wiley & Sons Ltd.

Toward a unified approach to dose-response modeling in ecotoxicology.

PubMed

Ritz, Christian

2010-01-01

This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

Acute and Short-Term Inhalation Toxicity Study of FT Fuel

DTIC Science & Technology

2011-02-01

Nasopharyngeal duct goblet cell hypertrophy/hyperplasia is evident in both sexes of rats exposed to the two highest doses of jet fuel. 47 Distribution A...findings in lung, nose and liver and, in male rats, kidneys. Inflammatory foci were evident in the lungs of both sexes of rat exposed to the two...highest doses of jet fuel. Olfactory epithelial degeneration was evident in both sexes of rats exposed to the two highest doses of jet fuel. An

Bridging the gap: a review of dose investigations in paediatric investigation plans

PubMed Central

Hampson, Lisa V; Herold, Ralf; Posch, Martin; Saperia, Julia; Whitehead, Anne

2014-01-01

Aims In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. Methods We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Results Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Conclusions Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure−response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies. PMID:24720849

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.

PubMed

Kusawake, Tomohiro; Kowalski, Donna; Takada, Akitsugu; Kato, Kota; Katashima, Masataka; Keirns, James J; Lewand, Michaelene; Lasseter, Kenneth C; Marbury, Thomas C; Preston, Richard A

2017-12-01

Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir. These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment. In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated. The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5-2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance FUNDING: Astellas Pharma.

Leukemia, lymphoma and multiple myeloma mortality (1950–1999) and incidence (1969–1999) in the Eldorado uranium workers cohort

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

Zablotska, Lydia B., E-mail: Lydia.Zablotska@ucsf.edu; Lane, Rachel S.D.; Frost, Stanley E.

Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932–1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months andmore » the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation. - Highlights: • We analyzed long-term follow-up for hematologic cancers of the Eldorado uranium workers. • Workers were exposed to a unique combination of radon decay products (RDP) and gamma (γ) ray doses. • Exposures to RDP and γ-ray doses were not associated with significantly increased risks of cancers. • Radiation risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma were increased. • Study findings provide additional support for radiation-related risks of CLL.« less

A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats.

PubMed

Cancel, Aida M; Dillberger, John E; Kelly, Catherine M; Bolte, Henry F; Creasy, Dianne M; Sokal, David C

2010-03-01

This study investigated if quinacrine can induce a tumorigenic response in rats when administered in a manner similar to the intended human use for female non-surgical sterilization. Young sexually mature female rats received two doses of quinacrine (or 1% methylcellulose control) into each uterine horn approximately 21 days apart, and were observed for 23 months after the second dose administration. Dose levels were 0/0, 0/0, 10/10, 70/70, and 70/250-350 mg/kg (first dose/second dose), which represent local doses in the uterus at approximate multiples of 1x, 8x and 40x the human dose (mg quinacrine/g uterine weight) used for female non-surgical sterilization. Rats were observed for viability, clinical signs of toxicity, and changes in body weight and food consumption. At necropsy, selected organs were weighed, macroscopic observations were recorded, and tissues were collected, fixed, processed, and examined for microscopic pathologic findings. Acute quinacrine toxicity was evident during the dosing period but did not affect long-term survival. Non-neoplastic findings were more common in treated animals than controls, providing evidence of the appropriateness of the bioassay. The incidence of uncommon tumors of the reproductive tract was similar to controls at doses of 10/10mg/kg but increased with dose level and was significantly greater than controls at >or=70/70 mg/kg. We conclude that two doses of quinacrine administered approximately 21 days apart into the uterus of young sexually mature rats at a local dose approximately 8 times the human dose used for non-surgical female sterilization increased the lifetime risk of tumor development in the reproductive tract. (c) 2009 Elsevier Inc. All rights reserved.

Effects of chronic cocaine, morphine and methamphetamine on the mobility, immobility and stereotyped behaviors in crayfish.

PubMed

Imeh-Nathaniel, Adebobola; Rincon, Natalia; Orfanakos, Vasiliki Bessie; Brechtel, Leanne; Wormack, Leah; Richardson, Erika; Huber, Robert; Nathaniel, Thomas I

2017-08-14

The worth of crayfish as a model system for studies of addiction was not previously recognized because a drug-reward phenomenon had not been documented in this model system. In our previous experiments, we demonstrate that the crayfish natural reward pathways are sensitive to human drugs of abuse. This finding supports crayfish as a suitable model to characterize specific behaviors that are relevant in drug addiction research, and the current study builds on our previous findings. The aim of the present study was to investigate unconditioned neurobehavioral effects of repeated treatment regimens using cocaine, morphine, and methamphetamine for three consecutive days. We analyzed mobility, immobility and characterized stereotypic behaviors following intracardial infusions of 2.0μg/g or 10.0μg/g doses of cocaine, morphine, and methamphetamine for three days. The results showed that systemic cocaine, morphine, and methamphetamine increased mobility at a low dose of 2.0μg/g more effectively than a high dose of 10.0μg/g, while simultaneously showing that the high dose exerted a more prominent effect in increasing immobility. Moreover, systemic cocaine, morphine, and methamphetamine injections have discerning effects towards a group of defined unconditioned stereotyped behavioral patterns associated with each drug, rather than a shared universal behavioral effect. These findings provide insight into the behavioral and pharmacological basis responsible for the unconditioned effects of these drugs in crayfish. Copyright © 2017. Published by Elsevier B.V.

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.

Monitoring late-onset toxicities in phase I trials using predicted risks

PubMed Central

Bekele, B. Nebiyou; Ji, Yuan; Shen, Yu; Thall, Peter F.

2008-01-01

Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average. PMID:18084008

High Dose Vitamin D Therapy for Chronic Pain in Children and Adolescents with Sickle Cell Disease: Results of a Randomized Double Blind Pilot Study

PubMed Central

I, Osunkwo; TR, Ziegler; J, Alvarez; C, McCracken; K, Cherry; CE, Osunkwo; SF, Ofori-Acquah; S, Ghosh; A, Ogunbobode; J, Rhodes; JR, Eckman; CD, Dampier; V, Tangpricha

2012-01-01

Summary We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were followed for 6 months after receiving a six-week course of oral high-dose cholecalciferol or placebo. Vitamin D insufficiency and deficiency was present at baseline in 82.5% and 52.5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects. PMID:22924607

Safety and pharmacokinetics of the oral iron chelator SP-420 in β-thalassemia.

PubMed

Taher, Ali T; Saliba, Antoine N; Kuo, Kevin H; Giardina, Patricia J; Cohen, Alan R; Neufeld, Ellis J; Aydinok, Yesim; Kwiatkowski, Janet L; Jeglinski, Brenda I; Pietropaolo, Keith; Berk, Gregory; Viprakasit, Vip

2017-12-01

Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for C max and AUC 0-τ over the dose range evaluated. The median t max ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug. © 2017 Wiley Periodicals, Inc.

Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors.

PubMed

Mizugaki, Hidenori; Yamamoto, Noboru; Murakami, Haruyasu; Kenmotsu, Hirotsugu; Fujiwara, Yutaka; Ishida, Yoshimasa; Kawakami, Tomohisa; Takahashi, Toshiaki

2016-10-01

Background Atezolizumab is an engineered immunoglobulin monoclonal antibody that targets the programmed death-1/programmed death-ligand 1 pathway. Methods In this phase I dose-finding study, we assessed the safety, feasibility, pharmacokinetics (PK), and exploratory anti-tumor activity of atezolizumab monotherapy up to 20 mg/kg in Japanese patients with advanced solid tumors who had failed standard therapy or for whom there is no standard therapy. Results Six patients were enrolled and received intravenous atezolizumab every 3 weeks (q3w) at doses of 10 or 20 mg/kg. Tumor types were non-small cell lung cancer (n = 3), melanoma (n = 1), pancreatic cancer (n = 1), and thymic cancer (n = 1). No dose-limiting toxicities were observed. All adverse events (AEs) were grade 1 or 2 in severity. No discontinuations or deaths due to AEs were observed. As of the data cutoff, no partial responses were observed; however, stable disease was observed in all six patients. The maximum mean serum atezolizumab concentration was 220 μg/mL (SD ± 21.9), with 10-mg/kg dosing and 536 μg/mL (SD ± 49.4) with 20-mg/kg dosing. Three patients were still on treatment, and three of the six had achieved a progression-free survival of >12 months. Conclusions Atezolizumab was well tolerated in Japanese patients at doses up to 20 mg/kg q3w. The safety profile and Cycle 1 serum atezolizumab concentrations were similar to those previously observed in non-Japanese patients. These data support the participation of Japanese patients in ongoing pivotal global studies of atezolizumab.

Cost-effectiveness of high-dose versus standard-dose inactivated influenza vaccine in adults aged 65 years and older: an economic evaluation of data from a randomised controlled trial.

PubMed

Chit, Ayman; Becker, Debbie L; DiazGranados, Carlos A; Maschio, Michael; Yau, Eddy; Drummond, Michael

2015-12-01

Adults aged 65 years and older account for most seasonal influenza-related hospital admissions and deaths. Findings from the randomised controlled FIM12 study showed that high-dose inactivated influenza vaccine is more effective than standard-dose vaccine for prevention of laboratory-confirmed influenza in this age group. We aimed to assess the economic impact of high-dose versus standard-dose influenza vaccine in participants in the FIM12 study population. The FIM12 study was a head-to-head randomised controlled trial in which 31,989 participants aged 65 years and older were randomly assigned (1:1) to receive either high-dose or standard-dose trivalent inactivated influenza vaccine over two influenza seasons (2011-12 and 2012-13). Data for health-care resource consumption obtained in the FIM12 study were summarised across vaccine groups. Unit costs obtained from standard US cost sources were applied to each resource item, including to the vaccines (high dose US$31·82, standard dose $12·04). Clinical illness data were mapped to existing quality-of-life data. The time horizon was one influenza season; however, quality-adjusted life-years (QALYs) lost due to death during the study were calculated over a lifetime. We calculated incremental cost-effectiveness ratios (ICERs) for high-dose versus standard-dose vaccine and used QALYs as an outcome in the cost-utility analysis. We undertook a probabilistic sensitivity analysis using bootstrapping to explore the effect of statistical uncertainty on the study results. Mean per-participant medical costs were lower in the high-dose vaccine group ($1376·72 [SD 6857·59]) than in the standard-dose group ($1492·64 [7447·14]; difference -$115·92 [95% CI -264·18 to 35·48]). Mean societal costs were likewise lower in the high-dose versus the standard-dose group ($1506·48 [SD 7305·19] vs $1634·50 [7952·99]; difference -$128·02 [95% CI -286·89 to 33·30]). Hospital admissions contributed 95% of the total health-care-payer cost and 87% of the total societal costs. The mean per-participant number of hospital admissions was 0·0937 (SD 0·3644) in the high-dose group and 0·1017 (0·3708) in the standard-dose group (difference -0·0080, 95% CI -0·0160 to -0·0003). The high-dose vaccine provided a gain in QALYs (mean 8·1502 QALYs gained per participant [SD 0·5693]) compared with the standard-dose vaccine (8·1499 QALYs [0·5697]) and, due to cost savings, dominated standard-dose vaccine in the cost-utility analysis. The probabilistic sensitivity analysis showed that the high-dose vaccine is 93% likely to be cost saving. High-dose trivalent inactivated influenza vaccine is a less costly and more effective alternative to the standard-dose vaccine, driven by a reduction in the number of hospital admissions. These findings are relevant to US health-care beneficiaries, providers, payers, and recommending bodies, especially those seeking to improve outcomes while containing costs. Sanofi Pasteur. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparisons of l-cysteine and d-cysteine toxicity in 4-week repeated-dose toxicity studies of rats receiving daily oral administration.

PubMed

Shibui, Yusuke; Sakai, Ryosei; Manabe, Yasuhiro; Masuyama, Takeshi

2017-07-01

Two 4-week repeated-dose toxicity studies were conducted to evaluate the potential toxicity of l-cysteine and d-cysteine. In one study, three groups of 6 male rats were each administered l-cysteine once daily by gavage at doses of 500, 1,000, or 2,000 mg/kg/day for 28 consecutive days. The control group was administered a 0.5% methylcellulose vehicle solution. The other study followed a similar protocol except that the experimental groups received d-cysteine. Toxicological observations showed that the l-cysteine-treated groups exhibited renal injuries such as basophilic tubules with eosinophilic material in the lumen, and there were increased numbers of basophilic tubules in all treated groups. In 1,000 or 2,000 mg/kg/day-treated groups, salivation and necropsy findings indicative of focal erosion in the stomach mucosa were found. Increases in reticulocyte counts were observed in the 2,000 mg/kg/day-treated group. Toxicological findings obtained for the d-cysteine-treated groups included anemia and renal injuries such as basophilic tubules with eosinophilic material in the lumen, increased numbers of basophilic tubules, and crystal deposition in the medulla in the 2,000 mg/kg/day-treated group. Additional findings included sperm granuloma in the epididymis, necropsy findings suggestive of focal erosion in the stomach mucosa, and salivation in the 1,000 or 2,000 mg/kg/day-treated groups. One rat in the 2,000 mg/kg/day-treated group died due to renal failure. In conclusion, the no-observed-adverse-effect levels (NOAELs) were estimated to be less than 500 mg/kg/day for l-cysteine and 500 mg/kg/day for d-cysteine under our study conditions. The toxicological profiles were similar for l-cysteine and d-cysteine; however, there were slight differences in the dose responses. The mechanisms underlying these differences remain to be determined.

Nurse dose: what's in a concept?

PubMed

Manojlovich, Milisa; Sidani, Souraya

2008-08-01

Many researchers have sought to address the relationship between nursing care and patient outcomes, with inconsistent and contradictory findings. We conducted a concept analysis and concept derivation, basing our work on theoretical and empirical literature, to derive nurse dose as a concept that pulls into a coherent whole disparate variables used in staffing studies. We defined nurse dose as the level of nursing reflected in the purity, amount, frequency, and duration of nursing care needed to produce favorable outcomes. All four parameters of nurse dose used together can facilitate our understanding of how nursing contributes to patient outcomes. Ongoing investigation will help to identify the parameters of nurse dose that have the greatest effect on outcomes. 2008 Wiley Periodicals, Inc

A phase I study of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors potentially responsive to mitoxantrone

PubMed Central

Resta, Lee P.; Pili, Roberto; Eisenberger, Mario A.; Spitz, Avery; King, Serina; Porter, Jennifer; Franke, Amy; Boinpally, Ramesh; Sweeney, Christopher J.

2010-01-01

Purpose To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors. Methods This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m2 given on Day 1 of each 21-day cycle. Results OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response. Conclusion The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued. PMID:20445979

Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer.

PubMed

Timmer-Bonte, J N H; Punt, C J A; vd Heijden, H F M; van Die, C E; Bussink, J; Beijnen, J H; Huitema, A D R; Tjan-Heijnen, V C G

2008-05-01

In advanced non-small cell lung cancer (NSCLC) the clinical benefit of a platinum-based doublet is only modest, therefore, attenuated dosed three-drug combinations are investigated. We hypothesized that with adequate support a full dosed chemotherapy triplet is feasible. The study was designed as a dose finding study of paclitaxel in chemotherapy-naive patients. Paclitaxel was given as a 3-h infusion on day 1, followed by fixed doses of teniposide (or etoposide) 100mg/m(2) days 1, 3, 5 and cisplatin 80 mg/m(2) day 1 every 3 weeks. As myelotoxicity was expected to be the dose-limiting toxicity, prophylactic G-CSF and antibiotic support was evaluated. Indeed, paclitaxel 120 mg/m(2) resulted in dose-limiting neutropenia, despite G-CSF support. Teniposide/etoposide day 1, 3, 5 was less myelotoxic compared to day 1, 2, 3. G-CSF support allowed paclitaxel dose-escalation to 250 mg/m(2). The addition of prophylactic antibiotics enabled dose-escalation to 275 mg/m(2) without reaching MTD. In conclusion, G-CSF and antibiotics prophylaxis enables the delivery of a full dosed chemotherapy triplet in previously untreated NSCLC patients.

Can the Equivalent Sphere Model Approximate Organ Doses in Space Radiation Environments?

NASA Technical Reports Server (NTRS)

Zi-Wei, Lin

2007-01-01

In space radiation calculations it is often useful to calculate the dose or dose equivalent in blood-forming organs (BFO). the skin or the eye. It has been customary to use a 5cm equivalent sphere to approximate the BFO dose. However previous studies have shown that a 5cm sphere gives conservative dose values for BFO. In this study we use a deterministic radiation transport with the Computerized Anatomical Man model to investigate whether the equivalent sphere model can approximate organ doses in space radiation environments. We find that for galactic cosmic rays environments the equivalent sphere model with an organ-specific constant radius parameter works well for the BFO dose equivalent and marginally well for the BFO dose and the dose equivalent of the eye or the skin. For solar particle events the radius parameters for the organ dose equivalent increase with the shielding thickness, and the model works marginally for BFO but is unacceptable for the eye or the skin The ranges of the radius parameters are also shown and the BFO radius parameters are found to be significantly larger than 5 cm in all eases.

Determining Cutoff Point of Ensemble Trees Based on Sample Size in Predicting Clinical Dose with DNA Microarray Data.

PubMed

Yılmaz Isıkhan, Selen; Karabulut, Erdem; Alpar, Celal Reha

2016-01-01

Background/Aim . Evaluating the success of dose prediction based on genetic or clinical data has substantially advanced recently. The aim of this study is to predict various clinical dose values from DNA gene expression datasets using data mining techniques. Materials and Methods . Eleven real gene expression datasets containing dose values were included. First, important genes for dose prediction were selected using iterative sure independence screening. Then, the performances of regression trees (RTs), support vector regression (SVR), RT bagging, SVR bagging, and RT boosting were examined. Results . The results demonstrated that a regression-based feature selection method substantially reduced the number of irrelevant genes from raw datasets. Overall, the best prediction performance in nine of 11 datasets was achieved using SVR; the second most accurate performance was provided using a gradient-boosting machine (GBM). Conclusion . Analysis of various dose values based on microarray gene expression data identified common genes found in our study and the referenced studies. According to our findings, SVR and GBM can be good predictors of dose-gene datasets. Another result of the study was to identify the sample size of n = 25 as a cutoff point for RT bagging to outperform a single RT.

Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers.

PubMed

Martin, David E; Blum, Robert; Wilton, John; Doto, Judy; Galbraith, Hal; Burgess, Gina L; Smith, Philip C; Ballow, Charles

2007-09-01

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n = 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n = 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.

Differences in botulinum toxin dosing between patients with adductor spasmodic dysphonia and essential voice tremor.

PubMed

Orbelo, Diana M; Duffy, Joseph R; Hughes Borst, Becky J; Ekbom, Dale; Maragos, Nicolas E

2014-01-01

To explore possible dose differences in average botulinum toxin (BTX) given to patients with adductor spasmodic dysphonia (ADSD) compared with patients with essential voice tremor (EVT). A retrospective study compared the average BTX dose injected in equal doses to the thyroarytenoid (TA) muscles of 51 patients with ADSD with 52 patients with EVT. Those with ADSD received significantly higher total doses (6.80 ± 2.79 units) compared with those with EVT (5.02 ± 1.65 units). Dose at time of first injection, age at time of first injection, gender, year of first injection, and average time between injections were included in multivariate analysis but did not interact with total average dose findings. Patients with ADSD may need relatively higher doses of BTX injections to bilateral TA muscles compared with patients with EVT. Copyright © 2014 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Low dose irradiation facilitates hepatocellular carcinoma genesis involving HULC.

PubMed

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

2018-03-24

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

Reproductive, teratologic, and mutagenic studies with some polydimethylsiloxanes.

PubMed

Kennedy, G L; Keplinger, M L; Calandra, J C

1976-07-01

The purpose of these studies was to evaluate the effects of selected polydimethylsiloxanes on reproduction and fetal development in rats and rabbits and to determine the mutagenic potential of one such material in mice. In two separate three-phase studies in rats and rabbits with a 350 centistoke medical grade fluid, the only significant effect noted was an apparent dose-related incidence of in utero mortality at dose levels of 200 and 1,000 mg/kg sc in rats in one study. No evidence of fetotoxicity was obtained in the second study at the same dose levels. The incidence of talipes varus at a sc dose level of 200 mg/kg in rabbits (8.8%) is at or above that expected for control populations. The nonoccurrence of talipes varus at the higher level of 1,000 mg/kg and the absence of this defect in the companion study casts doubt on the significance of this finding. A 7-cs pump fluid was nonteratogenic in rats at oral doses as high as 1,000 mg/kg and was nonmutagenic in ma1e mice at ip doses of 5 and 10 g/kg. A 10-cs fluid was nonteratogenic in rabbits at a dermal dose level of 200 mg/kg.

Representativeness of individual external doses estimated for one quarter of residents in the Fukushima Prefecture after the nuclear disaster: the Fukushima Health Management Survey.

PubMed

Ishikawa, Tetsuo; Takahashi, Hideto; Yasumura, Seiji; Ohtsuru, Akira; Sakai, Akira; Ohira, Tetsuya; Sakata, Ritsu; Ozasa, Kotaro; Akahane, Keiichi; Yonai, Shunsuke; Kurihara, Osamu; Kamiya, Kenji; Abe, Masafumi

2017-09-25

After the Fukushima Dai-ichi Nuclear Power Plant accident, the Fukushima Health Management Survey (FHMS) was launched. The Basic Survey, a component of FHMS, is a questionnaire used to survey residents across the Fukushima Prefecture about their behaviour in the first 4 months after the accident. The questionnaire findings are used to determine individual external doses by linking behaviour data to a computer programme with daily gamma ray dose rate maps, drawn after the accident. Through 30 June 2015, the response rate was only 27.2% (558 550 population), indicating that the findings might not be generalisable because of poor representativeness of the population. The objective of this study was to clarify if the data from the FHMS Basic Survey were representative of the entire population, by conducting a new survey to compare the external doses between non-respondents and respondents in the previous survey. A total of 5350 subjects were randomly selected from 7 local regions of Fukushima Prefecture. An interview survey was conducted with the non-respondents to the FHMS Basic Survey. A total of 990 responses were obtained from the previous non-responders by interview survey. For the regions Kempoku, Kenchu, Kennan, Aizu, Minami-Aizu, Soso, and Iwaki, differences in mean effective dose (95% confidence interval) in mSv between the non-responders and previous responders were 0.12 (0.01-0.23), -0.09 (-0.21-0.03), -0.06 (-0.18-0.07), 0.05 (-0.04-0.14), 0.01 (-0.01-0.02), 0.09 (0.01-0.17), 0.09 (0.00-0.17), respectively. The differences fall neither within the interval (-∞, -0.25) nor within the interval (0.25, ∞). These findings imply that mean effective doses between the previous and new respondents were not different, with a significantly indifferent region of 0.25 mSv according to equivalence tests. The present study indicates that the dose distribution obtained from about one-quarter of Fukushima residents represents the dose distribution for the entire Fukushima Prefecture.

Bridging the gap: a review of dose investigations in paediatric investigation plans.

PubMed

Hampson, Lisa V; Herold, Ralf; Posch, Martin; Saperia, Julia; Whitehead, Anne

2014-10-01

In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure-response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies. © 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Fluorine magnetic resonance spectroscopy measurement of brain fluvoxamine and fluoxetine in pediatric patients treated for pervasive developmental disorders.

PubMed

Strauss, Wayne L; Unis, Alan S; Cowan, Charles; Dawson, Geraldine; Dager, Stephen R

2002-05-01

Pediatric populations, including those with autistic disorder or other pervasive developmental disorders, increasingly are being prescribed selective serotonin reuptake inhibitors (SSRIs). Little is known about the age-related brain pharmacokinetics of SSRIs; there is a lack of data regarding optimal dosing of medications for children. The authors used fluorine magnetic resonance spectroscopy ((19)F MRS) to evaluate age effects on whole-brain concentrations of fluvoxamine and fluoxetine in children taking SSRIs. Twenty-one pediatric subjects with diagnoses of autistic disorder or other pervasive developmental disorders, 6-15 years old and stabilized with a consistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 successfully completed the imaging protocol. Whole-brain drug levels in this group were compared to similarly acquired data from 28 adults. A significant relationship between dose and brain drug concentration was observed for both drugs across the age range studied. Brain fluvoxamine concentration in the children was lower, consistent with a lower dose/body mass drug prescription; when brain concentration was adjusted for dose/mass, age effects were no longer significant. Brain fluoxetine concentration was similar between age groups; no significant age effects on brain fluoxetine drug levels remained after adjustment for dose/mass. Observations of brain fluoxetine bioavailability and elimination half-life also were similar between age groups. These findings suggest that fluvoxamine or fluoxetine prescriptions adjusted for dose/mass are an acceptable treatment approach for medicating children with autistic disorder or other pervasive developmental disorders. It must be determined whether these findings can be generalized to other pediatric populations.

Is a fecal occult blood test a useful tool for judging whether to perform capsule endoscopy in low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy?

PubMed

Endo, Hiroki; Kato, Takayuki; Sakai, Eiji; Taniguchi, Leo; Arimoto, Jun; Kawamura, Harunobu; Higurashi, Takuma; Ohkubo, Hidenori; Nonaka, Takashi; Taguri, Masataka; Inamori, Masahiko; Yamanaka, Takeharu; Sakaguchi, Takashi; Hata, Yasuo; Nagase, Hajime; Nakajima, Atsushi

2017-02-01

Aspirin use is reportedly not to be associated with fecal immunochemical occult blood test (FIT) false-positive results for the detection of colorectal cancer. The need for additional small bowel exploration in FIT-positive, low-dose aspirin users with a negative colonoscopy is controversial. The aim of this study was to assess the ability of FIT to judge whether capsule endoscopy (CE) should be performed in low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy findings by comparing FIT results with CE findings. A total of 264 consecutive low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy who were scheduled to undergo CE at five hospitals in Japan were enrolled. Patients had been offered FIT prior to the CE. The association between the FIT results and the CE findings was then assessed. One hundred and fifty-seven patients were included in the final analysis. Eighty-four patients (53.5 %) had positive FIT results. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of positive FIT results for small bowel ulcers were 0.56, 0.47, 0.30, and 0.73, respectively. Furthermore, the NPV of positive FIT results for severe small bowel injury (Lewis score ≥790) was markedly high (0.90). When the analysis was performed only in low-dose aspirin users with anemia, the sensitivity of the positive FIT results was notably improved (0.72). Small bowel evaluation using CE is not recommended for FIT-negative, low-dose aspirin users. However, small bowel evaluation using CE should be considered in both FIT-positive and anemic low-dose aspirin users.

SPIRIT: A seamless phase I/II randomized design for immunotherapy trials.

PubMed

Guo, Beibei; Li, Daniel; Yuan, Ying

2018-06-07

Immunotherapy-treatments that enlist the immune system to battle tumors-has received widespread attention in cancer research. Due to its unique features and mechanisms for treating cancer, immunotherapy requires novel clinical trial designs. We propose a Bayesian seamless phase I/II randomized design for immunotherapy trials (SPIRIT) to find the optimal biological dose (OBD) defined in terms of the restricted mean survival time. We jointly model progression-free survival and the immune response. Progression-free survival is used as the primary endpoint to determine the OBD, and the immune response is used as an ancillary endpoint to quickly screen out futile doses. Toxicity is monitored throughout the trial. The design consists of two seamlessly connected stages. The first stage identifies a set of safe doses. The second stage adaptively randomizes patients to the safe doses identified and uses their progression-free survival and immune response to find the OBD. The simulation study shows that the SPIRIT has desirable operating characteristics and outperforms the conventional design. Copyright © 2018 John Wiley & Sons, Ltd.

Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS)

PubMed Central

Diamond, David M.

2004-01-01

Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people. PMID:19330152

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.

Development of an objective dose distribution analysis method for OSL dating and pilot studies for planetary applications

NASA Astrophysics Data System (ADS)

Lepper, Kenneth Errol

Scope and method of study. Part I: In its simplest expression a luminescence age is the natural absorbed radiation dose (De) divided by the in-situ dose rate. The experimental techniques of Optically Stimulated Luminescence (OSL) dating have evolved to the point were hundreds of Des, and therefore depositional ages can be quickly and conveniently determined for a single sediment sample. The first major objective of this research was to develop an objective analysis method for analyzing dose distribution data and selecting an age-representative dose (Dp). The analytical method was developed based on dose data sets collected from 3 eolian and 3 fluvial sediment samples from Central Oklahoma. Findings and conclusions. Part I: An objective method of presenting the dose distribution data, and a mathematically rigorous means of determining the Dp, as well as a statistically meaningful definition of the uncertainty in Dp have been proposed. The concept of experimental error deconvolution was introduced. In addition a set of distribution shape parameters to facilitate comparison among samples have been defined. These analytical techniques hold the potential to greatly enhance the accuracy and utility of OSL dating for young fluvial sediments. Scope and method of study. Part II: The second major objective of this research was to propose the application of luminescence dating to sediments on Mars. A set of fundamental luminescence dating properties was evaluated for a martian surface materials analog and a polar deposit contextual analog. Findings and conclusions. Part II: The luminescence signals measured from the analogs were found to have a wide dynamic dose response range with no unusual or prohibitive short-term instabilities and were readily reset by exposure to sunlight. These properties form a stable base for continued investigations toward the development of luminescence dating instruments and procedures for Mars.

Sugammadex and neostigmine dose-finding study for reversal of residual neuromuscular block at a train-of-four ratio of 0.2 (SUNDRO20)†,.

PubMed

Kaufhold, N; Schaller, S J; Stäuble, C G; Baumüller, E; Ulm, K; Blobner, M; Fink, H

2016-02-01

The aim of this dose-finding study was to evaluate the dose-response relationship of sugammadex and neostigmine to reverse a commonly observed level of incomplete recovery from rocuronium-induced neuromuscular block, that is, a train-of-four ratio (TOFR) ≥0.2. Ninety-nine anaesthetized patients received rocuronium 0.6 mg kg(-1) i.v. for tracheal intubation and, if necessary, incremental doses of 0.1-0.2 mg kg(-1). Neuromuscular monitoring was performed by calibrated electromyography. Once the TOFR recovered to 0.2, patients were randomized to receive sugammadex (0.25, 0.5, 0.75, 1.0, or 1.25 mg kg(-1) i.v.), neostigmine (10, 25, 40, 55, or 70 µg kg(-1) i.v.), or saline (n=9 per group). Primary and secondary end points were the doses necessary to restore neuromuscular function to a TOFR≥0.9 with an upper limit of 5 and 10 min for 95% of patients, respectively. Neostigmine was not able to fulfil the end points. Based on the best-fitting model, the sugammadex dose estimation for recovery to a TOFR≥0.9 for 95% of patients within 5 and 10 min was 0.49 and 0.26 mg kg(-1), respectively. A residual neuromuscular block of a TOFR of 0.2 cannot be reversed reliably with neostigmine within 10 min. In the conditions studied, substantially lower doses of sugammadex than the approved dose of 2.0 mg kg(-1) may be sufficient to reverse residual rocuronium-induced neuromuscular block at a recovery of TOFR≥0.2. NCT01006720. © The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

PubMed Central

Todd, John A.; Porter, Linsey; Smyth, Deborah J.; Rainbow, Daniel B.; Ferreira, Ricardo C.; Yang, Jennie H.; Bell, Charles J. M.; Schuilenburg, Helen; Challis, Ben; Clarke, Pamela; Coleman, Gillian; Dawson, Sarah; Goymer, Donna; Kennet, Jane; Brown, Judy; Greatorex, Jane; Goodfellow, Ian; Evans, Mark; Mander, Adrian P.; Bond, Simon; Wicker, Linda S.

2016-01-01

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = −0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015–0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%–48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%–85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2–3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%–50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735 PMID:27727279

In vivo safety and tolerability study of QR-441(a) using three dose formulations and three routes of administration in chickens.

PubMed

Cummings, Timothy S; Guralnik, Mario; Rosenbloom, Richard A; Petteruti, Michael P; Digian, Kelly; Lefante, Carolyn

2007-01-01

The current study assessed the safety, tolerability, and palatability of the experimental drug QR-441(a) using three dose formulations and three routes of administration. A 4-day study was carried out using a total of 132 chickens. A total of 11 groups were formed (12 chickens per group) subjected to varying concentrations and routes of administration of QR-441(a). Chickens were given a high, medium, or low dose of QR-441(a) in either feed, water, or both for a period of 4 days. In addition, one group was dosed intranasally, one drop per nostril four times a day. Although no lesions were found to suggest toxicity or irritability, the medium- and high-dose water groups reduced their water intake. This reduction in water intake suggests that chickens may find the medium and high water doses unpalatable. There was no reduction in water intake in the low-dose water groups or in any of the formulated feed groups. There was also no evidence of toxicity or irritability in the nasal-dose group. These data support the use of the low, medium, and high doses in feed and the use of the low-dose concentration in water for the administration of QR-441(a). The data also suggest that QR-441(a) can be administered intranasally without the presence of any adverse events.

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients.

PubMed

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-12-01

This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better 'ideal dose' estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R(2) = 51%). Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.

Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel.

PubMed

Om, Ae-Son; Song, Yu-Na; Noh, GeonMin; Kim, HaengRan; Choe, JeongSook

2016-01-08

The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe.

Dose reduction of risperidone and olanzapine and estimated dopamine D₂ receptor occupancy in stable patients with schizophrenia: findings from an open-label, randomized, controlled study.

PubMed

Takeuchi, Hiroyoshi; Suzuki, Takefumi; Bies, Robert R; Remington, Gary; Watanabe, Koichiro; Mimura, Masaru; Uchida, Hiroyuki

2014-11-01

While acute-phase antipsychotic response has been attributed to 65%-80% dopamine D₂ receptor blockade, the degree of occupancy for relapse prevention in the maintenance treatment of schizophrenia remains unknown. In this secondary study of an open-label, 28-week, randomized, controlled trial conducted between April 2009 and August 2011, clinically stable patients with schizophrenia (DSM-IV) treated with risperidone or olanzapine were randomly assigned to the reduction group (dose reduced by 50%) or maintenance group (dose kept constant). Plasma antipsychotic concentrations at peak and trough before and after dose reduction were estimated with population pharmacokinetic techniques, using 2 collected plasma samples. Corresponding dopamine D₂ occupancy levels were then estimated using the model we developed. Relapse was defined as worsening in 4 Positive and Negative Syndrome Scale-Positive subscale items: delusion, conceptual disorganization, hallucinatory behavior, and suspiciousness. Plasma antipsychotic concentrations were available for 16 and 15 patients in the reduction and maintenance groups, respectively. Estimated dopamine D₂ occupancy (mean ± SD) decreased following dose reduction from 75.6% ± 4.9% to 66.8% ± 6.4% at peak and 72.3% ± 5.7% to 62.0% ± 6.8% at trough. In the reduction group, 10 patients (62.5%) did not demonstrate continuous D₂ receptor blockade above 65% (ie, < 65% at trough) after dose reduction; furthermore, 7 patients (43.8%) did not achieve a threshold of 65% occupancy even at peak. Nonetheless, only 1 patient met our relapse criteria after dose reduction during the 6 months of the study. The results suggest that the therapeutic threshold regarding dopamine D₂ occupancy may be lower for those who are stable in antipsychotic maintenance versus acute-phase treatment. Positron emission tomography studies are warranted to further test our preliminary findings. UMIN Clinical Trials Registry identifier: UMIN000001834. © Copyright 2014 Physicians Postgraduate Press, Inc.

Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis

PubMed Central

Callera, Glaucia E.; Antunes, Tayze T.; Correa, Jose W.; Moorman, Danielle; Gutsol, Alexey; He, Ying; Cat, Aurelie Nguyen Dinh; Briones, Ana M.; Montezano, Augusto C.; Burns, Kevin D.; Touyz, Rhian M.

2016-01-01

High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes. PMID:27612496

Sex, PrEP, and Stigma: Experiences with HIV Pre-exposure Prophylaxis Among New York City MSM Participating in the HPTN 067/ADAPT Study.

PubMed

Franks, Julie; Hirsch-Moverman, Yael; Loquere, Avelino S; Amico, K Rivet; Grant, Robert M; Dye, Bonnie J; Rivera, Yan; Gamboa, Robert; Mannheimer, Sharon B

2018-04-01

The HPTN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT) study evaluated daily and non-daily dosing schedules for oral pre-exposure prophylaxis (PrEP) to prevent HIV. A qualitative sub-study including focus groups and in-depth interviews was conducted among men who have sex with men participating in New York City to understand their experience with PrEP and study dosing schedules. The 37 sub-study participants were 68% black, 11% white, and 8% Asian; 27% were of Hispanic/Latino ethnicity. Mean age was 34 years. Themes resulting from qualitative analysis include: PrEP is a significant advance for HIV prevention; non-daily dosing of PrEP is congruent with HIV risk; and pervasive stigma connected to HIV and risk behavior is a barrier to PrEP adherence, especially for non-daily dosing schedules. The findings underscore how PrEP intersects with other HIV prevention practices and highlight the need to understand and address multidimensional stigma related to PrEP use.

Learning From Trials on Radiation Dose in Non-Small Cell Lung Cancer

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

Bradley, Jeffrey, E-mail: jbradley@wustl.edu; Hu, Chen

2016-11-15

In this issue of the International Journal of Radiation Oncology • Biology • Physics, Taylor et al present a meta-analysis of published data supporting 2 findings: (1) radiation dose escalation seems to benefit patients who receive radiation alone for non-small cell lung cancer; and (2) radiation dose escalation has a detrimental effect on overall survival in the setting of concurrent chemotherapy. The latter finding is supported by data but has perplexed the oncology community. Perhaps these findings are not perplexing at all. Perhaps it is simply another lesson in the major principle in radiation oncology, to minimize radiation dose to normalmore » tissues.« less

Prospective ECG-gated high-pitch dual-source cardiac CT angiography in the diagnosis of congenital cardiovascular abnormalities: Radiation dose and diagnostic efficacy in a pediatric population.

PubMed

Koplay, M; Kizilca, O; Cimen, D; Sivri, M; Erdogan, H; Guvenc, O; Oc, M; Oran, B

2016-11-01

The goal of this study was to investigate the radiation dose and diagnostic efficacy of cardiac computed tomography angiography (CCTA) using prospective ECG-gated high-pitch dual-source computed tomography (DSCT) in the diagnosis of congenital cardiovascular abnormalities in pediatric population. One hundred five pediatric patients who were clinically diagnosed with congenital heart disease with suspected extracardiac vascular abnormalities were included in the study. All CCTAs were performed on a 128×2-section DSCT scanner. CCTA findings were compared with surgical and/or conventional cardiac angiography findings. Dose-length product (DLP) and effective doses (ED) were calculated for each patient. Patients were divided into 4 groups by age, and ED and DLP values were compared among groups. The image quality was evaluated using a five-point scale. CCTA showed 173 abnormalities in 105 patients. There were 2 patients with false positive and 3 with false negative findings. The sensitivity and specificity of CCTA were 98.3% and 99.9%, respectively. The positive predictive value and negative predictive value of CCT were 98.9% and 99.9%, respectively. The average DLP and ED values were 15.6±9.6 (SD) mGy.cm and 0.34±0.10 (SD) mSv, respectively. The mean image quality score was 4.8±0.5 (SD) in all patients. The inter-observer agreement for the image quality scores was good (κ=0.80). CCTA is an excellent imaging modality for evaluation of cardiovascular abnormalities and provides excellent image quality with very low radiation exposure when low-dose prospective ECG-triggered high-pitch DSCT is used. Copyright © 2016 Editions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

A Simulation Study of Methods for Selecting Subgroup-Specific Doses in Phase I Trials

PubMed Central

Morita, Satoshi; Thall, Peter F.; Takeda, Kentaro

2016-01-01

Summary Patient heterogeneity may complicate dose-finding in phase I clinical trials if the dose-toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively, it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem, we consider a generalization of the continual reassessment method (O’Quigley, et al., 1990) based on a hierarchical Bayesian dose-toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup-specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to three alternative approaches, based on non-hierarchical models, that make different types of assumptions about within-subgroup dose-toxicity curves. The simulations show that the hierarchical model-based method is recommended in settings where the dose-toxicity curves are exchangeable between subgroups. We present practical guidelines for application, and provide computer programs for trial simulation and conduct. PMID:28111916

The real-world dose-relativity of sevelamer hydrochloride and lanthanum carbonate monotherapy in patients with end-stage renal disease.

PubMed

Wilson, Rosamund J; Keith, Michael S; Preston, Peter; Copley, J Brian

2013-12-01

Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to evaluate the real-world dose-relativity between SH and LC monotherapy in US patients with ESRD. This was a post hoc analysis of a 16-week, real-world study (Vemuri et al. in BMC Nephrol 12:49, 2011) of the efficacy of conversion to LC monotherapy from other phosphate binders. The SH:LC dose-relativity ratio, based on the mean daily dose, was calculated in the subset of patients from the Vemuri study who converted from SH to LC monotherapy and had available SH and LC dose data. A total of 950 patients converted from SH to LC monotherapy and had recorded dose data. The post hoc analysis population comprised 691 patients with available dose data for both SH at baseline and LC at week 16. The mean (SD) serum phosphate level at baseline was 5.91 (1.66) mg/dL. After conversion to LC monotherapy for 16 weeks, the mean (SD) serum phosphate level was 5.93 (1.85) mg/dL. The mean (SD) daily baseline SH dose was 7,703 (3,642) mg and the mean (SD) daily LC dose at week 16 was 2,800 (939) mg (9.6 versus 2.8 tablets, respectively; P < 0.0001), resulting in a SH:LC dose-relativity ratio of 2.8. The median individual patient SH:LC dose-relativity ratio was 2.6 (95% CI 2.6-2.8). Across baseline SH dose subgroups (2,400-4,800, >4,800-7,200, >7,200-9,600, and >9,600 mg/day), the mean daily SH dose was 4,051, 7,047, 9,253, and 13,150 mg, respectively. In comparison, the mean daily LC dose was 2,445-3,156 mg. Thus, patients requiring baseline SH doses >7,200 mg/day (41% of the analysis population) had higher SH:LC dose-relativity ratios of 3.1-4.2 (median individual patient ratios 3.1-4.0). In this post hoc analysis of real-world dose-relativity, the overall SH:LC dose-relativity ratio was 2.8 (median individual patient ratio 2.6 (95% CI 2.6-2.8). These findings are consistent with the World Health Organization-defined daily dose and previous studies of the relative phosphate binding capacity of the two drugs. Patients requiring SH doses >7,200 mg/day had higher SH:LC dose-relativities of 3.1-4.2 (median individual patient ratios 3.1-4.0). These findings have implications for the tablet burden and cost-effectiveness of SH and LC in the treatment of hyperphosphatemia.

Comparing the Efficacy of Low Dose and Conventional Dose of Oral Isotretinoin in Treatment of Moderate and Severe Acne Vulgaris

PubMed Central

Faghihi, Gita; Mokhtari, Fatemeh; Fard, Nasrin Motamedi; Motamedi, Narges; Hosseini, Sayed Mohsen

2017-01-01

Objective: This study was conducted to compare the effect of low-dose isotretinoin with its conventional dose in patients with moderate and severe acne. Methods: This was a clinical trial conducted on 60 male and female patients with moderate and severe acne vulgaris. The patients were divided into two treatment groups: 0.5 mg/kg/day isotretinoin capsule and low-dose isotretinoin capsule (0.25 mg/kg/day). Patients in both groups received 6-month treatment. At the end of the 6th month and 12th month (6 months after the end of the treatment), they were examined again, and their improvement was determined and compared. Findings: The average severity of acne in the two treatment groups did not differ significantly within any of the study periods. The most common side effects were nose dryness in the low-dose group (17%) and hair thinning and loss in the conventional-dose group (33.2%), although all the patients had dry lips. Conclusion: According to the same severity of the acne in two groups in different study periods, as well as fewer side effects and more patients' satisfaction, the low-dose isotretinoin can be considered in the treatment of acne. PMID:29417084

Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects.

PubMed

Gilbert, Ethel S; Curtis, Rochelle E; Hauptmann, Michael; Kleinerman, Ruth A; Lynch, Charles F; Stovall, Marilyn; Smith, Susan A; Weathers, Rita; Andersson, Michael; Dores, Graça M; Fraumeni, Joseph F; Fossa, Sophie D; Hall, Per; Hodgson, David C; Holowaty, Eric J; Joensuu, Heikki; Johannesen, Tom B; Langmark, Froydis; Kaijser, Magnus; Pukkala, Eero; Rajaraman, Preetha; Storm, Hans H; Vaalavirta, Leila; van den Belt-Dusebout, Alexandra W; Aleman, Berthe M; Travis, Lois B; Morton, Lindsay M; van Leeuwen, Flora E

2017-02-01

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

A randomized, double-blind, dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE®

PubMed Central

von Krempelhuber, Alfred; Vollmar, Jens; Pokorny, Rolf; Rapp, Petra; Wulff, Niels; Petzold, Barbara; Handley, Amanda; Mateo, Lyn; Siersbol, Henriette; Kollaritsch, Herwig; Chaplin, Paul

2009-01-01

IMVAMUNE® is a Modified Vaccinia Ankara-based virus that is being developed as a safer 3rd generation smallpox vaccine. In order to determine the optimal dose for further development, a double-blind, randomized Phase II trial was performed testing three different doses of IMVAMUNE® in 164 healthy volunteers. All three IMVAMUNE® doses displayed a favourable safety profile, with local reactions as the most frequent observation. The 1×108 TCID50 IMVAMUNE® dose induced a total antibody response in 94% of the subjects following the first vaccination and the highest peak seroconversion rates by ELISA (100%) and PRNT (71%). This IMVAMUNE® dose was considered to be optimal for the further clinical development of this highly attenuated poxvirus as a safer smallpox vaccine. PMID:19944151

Dosing of selective serotonin reuptake inhibitors in children and adults before and after the FDA black-box warning

PubMed Central

Bushnell, Greta A; Stürmer, Til; Swanson, Sonja A; White, Alice; Azrael, Deborah; Pate, Virginia; Miller, Matthew

2016-01-01

Objective Prior research evaluated various effects of the antidepressant black-box warning on the risk of suicidality in children, but the dosing of antidepressants has not been considered. This study estimated, relative to the FDA warnings, whether the initial antidepressant dose prescribed decreased and the proportion augmenting dose on the second fill increased. Method The study utilized the LifeLink Health Plan Claims Database. The study cohort consisted of commercially insured children (5–17 years), young adults (18–24 years), and adults (25–64 years) initiating an SSRI (citalopram, fluoxetine, paroxetine, or sertraline) from 1/1/2000 to 12/31/2009. Dose-per-day was determined by days supply, strength, and quantity dispensed. Initiation on low dose, defined based on guidelines, and dose augmentations (dose increase >1mg/day) on the second prescription were considered across time periods related to the antidepressant warnings. Results Of 51,948 children who initiated an SSRI, 15% initiated on low dose in the period before the 2004 black-box warning and 31% in the period after the warning (a 16 percentage-point change); there was a smaller percentage-point change in young adults (6%) and adults (3%). The overall increase in dose augmentations in children and young adults was driven by the increase in patients initiating on a low dose. Conclusions As guidelines recommend children initiate antidepressant treatment on low dose, findings that an increased proportion of commercially insured children initiated an SSRI on low dose after the 2004 black-box warning suggest prescribing practices surrounding SSRI dosing improved in children following the warning but dosing practices still fall short of guidelines. PMID:26567938

Interactive effects of N-acetylcysteine and antidepressants.

PubMed

Costa-Campos, Luciane; Herrmann, Ana P; Pilz, Luísa K; Michels, Marcus; Noetzold, Guilherme; Elisabetsky, Elaine

2013-07-01

N-acetylcysteine (NAC), a glutathione precursor and glutamate modulator, has been shown to possess various clinically relevant psychopharmacological properties. Considering the role of glutamate and oxidative stress in depressive states, the poor effectiveness of antidepressant drugs (ADs) and the benefits of drug combination for treating depression, the aim of this study was to explore the possible benefit of NAC as an add on drug to treat major depression. For that matter we investigated the combination of subeffective and effective doses of NAC with subeffective and effective doses of several ADs in the mice tail suspension test. The key finding of this study is that a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion. Moreover, the same subeffective dose of NAC increased the minimum effective dose of fluoxetine in the same model. In view of the advantages associated with using the lowest effective dose of antidepressant, the results of this study suggest the potential of a clinically useful interaction of NAC with imipramine and escitalopram. Further studies are necessary to better characterize the molecular basis of such interactions, as well as to typify the particular drug combinations that would optimize NAC as an alternative for treating depression. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of Methylphenidate on Sleep Functioning in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Becker, Stephen P; Froehlich, Tanya E; Epstein, Jeffery N

2016-06-01

To examine the effects of stimulant medication on the sleep functioning of children with attention-deficit/hyperactivity disorder (ADHD) and identify predictors of sleep problems as a side effect of taking stimulant medication. One hundred sixty-three stimulant-naïve children (72% boys) aged 7 to 11 years diagnosed with ADHD (120 with ADHD predominantly inattentive type, 43 with ADHD combined type) participated in a 4-week, randomized, double-blind, placebo-controlled trial of once-daily (long-acting) methylphenidate (MPH). Parents completed weekly side-effect ratings including an item related to sleep problems. Ten percent of patients had parent-rated sleep problems before the initiation of medication. Rates of parent-rated sleep problems during MPH titration generally increased with increasing MPH dose (placebo: 8%; low dose: 18%; medium dose: 15%; high dose: 25%). Differences emerged between children with (n = 16) or without (n = 147) preexisting sleep problems. Although 23% of children without preexisting sleep problems went on to have sleep problems at the highest MPH dose, only 37.5% of children with preexisting sleep problems still had sleep problems at the highest MPH dose. Lower weight and lower body mass index (BMI) were associated with increased sleep problems during MPH titration. This study demonstrated a general association between increased MPH dose and increased sleep problems in children with ADHD, particularly for children of lower weight/BMI. However, a substantial proportion of children with preexisting sleep difficulties no longer had sleep problems on the highest MPH dose, which may help explain mixed findings reported to date in studies examining the impact of MPH on sleep functioning in children with ADHD and suggests that MPH dose titration should not be avoided solely on the basis of a child's premorbid sleep problems. Future research is needed to replicate and extend these findings to more specific domains of sleep functioning and to identify differences between children with persistent or improved sleep functioning as a result of MPH use.

Robust EM Continual Reassessment Method in Oncology Dose Finding

PubMed Central

Yuan, Ying; Yin, Guosheng

2012-01-01

The continual reassessment method (CRM) is a commonly used dose-finding design for phase I clinical trials. Practical applications of this method have been restricted by two limitations: (1) the requirement that the toxicity outcome needs to be observed shortly after the initiation of the treatment; and (2) the potential sensitivity to the prespecified toxicity probability at each dose. To overcome these limitations, we naturally treat the unobserved toxicity outcomes as missing data, and use the expectation-maximization (EM) algorithm to estimate the dose toxicity probabilities based on the incomplete data to direct dose assignment. To enhance the robustness of the design, we propose prespecifying multiple sets of toxicity probabilities, each set corresponding to an individual CRM model. We carry out these multiple CRMs in parallel, across which model selection and model averaging procedures are used to make more robust inference. We evaluate the operating characteristics of the proposed robust EM-CRM designs through simulation studies and show that the proposed methods satisfactorily resolve both limitations of the CRM. Besides improving the MTD selection percentage, the new designs dramatically shorten the duration of the trial, and are robust to the prespecification of the toxicity probabilities. PMID:22375092

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

PubMed Central

2014-01-01

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

Is more better than less? An analysis of children's mental health services.

PubMed Central

Foster, E M

2000-01-01

OBJECTIVE: To assess the dose-response relationship for outpatient therapy received by children and adolescents-that is, to determine the impact of added outpatient visits on key mental health outcomes (functioning and symptomatology). DATA SOURCES/STUDY SETTING: The results presented involve analyses of data from the Fort Bragg Demonstration and are based on a sample of 301 individuals using outpatient services. STUDY DESIGN: This article provides estimates of the impact of outpatient therapy based on comparisons of individuals receiving differing treatment doses. Those comparisons involve standard multiple regression analyses as well as instrumental variables estimation. The latter provides a means of adjusting comparisons for unobserved or unmeasured differences among individuals receiving differing doses, differences that would otherwise be confounded with the impact of treatment dose. DATA COLLECTION/EXTRACTION METHODS: Using structured diagnostic interviews and behavior checklists completed by the child and his or her caretaker, detailed data on psychopathology, symptomatology, and psychosocial functioning were collected on individuals included in these analyses. Information on the use of mental health services was taken from insurance claims and a management information system. Services data were used to describe the use of outpatient therapy within the year following entry into the study. PRINCIPAL FINDINGS/CONCLUSIONS: Instrumental variables estimation indicates that added outpatient therapy improves functioning among children and adolescents. The effect is statistically significant and of moderate practical magnitude. These results imply that conventional analyses of the dose-response relationship may understate the impact of additional treatment on functioning. This finding is robust to choice of functional form, length of time over which outcomes are measured, and model specification. Dose does not appear to influence symptomatology. PMID:11130814

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

Yasmin-Karim, S; Makrigiorgos, GM; Moreau, M

Purpose: Oraya Therapy uses low-voltage, stereotactic, highly targeted X-rays for the treatment of wet age-related macular degeneration (AMD) — offering a new option for patients worldwide. Neovascular endothelial cells play a crucial role in the pathogenesis of this disease. This in-vitro study investigates the potential of gold nanoparticles (GNP) to enhance endothelial cell damage during low-voltage radiotherapy towards potential applications in the treatment of wet-AMD. Methods: Primary human umbilical cord vein endothelium cells (HUVEC) were treated with 1.4 nm sized GNPs for 24 hrs and then irradiated with variable X-ray doses using an Oraya therapy system (100 kVp) or amore » Small Animal Radiation and Research platform (SARRP) at other beam qualities (up to 220 kVp). Radio-sensitization was assessed by clonogenic assays. Variable concentrations of GNPs (0.05 mg/ml, 0.1 mg/ml, 0.25 mg/ml, 0.5 mg/ml, and 1 mg/ml) where employed. The dose enhancement factor (DEF) was calculated as the ratio of radiation doses required to give the same biological effect (survival factor, SF) with and without GNPs. Results: Preliminary results show DEFs of up to 2.62 for the different combinations of x-ray doses and GNP concentrations and beam qualities. In general the DEF increased with increase in GNP concentration. However, for high doses the effect of GNP becomes less apparent likely due to already high cell kill by the radiation alone. Conclusion: The findings suggest that targeted GNPs can play a significant synergistic role in enhancing stereotactic radiosurgery for wet AMD. The results also provide impetus for ongoing studies to find the optimal synergy between the doses or beam energies and GNPs concentration. This will benefit in-vivo studies towards development of nanoparticle-aided radiotherapy for treatment of wet-AMD and potentially ocular cancers.« less

Effect of radiation dose reduction and iterative reconstruction on computer-aided detection of pulmonary nodules: Intra-individual comparison.

PubMed

Den Harder, Annemarie M; Willemink, Martin J; van Hamersvelt, Robbert W; Vonken, Evert-Jan P A; Milles, Julien; Schilham, Arnold M R; Lammers, Jan-Willem; de Jong, Pim A; Leiner, Tim; Budde, Ricardo P J

2016-02-01

To evaluate the effect of radiation dose reduction and iterative reconstruction (IR) on the performance of computer-aided detection (CAD) for pulmonary nodules. In this prospective study twenty-five patients were included who were scanned for pulmonary nodule follow-up. Image acquisition was performed at routine dose and three reduced dose levels in a single session by decreasing mAs-values with 45%, 60% and 75%. Tube voltage was fixed at 120 kVp for patients ≥ 80 kg and 100 kVp for patients < 80 kg. Data were reconstructed with filtered back projection (FBP), iDose(4) (levels 1,4,6) and IMR (levels 1-3). All noncalcified solid pulmonary nodules ≥ 4 mm identified by two radiologists in consensus served as the reference standard. Subsequently, nodule volume was measured with CAD software and compared to the reference consensus. The numbers of true-positives, false-positives and missed pulmonary nodules were evaluated as well as the sensitivity. Median effective radiation dose was 2.2 mSv at routine dose and 1.2, 0.9 and 0.6 mSv at respectively 45%, 60% and 75% reduced dose. A total of 28 pulmonary nodules were included. With FBP at routine dose, 89% (25/28) of the nodules were correctly identified by CAD. This was similar at reduced dose levels with FBP, iDose(4) and IMR. CAD resulted in a median number of false-positives findings of 11 per scan with FBP at routine dose (93% of the CAD marks) increasing to 15 per scan with iDose(4) (95% of the CAD marks) and 26 per scan (96% of the CAD marks) with IMR at the lowest dose level. CAD can identify pulmonary nodules at submillisievert dose levels with FBP, hybrid and model-based IR. However, the number of false-positive findings increased using hybrid and especially model-based IR at submillisievert dose while dose reduction did not affect the number of false-positives with FBP. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dose-finding study of carbamylated monomeric allergoid tablets in grass-allergic rhinoconjunctivitis patients.

PubMed

Mösges, Ralph; Rohdenburg, Christina; Eichel, Andrea; Zadoyan, Gregor; Kasche, Elena-Manja; Shah-Hosseini, Kija; Lehmacher, Walter; Schmalz, Petra; Compalati, Enrico

2017-11-01

To determine the optimal effective and safe dose of sublingual immunotherapy tablets containing carbamylated monomeric allergoids in patients with grass pollen-induced allergic rhinoconjunctivitis. In this prospective, randomized, double-blind, active-controlled, multicenter, Phase II study, four different daily doses were applied preseasonally for 12 weeks. Of 158 randomized adults, 155 subjects (safety population) received 300 units of allergy (UA)/day (n = 36), 600 UA/day (n = 43), 1000 UA/day (n = 39), or 2000 UA/day (n = 37). After treatment, 54.3, 47.6, 59.0 and 51.4% of patients, respectively, ceased to react to the highest allergen concentration in a conjunctival provocation test. Furthermore, the response threshold improved in 70.4, 62.9, 76.7 and 66.7% of patients, respectively. No serious adverse events occurred. This study found 1000 UA/day to be the optimal effective and safe dose.

High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study.

PubMed

Osunkwo, Ifeyinwa; Ziegler, Thomas R; Alvarez, Jessica; McCracken, Courtney; Cherry, Korin; Osunkwo, Chinyere E; Ofori-Acquah, Solomon F; Ghosh, Samit; Ogunbobode, Adeolu; Rhodes, Jim; Eckman, James R; Dampier, Carlton; Tangpricha, Vin

2012-10-01

We report results of a pilot study of high-dose vitamin D in sickle cell disease (SCD). Subjects were given a 6-week course of oral high-dose cholecalciferol (4000-100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82·5% and 52·5% of subjects, respectively. Subjects who received high-dose vitamin D achieved higher serum 25-hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality-of-life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects. © 2012 Blackwell Publishing Ltd.

Dose-Response Relation between Work Hours and Cardiovascular Disease Risk: Findings from the Panel Study of Income Dynamics

PubMed Central

Conway, Sadie H.; Pompeii, Lisa A.; Roberts, Robert E.; Follis, Jack L.; Gimeno, David

2015-01-01

Objectives To examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. Methods Retrospective cohort study of 1,926 individuals from the Panel Study of Income Dynamics (1986–2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. Results A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with increased risk of CVD. Compared to working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. Conclusions Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD. PMID:26949870

Dose-dependent effects of hydrocortisone infusion on autobiographical memory recall

PubMed Central

Young, Kymberly; Drevets, Wayne C.; Schulkin, Jay; Erickson, Kristine

2011-01-01

The glucocorticoid hormone cortisol has been shown to impair episodic memory performance. The present study examined the effect of two doses of hydrocortisone (synthetic cortisol) administration on autobiographical memory retrieval. Healthy volunteers (n=66) were studied on two separate visits, during which they received placebo and either moderate-dose (0.15 mg/kg IV; n=33) or high-dose (0.45 mg/kg IV; n=33) hydrocortisone infusion. From 75 to 150 min post-infusion subjects performed an Autobiographical Memory Test and the California Verbal Learning Test (CVLT). The high-dose hydrocortisone administration reduced the percent of specific memories recalled (p = 0.04), increased the percent of categorical (nonspecific) memories recalled, and slowed response times for categorical memories (p <0.001), compared to placebo performance (p < 0.001). Under moderate-dose hydrocortisone the autobiographical memory performance did not change significantly with respect to percent of specific or categorical memories recalled or reaction times. Performance on the CVLT was not affected by hydrocortisone. These findings suggest that cortisol affects accessibility of autobiographical memories in a dose-dependent manner. Specifically, administration of hydrocortisone at doses analogous to those achieved under severe psychosocial stress impaired the specificity and speed of retrieval of autobiographical memories. PMID:21942435

Dextromethorphan Interactions with Histaminergic and Serotonergic Treatments to Reduce Nicotine Self-administration in Rats

PubMed Central

Briggs, Scott A.; Hall, Brandon J.; Wells, Corinne; Slade, Susan; Jaskowski, Paul; Morrison, Margaret; Rezvani, Amir H.; Rose, Jed E.; Levin, Edward D.

2015-01-01

Combining effective treatments with diverse mechanisms of action for smoking cessation may provide better therapy by targeting multiple points of control in the neural circuits underlying addiction. Previous research in a rat model has shown that dextromethorphan, which has α3β4 nicotinic and NMDA glutamatergic antagonist actions, significantly decreases nicotine self-administration. We have found in the rat model that the H1 histamine antagonist pyrilamine and the serotonin 5HT2c agonist lorcaserin also significantly reduce nicotine self-administration. The current studies were conducted to determine the interactive effects of dextromethorphan with pyrilamine and lorcaserin on nicotine self-administration in rats. Young adult female rats were fitted with jugular IV catheters and trained to self-administer a nicotine infusion dose of 0.03-mg/kg/infusion. In an initial dose-effect function study of dextromethorphan, we found a monotonic decrease in nicotine self-administration over a dose range of 1 to 30-mg/kg with a lowest effective dose of 3-mg/kg. Then, with two separate cohorts of rats, dextromethorphan (0, 3.3, and 10-mg/kg) interactions with pyrilamine (0, 4.43, and 13.3-mg/kg) were investigated as well as interactions with lorcaserin (0, 0.3125 and 0.625-mg/kg). In the pyrilamine-dextromethorphan interaction study, the acute dose of pyrilamine (13.3-mg/kg) as well as an acute dose of dextromethorphan caused a significant decrease in nicotine self-administration. There were mutually augmenting effects of these two drugs. The combination of dextromethorphan (10-mg/kg) and pyrilamine (13.3-mg/kg) significantly lowered nicotine self-administration relative to either 10-mg/kg of dextromethorphan alone (p<0.05) or 13.3-mg/kg of pyrilamine alone (p<0.0005). In the lorcaserin-dextromethorphan study, an acute dose of lorcaserin (0.312-mg/kg) as well as an acute dose of dextromethorphan (10-mg/kg) caused a significant decrease in nicotine self-administration replicating previous findings. Augmenting interactions were observed with dextromethorphan and pyrilamine as well as lorcaserin. These findings suggest that combination therapy may be more effective smoking cessation treatments than monotherapy. PMID:26704812

Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats.

PubMed

Briggs, Scott A; Hall, Brandon J; Wells, Corinne; Slade, Susan; Jaskowski, Paul; Morrison, Margaret; Rezvani, Amir H; Rose, Jed E; Levin, Edward D

2016-03-01

Combining effective treatments with diverse mechanisms of action for smoking cessation may provide better therapy by targeting multiple points of control in the neural circuits underlying addiction. Previous research in a rat model has shown that dextromethorphan, which has α3β4 nicotinic and NMDA glutamatergic antagonist actions, significantly decreases nicotine self-administration. We have found in the rat model that the H1 histamine antagonist pyrilamine and the serotonin 5HT2C agonist lorcaserin also significantly reduce nicotine self-administration. The current studies were conducted to determine the interactive effects of dextromethorphan with pyrilamine and lorcaserin on nicotine self-administration in rats. Young adult female rats were fitted with jugular IV catheters and trained to self-administer a nicotine infusion dose of 0.03-mg/kg/infusion. In an initial dose-effect function study of dextromethorphan, we found a monotonic decrease in nicotine self-administration over a dose range of 1 to 30-mg/kg with the lowest effective dose of 3-mg/kg. Then, with two separate cohorts of rats, dextromethorphan (0, 3.3, and 10-mg/kg) interactions with pyrilamine (0, 4.43, and 13.3-mg/kg) were investigated as well as interactions with lorcaserin (0, 0.3125 and 0.625-mg/kg). In the pyrilamine-dextromethorphan interaction study, an acute dose of pyrilamine (13.3-mg/kg) as well as an acute dose of dextromethorphan caused a significant decrease in nicotine self-administration. There were mutually augmenting effects of these two drugs. The combination of dextromethorphan (10-mg/kg) and pyrilamine (13.3-mg/kg) significantly lowered nicotine self-administration relative to either 10-mg/kg of dextromethorphan alone (p<0.05) or 13.3-mg/kg of pyrilamine alone (p<0.0005). In the lorcaserin-dextromethorphan study, an acute dose of lorcaserin (0.312-mg/kg) as well as an acute dose of dextromethorphan (10-mg/kg) caused a significant decrease in nicotine self-administration replicating previous findings. Augmenting interactions were observed with dextromethorphan and pyrilamine as well as lorcaserin. These findings suggest that combination therapy may be more effective smoking cessation treatments than monotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Design, development of water tank-type lung phantom and dosimetric verification in institutions participating in a phase I study of stereotactic body radiation therapy in patients with T2N0M0 non-small cell lung cancer: Japan Clinical Oncology Group trial (JCOG0702).

PubMed

Nishio, Teiji; Shirato, Hiroki; Ishikawa, Masayori; Miyabe, Yuki; Kito, Satoshi; Narita, Yuichirou; Onimaru, Rikiya; Ishikura, Satoshi; Ito, Yoshinori; Hiraoka, Masahiro

2014-05-01

A domestic multicenter phase I study of stereotactic body radiotherapy (SBRT) for T2N0M0 non-small cell lung cancer in inoperable patients or elderly patients who refused surgery was initiated as the Japan Clinical Oncology Group trial (JCOG0702) in Japan. Prior to the clinical study, the accuracy of dose calculation in radiation treatment-planning systems was surveyed in participating institutions, and differences in the irradiating dose between the institutions were investigated. We developed a water tank-type lung phantom appropriate for verification of the exposure dose in lung SBRT. Using this water tank-type lung phantom, the dose calculated in the radiation treatment-planning system and the measured dose using a free air ionization chamber and dosimetric film were compared in a visiting survey of the seven institutions participating in the clinical study. In all participating institutions, differences between the calculated and the measured dose in the irradiation plan were as follows: the accuracy of the absolute dose in the center of the simulated tumor measured using a free air ionization chamber was within 2%, the mean gamma value was ≤ 0.47 on gamma analysis following the local dose criteria, and the pass rate was >87% for 3%/3 mm from measurement of dose distribution with dosimetric film. These findings confirmed the accuracy of delivery doses in the institutions participating in the clinical study, so that a study with integration of the institutions could be initiated.

A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: A case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.

PubMed

Sun, Haoyu; Calabrese, Edward J; Zheng, Min; Wang, Dali; Pan, Yongzheng; Lin, Zhifen; Liu, Ying

2018-08-01

Hormesis occurs frequently in broadly ranging biological areas (e.g. plant biology, microbiology, biogerontology), toxicology, pharmacology and medicine. While numerous mechanisms (e.g. receptor and pathway mediated pathway responses) account for stimulatory and inhibitory features of hormetic dose responses, the vast majority emphasizes the inclusion of many doses but only one timepoint or use of a single optimized dose that is assessed over a broad range of timepoints. In this paper, a toxicity study was designed using a large number of properly spaced doses with responses determined over a large number of timepoints, which could help us reveal the underlying mechanism of hormesis. We present the results of a dose-time-response study on hormesis using five antibacterial chemicals on the bioluminescence of Aliivibrio fischeri, measuring expression of protein mRNA based on quorum sensing, simulating bioluminescent reaction and analyzing toxic actions of test chemicals. The findings show dose-time-dependent responses conforming to the hormetic dose-response model, while revealing unique response dynamics between agent induced stimulatory and inhibitory effects within bacterial growth phase dynamics. These dynamic dose-time features reveal a type of biological seesaw model that integrates stimulatory and inhibitory responses within unique growth phase, dose and time features, which has faultlessly explained the time-dependent hormetic phenomenon induced by five antibacterial chemicals (characterized by low-dose stimulation and high-dose inhibition). This study offers advances in understanding cellular dynamics, the biological integration of diverse and opposing responses and their role in evolutionary adaptive strategies to chemicals, which can provide new insight into the mechanistic investigation of hormesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Prophylaxis of thromboembolism in bariatric surgery with parnaparin.

PubMed

Forestieri, Pietro; Quarto, Gennaro; De Caterina, Maurizio; Cuocolo, Alberto; Pilone, Vincenzo; Formato, Antonio; Ruocco, Aldo; Ferrari, Patrizio

2007-12-01

There are limited data on appropriate dosing of low-molecular-weight heparins (LMWHs) for venous thromboembolism (VTE) prophylaxis in bariatric surgery. The primary objective of this preliminary study was to evaluate the preoperative effects of increasing doses of the LMWH parnaparin on coagulation in severely obese patients undergoing bariatric surgery. Severely obese patients (BMI > 50 kg/m(2)) were administered three increasing single doses of parnaparin (3200, 4250, and 6400 IU) on the three consecutive days leading up to biliointestinal bypass surgery. Activated partial thromboplastin time (APTT), anti-factor IIa and anti-factor Xa levels were measured 1 h before and 4 h after dosing. The highest dose (6400 IU/day) was continued from the day of surgery until day 30 (recovery period). Intermittent pneumatic compression and stockings were applied during surgery and the recovery period, respectively. Lower limb echoDoppler and phleboscintigraphy, and pulmonary scintigraphy were used for VTE detection. Ten patients (mean BMI 52.4 kg/m(2)) were recruited into this study. During the preoperative dosing phase, parnaparin dose-dependently prolonged APTT, with the 6400 IU dose significantly prolonging APTT versus the lower doses. Meanwhile, anti-factor Xa and anti-factor IIa activity was increased by the 4250 and 6400 IU doses. After surgery, one patient with heparin resistance experienced pulmonary embolization. No bleeding complications were observed. The dose-response data reported in this preliminary study suggest that parnaparin doses of 4250 and 6400 IU may provide effective prophylaxis for VTE in patients undergoing bariatric surgery. However, given the small number of patients, larger, well-controlled trials are required to confirm these findings.

SU-C-204-02: Behavioral and Pathologic Differences in Mice Exposed to Proton Minibeam Arrays Versus Proton Broad Beams

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

Eley, J; Zhang, C; Wolfe, T

Purpose: Minibeam therapy using protons or light-ions offers a theoretical reduction of biologic damage to tissues upstream of a tumor compared to broad-beam therapy while providing equal tumor control. The purpose of this study was to investigate behavioral and pathologic differences in mice after exposure of healthy brain to proton minibeam arrays versus proton broad beams. Methods: Twenty-four C57BL/6J juvenile mice were divided into 5 study arms: sham irradiation (NoRT), broad-beam 10 Gy (BB10), minibeam 10Gy (MB10), broad-beam 30 Gy (BB30), and minibeam 30 Gy (MB30), approximate integral entrance doses. Circular beams of 100 MeV protons with 7-mm diameter weremore » delivered laterally through the brain, either as broad beams or as planar minibeam arrays having 300-micron beam width and 1-mm spacing on center. Mice were followed for 8 months using standard behavioral tests. Pathologic studies were carried out at 8 months after irradiation. Results: Peak entrance doses were 10.0, 23.8, 30.0, and 71.3 Gy for mice in BB10, MB10, BB30, and MB30, respectively. Despite the high single-fraction doses, no animals showed signs of radiation sickness or neurophysical impairment over the 8-month study duration. The Morris water maze alternate-starting-position trial showed significant evidence of better spatial learning for mice in MB10 versus BB10 (p=0.026), but other behavioral tests showed no significant differences. Glial fibrillary acidic protein stains showed gliosis in arms BB10, BB30, and MB30 but not in NoRT or MB10. A secondary finding was categorically higher epilation in broad-beam arms compared with their minibeam dose counterparts. Conclusion: Our findings indicate trends that, despite the higher peak doses, proton minibeam therapy can reduce radiation side effects in shallow tissue and brain compared to proton broadbeam therapy. As the behavioral findings were mixed, confirmation studies are needed with larger numbers of animals. AAPM Research Seed Funding Grant.« less

Optimization of a murine and human tissue model to recapitulate dermal and pulmonary features of systemic sclerosis

PubMed Central

Watanabe, Tomoya; Mlakar, Logan; Heywood, Jonathan; Malaab, Maya; Hoffman, Stanley

2017-01-01

The murine bleomycin (BLM)-induced fibrosis model is the most widely used in systemic sclerosis (SSc) studies. It has been reported that systemic delivery of BLM via continuous diffusion from subcutaneously implanted osmotic minipumps can cause fibrosis of the skin, lungs, and other internal organs. However, the mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the next. In this study, by employing the pump model in C57BL/6J mice, we show a dose-dependent increase in lung fibrosis by day 28 and a transient increase in dermal thickness. Dermal thickness and the level of collagen in skin treated with high-dose BLM was significantly higher than in skin treated with low dose BLM or vehicle. A reduction in the thickness of the adipose layer was noted in both high and low dose groups at earlier time points suggesting that the loss of the fat layer precedes the onset of fibrosis. High-dose BLM also induced dermal fibrosis and increased expression of fibrosis-associated genes ex vivo in human skin, thus confirming and extending the in vivo findings, and demonstrating that a human organ culture model can be used to assess the effect of BLM on skin. In summary, our findings suggest that the BLM pump model is an attractive model to analyze the underlying mechanisms of fibrosis and test the efficacy of potential therapies. However, the choice of mouse strain, duration of BLM administration and dose must be carefully considered when using this model. PMID:28651005

Optimization of a murine and human tissue model to recapitulate dermal and pulmonary features of systemic sclerosis.

PubMed

Watanabe, Tomoya; Nishimoto, Tetsuya; Mlakar, Logan; Heywood, Jonathan; Malaab, Maya; Hoffman, Stanley; Feghali-Bostwick, Carol

2017-01-01

The murine bleomycin (BLM)-induced fibrosis model is the most widely used in systemic sclerosis (SSc) studies. It has been reported that systemic delivery of BLM via continuous diffusion from subcutaneously implanted osmotic minipumps can cause fibrosis of the skin, lungs, and other internal organs. However, the mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the next. In this study, by employing the pump model in C57BL/6J mice, we show a dose-dependent increase in lung fibrosis by day 28 and a transient increase in dermal thickness. Dermal thickness and the level of collagen in skin treated with high-dose BLM was significantly higher than in skin treated with low dose BLM or vehicle. A reduction in the thickness of the adipose layer was noted in both high and low dose groups at earlier time points suggesting that the loss of the fat layer precedes the onset of fibrosis. High-dose BLM also induced dermal fibrosis and increased expression of fibrosis-associated genes ex vivo in human skin, thus confirming and extending the in vivo findings, and demonstrating that a human organ culture model can be used to assess the effect of BLM on skin. In summary, our findings suggest that the BLM pump model is an attractive model to analyze the underlying mechanisms of fibrosis and test the efficacy of potential therapies. However, the choice of mouse strain, duration of BLM administration and dose must be carefully considered when using this model.

Interaction of different antidepressants with acute and chronic methadone in mice, and possible clinical implications.

PubMed

Schreiber, Shaul; Barak, Yonatan; Hostovsky, Avner; Baratz-Goldstein, Renana; Volis, Ina; Rubovitch, Vardit; Pick, Chaim G

2014-04-01

We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn.

[Prolonged clinical pattern of brain death in patients under barbiturate sedation: usefulness of transcranial Doppler].

PubMed

Segura, T; Jiménez, P; Jerez, P; García, F; Córcoles, V

2002-04-01

Throughout the world, is fully accepted that a person is dead when brain death exists. In most situations, neurological criteria permit the diagnosis of brain death, but in some instances, as when high-dose barbiturate therapy has been used, confirmatory testing are required by law. We report the case of a 17 year-old women who suffered high-dose barbiturate therapy due to post traumatic intracranial hypertension. During the period of the barbiturate infusion and until six days after the suppression of this therapy, neurological exploration and EEG findings seem to confirm brain death, while transcranial Doppler (TCD) study remained normal. TCD is a fast, simple and accurate confirmatory testing in the determination of brain death and its findings are not affected by high-dose barbiturate therapy. We think that TCD must be present in all hospitals where mechanical ventilation and support of patients are carried out.

A Critique of Recent Epidemiologic Studies of Cancer Mortality Among Nuclear Workers.

PubMed

Scott, Bobby R

2018-01-01

Current justification by linear no-threshold (LNT) cancer risk model advocates for its use in low-dose radiation risk assessment is now mainly based on results from flawed and unreliable epidemiologic studies that manufacture small risk increases (ie, phantom risks). Four such studies of nuclear workers, essentially carried out by the same group of epidemiologists, are critiqued in this article. Three of the studies that forcibly applied the LNT model (inappropriate null hypothesis) to cancer mortality data and implicated increased mortality risk from any radiation exposure, no matter how small the dose, are demonstrated to manufacture risk increases for doses up to 100 mSv (or 100 mGy). In a study where risk reduction (hormetic effect/adaptive response) was implicated for nuclear workers, it was assumed by the researchers to relate to a "strong healthy worker effect" with no consideration of the possibility that low radiation doses may help prevent cancer mortality (which is consistent with findings from basic radiobiological research). It was found with basic research that while large radiation doses suppress our multiple natural defenses (barriers) against cancer, these barriers are enhanced by low radiation doses, thereby decreasing cancer risk, essentially rendering the LNT model to be inconsistent with the data.

Standard and reduced radiation dose liver CT images: adaptive statistical iterative reconstruction versus model-based iterative reconstruction-comparison of findings and image quality.

PubMed

Shuman, William P; Chan, Keith T; Busey, Janet M; Mitsumori, Lee M; Choi, Eunice; Koprowicz, Kent M; Kanal, Kalpana M

2014-12-01

To investigate whether reduced radiation dose liver computed tomography (CT) images reconstructed with model-based iterative reconstruction ( MBIR model-based iterative reconstruction ) might compromise depiction of clinically relevant findings or might have decreased image quality when compared with clinical standard radiation dose CT images reconstructed with adaptive statistical iterative reconstruction ( ASIR adaptive statistical iterative reconstruction ). With institutional review board approval, informed consent, and HIPAA compliance, 50 patients (39 men, 11 women) were prospectively included who underwent liver CT. After a portal venous pass with ASIR adaptive statistical iterative reconstruction images, a 60% reduced radiation dose pass was added with MBIR model-based iterative reconstruction images. One reviewer scored ASIR adaptive statistical iterative reconstruction image quality and marked findings. Two additional independent reviewers noted whether marked findings were present on MBIR model-based iterative reconstruction images and assigned scores for relative conspicuity, spatial resolution, image noise, and image quality. Liver and aorta Hounsfield units and image noise were measured. Volume CT dose index and size-specific dose estimate ( SSDE size-specific dose estimate ) were recorded. Qualitative reviewer scores were summarized. Formal statistical inference for signal-to-noise ratio ( SNR signal-to-noise ratio ), contrast-to-noise ratio ( CNR contrast-to-noise ratio ), volume CT dose index, and SSDE size-specific dose estimate was made (paired t tests), with Bonferroni adjustment. Two independent reviewers identified all 136 ASIR adaptive statistical iterative reconstruction image findings (n = 272) on MBIR model-based iterative reconstruction images, scoring them as equal or better for conspicuity, spatial resolution, and image noise in 94.1% (256 of 272), 96.7% (263 of 272), and 99.3% (270 of 272), respectively. In 50 image sets, two reviewers (n = 100) scored overall image quality as sufficient or good with MBIR model-based iterative reconstruction in 99% (99 of 100). Liver SNR signal-to-noise ratio was significantly greater for MBIR model-based iterative reconstruction (10.8 ± 2.5 [standard deviation] vs 7.7 ± 1.4, P < .001); there was no difference for CNR contrast-to-noise ratio (2.5 ± 1.4 vs 2.4 ± 1.4, P = .45). For ASIR adaptive statistical iterative reconstruction and MBIR model-based iterative reconstruction , respectively, volume CT dose index was 15.2 mGy ± 7.6 versus 6.2 mGy ± 3.6; SSDE size-specific dose estimate was 16.4 mGy ± 6.6 versus 6.7 mGy ± 3.1 (P < .001). Liver CT images reconstructed with MBIR model-based iterative reconstruction may allow up to 59% radiation dose reduction compared with the dose with ASIR adaptive statistical iterative reconstruction , without compromising depiction of findings or image quality. © RSNA, 2014.

SU-F-T-389: Validation in 4D Dosimetry Using Dynamic Phantom

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

Lin, C; Lin, C; Tu, P

2016-06-15

Purpose: Tumor motion due to respiration causes the uncertainties during the radiotherapy. This study aims to find the differences between planning dose by treatment planning and the received dose using dynamic phantom. Methods: Respiratory motion was simulated by the DYNAMIC THORAX PHANTOM (Model 008A). 4D-CT scans and maximum intensity projection (MIP) images for GTV were acquired for analysis. The amplitude of craniocaudal tumor motion including 2mm, 5mm, 10mm and 20mm with 3cm2 tumor size were performed in this study. The respiratory cycles of 4-seconds and 6-seconds were included as the different breathing modes. IMRT, VAMT, and Tomotherapy were utilized formore » treatment planning. Ion chamber and EBT3 were used to measure the point dose and planar dose. Dose distributions with different amplitudes, respiratory cycles, and planning techniques were all measured and compared to calculations. Results: The variations between the does measurements and calculation dose by treatment planning system were found in both point dose and dose distribution. The 0.83% and 5.46 % differences in dose average were shown on phantom with motions using 2mm amplitude in 4 second respiratory cycle, and 20mm amplitude in 4 second respiratory cycle, respectively. The most point dose overestimation as compared of the calculations was shown the plan generated by Tomotherapy. The underestimations of planar dose as compared of calculations was found in the 100% coverage doses for GTV. Conclusion: The loss of complete (100%) GTV coverage was the predominant effect of respiratory motion observed in this study. Motion amplitude and treatment planning system were the major factors leading the dose measurement variation as compared of planning calculations.« less

Thermoluminescence response of flat optical fiber subjected to 9 MeV electron irradiations

NASA Astrophysics Data System (ADS)

Hashim, S.; Omar, S. S. Che; Ibrahim, S. A.; Hassan, W. M. S. Wan; Ung, N. M.; Mahdiraji, G. A.; Bradley, D. A.; Alzimami, K.

2015-01-01

We describe the efforts of finding a new thermoluminescent (TL) media using pure silica flat optical fiber (FF). The present study investigates the dose response, sensitivity, minimum detectable dose and glow curve of FF subjected to 9 MeV electron irradiations with various dose ranges from 0 Gy to 2.5 Gy. The above-mentioned TL properties of the FF are compared with commercially available TLD-100 rods. The TL measurements of the TL media exhibit a linear dose response over the delivered dose using a linear accelerator. We found that the sensitivity of TLD-100 is markedly 6 times greater than that of FF optical fiber. The minimum detectable dose was found to be 0.09 mGy for TLD-100 and 8.22 mGy for FF. Our work may contribute towards the development of a new dosimeter for personal monitoring purposes.

Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. The Granisetron Study Group.

PubMed Central

Riviere, A.

1994-01-01

The efficacy and safety of three different doses of granisetron (2 micrograms kg-1, group A; 10 micrograms kg-1, group B; 40 micrograms kg-1, group C) were compared in a randomised, double-blind study of 157 patients due to receive high-dose cisplatin therapy (mean dose > 97 mg m-2). In each group, up to two 3 mg rescue doses of granisetron were allowed if more than mild nausea or vomiting occurred. In group A 30.8%, in group B 61.5% and in group C 67.9% of patients were complete responders (i.e. no vomiting or nothing worse than mild nausea) during the first 24 h. These differences are significant between groups A and B, and A and C. There were no statistically significant differences in any efficacy variable between the 10 micrograms kg-1 and 40 micrograms kg-1 groups, although in each case the trend favoured the higher dose. Additional rescue doses resulted in resolved or improved symptoms in 95.3% for the first rescue dose and 93.3% for the second. Over the 7 days of the study, 82.7%, 82.7% and 86.8% of patients in groups A, B and C respectively were treated with granisetron alone. Headache was the most common side-effect, reported by 9.6% of patients; the majority of headaches were mild. There was no difference between the treatment groups regarding the adverse event rate. We concluded that prophylactic doses of 10 or 40 micrograms kg-1 lead to a safe and satisfactory degree of control of nausea and vomiting induced by high-dose cisplatin. PMID:8180032

Pretransplant Tacrolimus Dose Requirements Predict Early Posttransplant Dose Requirements in Blood Group AB0-Incompatible Kidney Transplant Recipients.

PubMed

Shuker, Nauras; de Man, Femke M; de Weerd, Annelies E; van Agteren, Madelon; Weimar, Willem; Betjes, Michiel G H; van Gelder, Teun; Hesselink, Dennis A

2016-04-01

The aim of this study was to investigate whether pretransplant tacrolimus (Tac) dose requirements of patients scheduled to undergo living donor kidney transplantation correlate with posttransplantation dose requirements. The predictive value of Tac dose requirements (defined as the ratio of the Tac predose concentration, C0, divided by the total daily Tac dose, D) pretransplantation on this same parameter posttransplantation was assessed retrospectively in a cohort of 57 AB0-incompatible kidney transplant recipients. These patients started immunosuppressive therapy 14 days before transplant surgery. All patients were using a stable dose of glucocorticoids and were at steady-state Tac exposure before transplantation. Tac dose requirements immediately before transplantation (C0/Dbefore) explained 63% of the Tac dose requirements on day 3 after transplantation: r = 0.633 [F (1, 44) = 75.97, P < 0.01]. No other clinical and demographic variables predicted Tac dose requirements early after transplantation. Steady-state Tac dose requirement before transplantation largely predicted posttransplantation Tac dose requirements in AB0-incompatible kidney transplant recipients. The importance of this finding is that the posttransplantation Tac dose can be individualized based on a patient's pretransplantation Tac concentration/dose ratio. Pretransplant Tac phenotyping therefore has the potential to improve transplantation outcomes.

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

PubMed

McKeand, William

2017-09-01

Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation. Food did not seem to have any clinically relevant impact on pharmacokinetic parameters. Bazedoxifene had an estimated oral bioavailability of ~6% and was safe and well tolerated in the range of doses evaluated. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Dose mapping inside a gamma irradiator measured with doped silica fibre dosimetry and Monte Carlo simulation

NASA Astrophysics Data System (ADS)

Moradi, F.; Khandaker, M. U.; Mahdiraji, G. A.; Ung, N. M.; Bradley, D. A.

2017-11-01

In recent years doped silica fibre thermoluminescent dosimeters (TLD) have been demonstrated to have considerable potential for irradiation applications, benefitting from the available sensitivity, spatial resolution and dynamic dose range, with primary focus being on the needs of medical dosimetry. Present study concerns the dose distribution inside a cylindrically shaped gamma-ray irradiator cavity, with irradiator facilities such as the familiar 60Co versions being popularly used in industrial applications. Quality assurance of the radiation dose distribution inside the irradiation cell of such a device is of central importance in respect of the delivered dose to the irradiated material. Silica fibre TLD dose-rates obtained within a Gammacell-220 irradiator cavity show the existence of non-negligible dose distribution heterogeneity, by up to 20% and 26% in the radial and axial directions respectively, Monte Carlo simulations and available literature providing some support for present findings. In practice, it is evident that there is need to consider making corrections to nominal dose-rates in order to avoid the potential for under-dosing.

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study

PubMed Central

Müller, Daniel J.; Ng, Chee H.; Byron, Keith; Berk, Michael; Singh, Ajeet B.

2017-01-01

Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. Objective To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. Materials and methods A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Results Among remitters (n=95), there was a strong concordance (Kendall’s τ-b=0.84, P=0.0001; Cohen’s κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Conclusion Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing. PMID:27779571

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study.

PubMed

Bousman, Chad A; Müller, Daniel J; Ng, Chee H; Byron, Keith; Berk, Michael; Singh, Ajeet B

2017-01-01

Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Among remitters (n=95), there was a strong concordance (Kendall's τ-b=0.84, P=0.0001; Cohen's κ=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing.

Evaluation of β-blocker gel and effect of dosing volume for topical delivery.

PubMed

Zhang, Qian; Chantasart, Doungdaw; Li, S Kevin

2015-05-01

Although topical administration of β-blockers is desired because of the improved therapeutic efficacy and reduced systemic adverse effects compared with systemic administration in the treatment of infantile hemangioma, the permeation of β-blockers across skin under finite dose conditions has not been systematically studied and an effective topical β-blocker formulation for skin application is not available. The present study evaluated the permeation of β-blockers propranolol, betaxolol, and timolol across human epidermal membrane (HEM) from a topical gel in Franz diffusion cells in vitro under various dosing conditions. The effects of occlusion and dosing volume on percutaneous absorption of β-blockers from the gel were studied. The permeation data were compared with those of finite dose diffusion theory. The results showed that skin permeation of β-blockers generally could be enhanced two to three times by skin occlusion. The cumulative amounts of β-blockers permeated across HEM increased with increasing dosing volume. An adequate fit was obtained between the theoretical curve and experimental permeation data, indicating that the experimental results of the gel are consistent with finite dose diffusion theory. In conclusion, the findings suggest the feasibility of using topical gels of β-blockers for infantile hemangioma treatment and topical application with skin occlusion is preferred. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Eye Lens Opacities Among Physicians Occupationally Exposed to Ionizing Radiation.

PubMed

Auvinen, Anssi; Kivelä, Tero; Heinävaara, Sirpa; Mrena, Samy

2015-08-01

We compared the frequency of lens opacities among physicians with and without occupational exposure to ionizing radiation, and estimated dose-response between cumulative dose and opacities. We conducted ophthalmologic examinations of 21 physicians with occupational exposure to radiation and 16 unexposed physicians. Information on cumulative radiation doses (mean 111 mSv) was based on dosimeter readings recorded in a national database on occupational exposures. Lens changes were evaluated using the Lens Opacities Classification System II, with an emphasis on posterior subcapsular (PSC) and cortical changes. Among the exposed physicians, the prevalences of cortical and PSC changes were both 11% (3/21), and the corresponding frequencies in the unexposed group were 44% (n = 7) and 6% (n = 1). For dose-response analysis, the data were pooled with 29 exposed physicians from our previous study. No association of either type of lens changes with cumulative recorded dose was observed. Our findings do not indicate an increased frequency of lens opacities in physicians with occupational exposure to ionizing radiation. However, the subjects in this study have received relatively low doses and therefore the results do not exclude small increases in lens opacities or contradict the studies reporting increases among interventional cardiologists with materially higher cumulative doses. © The Author 2015. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Dose-Response Relation Between Work Hours and Cardiovascular Disease Risk: Findings From the Panel Study of Income Dynamics.

PubMed

Conway, Sadie H; Pompeii, Lisa A; Roberts, Robert E; Follis, Jack L; Gimeno, David

2016-03-01

The aim of this study was to examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. A retrospective cohort study of 1926 individuals from the Panel Study of Income Dynamics (1986 to 2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with an increased risk of CVD. Compared with working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD.

Treatment of traumatic infra orbital nerve paresthesia

PubMed Central

Lone, Parveen Akhter; Singh, R. K.; Pal, U. S.

2012-01-01

This study was done to find out the role of topiramate therapy in infraorbital nerve paresthesia after miniplate fixation in zygomatic complxex fractures. A total 2 cases of unilateral zygomatic complex fracture, 2-3 weeks old with infra orbital nerve paresthesia were slected. Open reduction and plating was done in frontozygomaticregion. Antiepileptic drug tab topiramate was given in therapeutic doses and dose was increased slowly until functional recovery was noticed. PMID:23833503

Fluctuating asymmetry as risk marker for stress and structural defects in a toxicologic experiment.

PubMed

Breno, Matteo; Bots, Jessica; De Schaepdrijver, Luc; Van Dongen, Stefan

2013-08-01

Fluctuating asymmetry (the directionally random asymmetry of bilateral structures, FA) is commonly used as a measure of developmental instability, and may increase with stress. As several studies reported a relation between FA and developmental abnormalities, we investigate whether FA could be an additional perhaps more sensitive marker of developmental toxicity. The aim of this work is analyzing patterns of FA in multiple traits in a large dataset of rabbit fetuses, which were prenatally exposed to a toxic compound and sacrificed just before natural delivery. Gravid females were exposed to three doses of this compound, inducing abnormalities in the fetuses at the high dose only. The average FA, however, was already higher than control in rabbit fetuses of the low-dose group but did not further increase with higher concentrations. Moreover, the increase in FA differed between traits, with the hindlimbs showing the strongest response. In addition, we did not find any association between FA and the presence of fetal abnormalities at the individual level. Although these results suggest that FA may act as "an early warning system," we did not find a dose-response relationship with increasing stress and effects were trait-specific. Further testing is needed before FA may be considered as a sensitive marker in developmental toxicity studies. © 2013 Wiley Periodicals, Inc.

Further development of LLNA:DAE method as stand-alone skin-sensitization testing method and applied for evaluation of relative skin-sensitizing potency between chemicals.

PubMed

Yamashita, Kunihiko; Shinoda, Shinsuke; Hagiwara, Saori; Itagaki, Hiroshi

2015-04-01

To date, there has been no well-established local lymph node assay (LLNA) that includes an elicitation phase. Therefore, we developed a modified local lymph node assay with an elicitation phase (LLNA:DAE) to discriminate true skin sensitizers from chemicals that gave borderline positive results and previously reported this assay. To develop the LLNA:DAE method as a useful stand-alone testing method, we investigated the complete procedure for the LLNA:DAE method using hexyl cinnamic aldehyde (HCA), isoeugenol, and 2,4-dinitrochlorobenzene (DNCB) as test compounds. We defined the LLNA:DAE procedure as follows: in the dose-finding test, four concentrations of chemical applied to dorsum of the right ear on days 1, 2, and 3 and dorsum of both ears on day 10. Ear thickness and skin irritation score were measured on days 1, 3, 5, 10, and 12. Local lymph nodes were excised and weighed on day 12. The test dose for the primary LLNA:DAE study was selected as the dose that gave the highest left ear lymph node weight in the dose-finding study, or the lowest dose that produced a left ear lymph node of over 4 mg. This procedure was validated using nine different chemicals. Furthermore, qualitative relationship was observed between the degree of elicitation response in the left ear lymph node and the skin sensitizing potency of 32 chemicals tested in this study and the previous study. These results indicated that LLNA:DAE method was as first LLNA method that was able to evaluate the skin sensitizing potential and potency in elicitation response.

Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease.

PubMed

Black, Kevin J; Koller, Jonathan M; Campbell, Meghan C; Gusnard, Debra A; Bandak, Stephen I

2010-12-01

Adenosine A(2a) receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A(2a) antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion magnetic resonance imaging (MRI) study of the novel adenosine A(2a) antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development.

Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease

PubMed Central

Black, Kevin J.; Koller, Jonathan M.; Campbell, Meghan C.; Gusnard, Debra A.; Bandak, Stephen I.

2010-01-01

Adenosine A2a receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A2a antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose-finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion MRI study of the novel adenosine A2a antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally-focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development. PMID:21123574

Limiting CT radiation dose in children with craniosynostosis: phantom study using model-based iterative reconstruction.

PubMed

Kaasalainen, Touko; Palmu, Kirsi; Lampinen, Anniina; Reijonen, Vappu; Leikola, Junnu; Kivisaari, Riku; Kortesniemi, Mika

2015-09-01

Medical professionals need to exercise particular caution when developing CT scanning protocols for children who require multiple CT studies, such as those with craniosynostosis. To evaluate the utility of ultra-low-dose CT protocols with model-based iterative reconstruction techniques for craniosynostosis imaging. We scanned two pediatric anthropomorphic phantoms with a 64-slice CT scanner using different low-dose protocols for craniosynostosis. We measured organ doses in the head region with metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters. Numerical simulations served to estimate organ and effective doses. We objectively and subjectively evaluated the quality of images produced by adaptive statistical iterative reconstruction (ASiR) 30%, ASiR 50% and Veo (all by GE Healthcare, Waukesha, WI). Image noise and contrast were determined for different tissues. Mean organ dose with the newborn phantom was decreased up to 83% compared to the routine protocol when using ultra-low-dose scanning settings. Similarly, for the 5-year phantom the greatest radiation dose reduction was 88%. The numerical simulations supported the findings with MOSFET measurements. The image quality remained adequate with Veo reconstruction, even at the lowest dose level. Craniosynostosis CT with model-based iterative reconstruction could be performed with a 20-μSv effective dose, corresponding to the radiation exposure of plain skull radiography, without compromising required image quality.

Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity

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

Kleiman, Norman Jay

The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiationmore » exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9, influence cataract development and thus radiosensitivity. These observations have direct applicability to various human populations including accidentally exposed individuals, interventional medical workers, astronauts and nuclear plant workers.« less

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

A Monte Carlo study of the impact of the choice of rectum volume definition on estimates of equivalent uniform doses and the volume parameter

NASA Astrophysics Data System (ADS)

Kvinnsland, Yngve; Muren, Ludvig Paul; Dahl, Olav

2004-08-01

Calculations of normal tissue complication probability (NTCP) values for the rectum are difficult because it is a hollow, non-rigid, organ. Finding the true cumulative dose distribution for a number of treatment fractions requires a CT scan before each treatment fraction. This is labour intensive, and several surrogate distributions have therefore been suggested, such as dose wall histograms, dose surface histograms and histograms for the solid rectum, with and without margins. In this study, a Monte Carlo method is used to investigate the relationships between the cumulative dose distributions based on all treatment fractions and the above-mentioned histograms that are based on one CT scan only, in terms of equivalent uniform dose. Furthermore, the effect of a specific choice of histogram on estimates of the volume parameter of the probit NTCP model was investigated. It was found that the solid rectum and the rectum wall histograms (without margins) gave equivalent uniform doses with an expected value close to the values calculated from the cumulative dose distributions in the rectum wall. With the number of patients available in this study the standard deviations of the estimates of the volume parameter were large, and it was not possible to decide which volume gave the best estimates of the volume parameter, but there were distinct differences in the mean values of the values obtained.

Effects of fenfluramine on plasma homovanillic acid in healthy subjects.

PubMed

Hollander, E; Stein, D J; Saoud, J B; DeCaria, C M; Cooper, T B; Islam, M N; Liebowitz, M R; Stanley, M

1992-01-01

The specificity of fenfluramine as a pharmacological probe of the serotonin system has been questioned, since animal studies with high dose l-fenfluramine show increases in striatal levels of the dopamine metabolite homovanillic acid. To test the specificity of fenfluramine in humans with clinical doses, we compared plasma homovanillic acid (pHVA) concentration in healthy volunteers after administration of fenfluramine (60 mg) and placebo. There were no significant effects on pHVA, which supports previous findings that at doses used in pharmacological challenge paradigms, the effect of fenfluramine on the dopamine system is insufficient to alter measures of its change.

Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia.

PubMed

Dougherty, T B; Porche, V H; Thall, P F

2000-04-01

This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20. The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20. The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

Dose-Dependent Negative Effects of Prior Multiple Vaccinations against Influenza A and Influenza B among School Children: A Study of Kamigoto Island in Japan during the 2011/12, 2012/13 and 2013/14 Influenza Seasons.

PubMed

Saito, Nobuo; Komori, Kazuhiro; Suzuki, Motoi; Kishikawa, Takayuki; Yasaka, Takahiro; Ariyoshi, Koya

2018-03-08

We investigated the negative effects of prior multiple vaccinations on influenza vaccine effectiveness (VE) and analysed the association of VE with prior vaccine doses. Patients aged 9-18 years presenting with influenza-like illness at a community hospital on a Japanese remote island during the 2011/12, 2012/13 and 2013/14 seasons were tested for influenza using a rapid diagnostic test (RDT). A test-negative case-control study design was used to estimate the VEs of trivalent inactivated influenza vaccine (TIV). Histories of vaccination and medically-attended influenza (MA-flu) A and B during three previous seasons were collected from registry systems. VE was calculated using multi-level mixed-effects logistic regression models adjusted for the history of RDT-confirmed MA-flu. During three influenza seasons, 1668 influenza-like illness episodes were analysed, including 421 and 358 episodes of MA-fluA and MA-fluB, respectively. The adjusted VE yielded significant dose-dependent attenuations by prior vaccinations against both MA-fluA [0 doses during previous three seasons: 96% (95% CI: 69%-100%), 1 dose: 48% (-7% to 74%), 2 doses: 52% (11%-74%), 3 doses: 21% (-25% to 51%); P for trend <0.05] and MA-fluB [0 doses: 66% (-5% to 89%), 1 dose: 48% (-14% to 76%), 2 doses: 34% (-33% to 67%), 3 doses: -7% (-83% to 37%); P for trend <0.05]. After excluding episodes of MA-flu during prior three seasons, similar trends were observed. Repeated previous vaccinations over multiple seasons had significant dose-dependent negative impacts on VE against both MA-fluA and MA-fluB. Further studies to confirm this finding are necessary.

A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

PubMed

Hughes, D A; Deegan, P B; Milligan, A; Wright, N; Butler, L H; Jacobs, A; Mehta, A B

2013-07-01

Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule. Copyright © 2013 Elsevier Inc. All rights reserved.

Development of a Bayesian response-adaptive trial design for the Dexamethasone for Excessive Menstruation study.

PubMed

Holm Hansen, Christian; Warner, Pamela; Parker, Richard A; Walker, Brian R; Critchley, Hilary Od; Weir, Christopher J

2017-12-01

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. This article describes the preparatory simulation study for a Bayesian response-adaptive dose-finding trial design. Dexamethasone for Excessive Menstruation aims to assess the efficacy of Dexamethasone in reducing excessive menstrual bleeding and to determine the best dose for further study. To maximise learning about the dose response, patients receive placebo or an active dose with randomisation probabilities adapting based on evidence from patients already recruited. The dose-response relationship is estimated using a flexible Bayesian Normal Dynamic Linear Model. Several competing design options were considered including: number of doses, proportion assigned to placebo, adaptation criterion, and number and timing of adaptations. We performed a fractional factorial study using SAS software to simulate virtual trial data for candidate adaptive designs under a variety of scenarios and to invoke WinBUGS for Bayesian model estimation. We analysed the simulated trial results using Normal linear models to estimate the effects of each design feature on empirical type I error and statistical power. Our readily-implemented approach using widely available statistical software identified a final design which performed robustly across a range of potential trial scenarios.

Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

PubMed

Gentry, P R; Yager, J W; Clewell, R A; Clewell, H J

2014-10-01

In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview

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

Calabrese, Edward J.; Blain, Robyn

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying amore » broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.« less

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview.

PubMed

Calabrese, Edward J; Blain, Robyn

2005-02-01

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

PubMed

Palmer, Melissa; Jennings, Lee; Silberg, Debra G; Bliss, Caleb; Martin, Patrick

2018-03-16

Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990 mmol/L (- 3.341 to 0.570), respectively. This study indicates that maximal inhibition of bile acid reabsorption, as assessed by FBA excretion, occurs at volixibat doses of ≥20 mg/day in obese and overweight adults, without appreciable change in gastrointestinal tolerability. These findings guided dose selection for an ongoing phase 2 study in patients with non-alcoholic steatohepatitis. ClinicalTrials.gov identifier: NCT02287779 (registration first received 6 November 2014).

Lymphoid cell kinetics under continuous low dose-rate gamma irradiation: A comparison study

NASA Technical Reports Server (NTRS)

Foster, B. R.

1975-01-01

A comparison study was conducted of the effects of continuous low dose-rate gamma irradiation on cell population kinetics of lymphoid tissue (white pulp) of the mouse spleen with findings as they relate to the mouse thymus. Experimental techniques employed included autoradiography and specific labeling with tritiated thymidine (TdR-(h-3)). The problem studied involved the mechanism of cell proliferation of lymphoid tissue of the mouse spleen and thymus under the stress of continuous irradiation at a dose rate of 10 roentgens (R) per day for 105 days (15 weeks). The aim was to determine whether or not a steady state or near-steady state of cell population could be established for this period of time, and what compensatory mechanisms of cell population were involved.

A comparison of masking effects of haloperidol versus molindone in tardive dyskinesia.

PubMed

Glazer, W M; Hafez, H

1990-01-01

An experimental method was utilized to compare the masking effects of two neuroleptic agents--molindone and haloperidol--on 18 neuroleptic-treated schizophrenic patients exhibiting operationally defined withdrawal-exacerbated tardive dyskinesia. After a week on one of these two medications at preestablished doses equivalent to that of the pre-study neuroleptic, molindone-masked total AIMS scores by significantly less (12%) than haloperidol (27%). Similarly, during a second week when the dose of these neuroleptics was equivalent to 200% that of the pre-study dose, molindone masked the total AIMS score significantly less (23%) as compared to haloperidol (53%). Several interpretations of this finding are considered. This study demonstrates the feasibility of a method that may offer a model for understanding pharmacological differences among neuroleptic medications.

Toxicology of brotizolam

PubMed Central

Hewett, C.; Kreuzer, H.; Köllmer, H.; Niggeschulze, A.; Stötzer, H.

1983-01-01

1 Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents > 10,000 and > 900 mg/kg, respectively). 2 Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. 3 Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. 4 Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams were treated with 400 mg/kg, litter mortality was markedly increased. 5 Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. 6 Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. 7 Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. 8 The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose. PMID:6686462

Novel, single-dose, topical treatment of tinea pedis using terbinafine: results of a dose-finding clinical trial.

PubMed

de Chauvin, Martine Feuilhade; Viguié-Vallanet, Claude; Kienzler, Jean-Luc; Larnier, Catherine

2008-01-01

Tinea pedis is the most common dermatophytosis requiring topical antifungals for at least 1-4 weeks. To determine the effectiveness of a novel topical single dose formulation of terbinafine (film forming solution-FFS) in the treatment of tinea pedis, 344 outpatients from 43 dermatological centres in France and Bulgaria suffering from tinea pedis with possible extension to soles confirmed by mycological examination (direct and culture) were evaluated for efficacy of terbinafine 1%, 5%, 10% FFS in a randomised double blind vehicle controlled parallel group dose finding study. Evaluations were carried out at baseline, 1 and 6 weeks after a single application of FFS. Effective treatment rate based on negative mycology (direct and culture) and minimal signs and symptoms (two or less with only mild recorded) was measured at week 6. Effective treatment rates at week 6 with terbinafine 1%, 5% and 10% FFS were 66%, 70%, 61% compared with 18% with placebo. All three active preparations were shown to be significantly superior to placebo (P < 0.001). Terbinafine 1% and 5% FFS were shown to be non-inferior to terbinafine 10% FFS. Terbinafine 1% FFS is an effective, safe dose for the treatment of tinea pedis. This novel product represents a significant advance with the enhanced compliance and convenience that it offers.

Effects of acute buspirone administration on inhibitory control and sexual discounting in cocaine users.

PubMed

Strickland, Justin C; Bolin, B Levi; Romanelli, Michael R; Rush, Craig R; Stoops, William W

2017-01-01

Cocaine users display deficits in inhibitory control and make impulsive choices that may increase risky behavior. Buspirone is an anxiolytic that activates dopaminergic and serotonergic systems and improves impulsive choice (i.e., reduces sexual risk-taking intent) in cocaine users when administered chronically. We evaluated the effects of acutely administered buspirone on inhibitory control and impulsive choice. Eleven subjects with a recent history of cocaine use completed this within-subject, placebo-controlled study. Subjects performed two cued go/no-go and a sexual risk delay-discounting task following oral administration of buspirone (10 and 30 mg), triazolam (0.375 mg; positive control), and placebo (negative control). Physiological and psychomotor performance and subject-rated data were also collected. Buspirone failed to change inhibitory control or impulsive choice; however, slower reaction times were observed at the highest dose tested. Buspirone did not produce subject-rated drug effects but dose-dependently decreased diastolic blood pressure. Triazolam impaired psychomotor performance and increased ratings of positive subject-rated effects (e.g., Like Drug). These findings indicate that acutely administered buspirone has little impact on behavioral measures of inhibitory control and impulsive sexual decision-making. Considering previous findings with chronic dosing, these findings highlight that the behavioral effects of buspirone differ as a function of dosing conditions. Copyright © 2017 John Wiley & Sons, Ltd.

The frequency of U-shaped dose responses in the toxicological literature.

PubMed

Calabrese, E J; Baldwin, L A

2001-08-01

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, > or = 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.

A robust two-stage design identifying the optimal biological dose for phase I/II clinical trials.

PubMed

Zang, Yong; Lee, J Jack

2017-01-15

We propose a robust two-stage design to identify the optimal biological dose for phase I/II clinical trials evaluating both toxicity and efficacy outcomes. In the first stage of dose finding, we use the Bayesian model averaging continual reassessment method to monitor the toxicity outcomes and adopt an isotonic regression method based on the efficacy outcomes to guide dose escalation. When the first stage ends, we use the Dirichlet-multinomial distribution to jointly model the toxicity and efficacy outcomes and pick the candidate doses based on a three-dimensional volume ratio. The selected candidate doses are then seamlessly advanced to the second stage for dose validation. Both toxicity and efficacy outcomes are continuously monitored so that any overly toxic and/or less efficacious dose can be dropped from the study as the trial continues. When the phase I/II trial ends, we select the optimal biological dose as the dose obtaining the minimal value of the volume ratio within the candidate set. An advantage of the proposed design is that it does not impose a monotonically increasing assumption on the shape of the dose-efficacy curve. We conduct extensive simulation studies to examine the operating characteristics of the proposed design. The simulation results show that the proposed design has desirable operating characteristics across different shapes of the underlying true dose-toxicity and dose-efficacy curves. The software to implement the proposed design is available upon request. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Caffeinated and decaffeinated coffee consumption and melanoma risk: a dose-response meta-analysis of prospective cohort studies.

PubMed

Micek, Agnieszka; Godos, Justyna; Lafranconi, Alessandra; Marranzano, Marina; Pajak, Andrzej

2018-06-01

To determine the association between total, caffeinated and decaffeinated coffee consumption and melanoma risk a dose-response meta-analysis on prospective cohort studies were performed. Eligible studies were identified searching PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by random-effects meta-analysis and the shape of the exposure-outcome curve was modelled linearly and using restricted cubic splines. A total of seven studies eligible for meta-analysis were identified that comprised 1,418,779 participants and 9211 melanoma cases. A linear dose-response meta-analysis showed a significant association between total coffee consumption and melanoma risk. An increase in coffee consumption of one cup per day was associated with a 3% reduction in melanoma risk (RR 0.97; 95% CI 0.95-0.99). Our findings suggest that coffee intake may be inversely associated with incidence of melanoma. Nevertheless, further studies exploring also the role of confounding factors are needed to explain the heterogeneity among studies.

A pharmacometric case study regarding the sensitivity of structural model parameter estimation to error in patient reported dosing times.

PubMed

Knights, Jonathan; Rohatagi, Shashank

2015-12-01

Although there is a body of literature focused on minimizing the effect of dosing inaccuracies on pharmacokinetic (PK) parameter estimation, most of the work centers on missing doses. No attempt has been made to specifically characterize the effect of error in reported dosing times. Additionally, existing work has largely dealt with cases in which the compound of interest is dosed at an interval no less than its terminal half-life. This work provides a case study investigating how error in patient reported dosing times might affect the accuracy of structural model parameter estimation under sparse sampling conditions when the dosing interval is less than the terminal half-life of the compound, and the underlying kinetics are monoexponential. Additional effects due to noncompliance with dosing events are not explored and it is assumed that the structural model and reasonable initial estimates of the model parameters are known. Under the conditions of our simulations, with structural model CV % ranging from ~20 to 60 %, parameter estimation inaccuracy derived from error in reported dosing times was largely controlled around 10 % on average. Given that no observed dosing was included in the design and sparse sampling was utilized, we believe these error results represent a practical ceiling given the variability and parameter estimates for the one-compartment model. The findings suggest additional investigations may be of interest and are noteworthy given the inability of current PK software platforms to accommodate error in dosing times.

A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

PubMed

Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

2015-07-31

Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis.

PubMed

Cakici, Cagri; Yigitbasi, Turkan; Ayla, Sule; Karimkhani, Hadi; Bayramoglu, Feyza; Yigit, Pakize; Kilic, Ertugrul; Emekli, Nesrin

2018-02-08

Background The purpose of this study is to examine the dose-dependent effects of vitamin 1,25(OH)2D3 on apoptosis and oxidative stress. Methods In this study, 50 male Balb/c mice were used as control and experiment groups. The mice were divided into 5 groups each consisting of 10 mice. Calcitriol was intraperitoneally administered as low dose, medium dose, medium-high dose and high dose vitamin D groups (at 0.5, 1, 5 and 10 μg/kg, respectively), for three times a week during 14 days. At the end of the study, annexin V was measured by enzyme-linked immunosorbent assay method, and total antioxidant capacity and total oxidant status values were measured by colorimetric method in serum. Hematoxylin eosin staining was performed in liver tissues and periodic acid schiff staining was performed in kidney tissues. Results While comparing the results of medium-high dose (5 μg/kg) and high dose (10 μg/kg) vitamin D administration to that of the control group, it was observed that serum antioxidant status and annexin V levels decreased and glomerular mesenchial matrix ratio increased in kidney (p<0.05). In addition to these findings, in the group receiving high dose vitamin D (10 μg/kg), it was observed that the damage to the liver increased together with the the oxidative stress index values (p<0.05). Conclusions As a result, this study was the first in the literature to report that use of high-dose vitamin D (10 μg/kg) results in oxidant effect, rather than being an antioxidant, and causes severe histopathological toxicity in the liver and kidney.

Characterization of optically stimulated luminescence dosimeters and investigating their potential for estimating pediatric organ doses in multi-slice computed tomography

NASA Astrophysics Data System (ADS)

Al-Senan, Rani Mohammed

Recent epidemiologic studies have shown a strong association between the relatively high doses of pediatric CT and the risk of cancer. Quantifying organ doses, as a measure of the risk, is commonly based on either direct anthropomorphic phantom measurements or Monte Carlo simulation. The major disadvantage in the phantom approach is its high cost especially that, for pediatric CT dosimetry, various phantom sizes are required to represent different age groups of children. On the other hand, Monte Carlo simulation, although not considered costly, requires validation by anthropomorphic phantom measurements. The aim of this project was to develop two methods of organ dose estimation in pediatric CT: 1) from the measured surface dose using optically stimulated luminescence dosimeters (OSLDs) and 2) by measuring the circumference of the body part being scanned as well as knowing the scan parameters. The project was based on a study proposed by the surgery department to monitor radiation exposure to children during their CT examination in the ER. A total of 200 pediatric patients were enrolled in this study which used OSLDs to monitor the doses. Specific aim 1 of this project was to characterize the OSLDs in the diagnostic energy range. Specific aim 2(a) was to find relationships between the patients' doses from OSLDs and both scan CTDI and the measured circumference. In specific aim 2(b) we carried out measurements using CTDI phantoms to investigate the relationships studied in specific aim 2(a). Specific aim 3 was to come up with models to estimate select organ doses from measuring surface dose or by using the circumference of the body part. To do this, pediatric examinations were simulated using a set of pediatric anthropomorphic phantoms in which doses of select organs were measured.

Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects

PubMed Central

Gilbert, Ethel S.; Curtis, Rochelle E.; Hauptmann, Michael; Kleinerman, Ruth A.; Lynch, Charles F.; Stovall, Marilyn; Smith, Susan A.; Weathers, Rita; Andersson, Michael; Dores, Graça M.; Fraumeni, Joseph F.; Fossa, Sophie D.; Hall, Per; Hodgson, David C.; Holowaty, Eric J.; Joensuu, Heikki; Johannesen, Tom B.; Langmark, Froydis; Kaijser, Magnus; Pukkala, Eero; Rajaraman, Preetha; Storm, Hans H.; Vaalavirta, Leila; van den Belt-Dusebout, Alexandra W.; Aleman, Berthe M.; Travis, Lois B.; Morton, Lindsay M.; van Leeuwen, Flora E.

2017-01-01

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036–0.20] with estimates of 0.049 (95% CI: 0.007–0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054–1.44) for testicular cancer and 0.096 (95% CI: −0.002–0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12–1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses. PMID:28118119

Neonatal Neurobehavioral and Neuroanatomic Correlates of Prenatal Cocaine Exposure

PubMed Central

FRANK, DEBORAH A.; AUGUSTYN, MARILYN; ZUCKERMAN, BARRY S.

2008-01-01

Complex methodologic challenges face researchers studying the effects of prenatal cocaine exposure on infant outcome. These include unavoidable imprecision in ascertaining the gestational timing and dose of cocaine to which the fetus was exposed and difficulties in identifying and quantifying the confounding, mediating, and moderating variables. Review of research on neonatal behavioral and cranial ultrasound findings following in utero cocaine exposure is used to illustrate these issues. We conclude that there are measurable but not dramatic dose-related effects of prenatal cocaine exposure on infant central nervous system structure and function. The effects of dose of prenatal cocaine exposure on later child development remain to be determined. Such research would be facilitated by a scientific consensus delineating relative doses of prenatal cocaine exposure. PMID:9668396

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

Impact of high- versus low-dose neuromuscular blocking agent administration on unplanned 30-day readmission rates in retroperitoneal laparoscopic surgery.

PubMed

Boon, Martijn; Martini, Chris; Yang, H Keri; Sen, Shuvayu S; Bevers, Rob; Warlé, Michiel; Aarts, Leon; Niesters, Marieke; Dahan, Albert

2018-01-01

Recent data shows that a neuromuscular block (NMB) induced by administration of high doses of rocuronium improves surgical conditions in certain procedures. However, there are limited data on the effect such practices on postoperative outcomes. We performed a retrospective analysis to compare unplanned 30-day readmissions in patients that received high-dose versus low-dose rocuronium administration during general anesthesia for laparoscopic retroperitoneal surgery. This retrospective cohort study was performed in the Netherlands in an academic hospital where routine high-dose rocuronium NMB has been practiced since July 2015. Charts of patients receiving anesthesia between January 2014 and December 2016 were searched for surgical cases receiving high-dose rocuronium and matched with respect to procedure, age, sex and ASA classification to patients receiving low-dose rocuronium. The primary post-operative outcome was unplanned 30-day readmission rate. There were 130 patients in each cohort. Patients in the high- and low-dose rocuronium cohorts received 217 ± 49 versus 37 ± 5 mg rocuronium, respectively. In the high-dose rocuronium group neuromuscular activity was consistently monitored; matched patients were unreliably monitored. All patients receiving high-dose rocuronium were reversed with sugammadex, while just 33% of matched patients were reversed with sugammadex and 20% with neostigmine; the remaining patients were not reversed. Unplanned 30-day readmission rate was significantly lower in the high-dose compared to the low-dose rocuronium cohort (3.8% vs. 12.7%; p = 0.03; odds ratio = 0.33, 95% C.I. 0.12-0.95). This small retrospective study demonstrates a lower incidence of unplanned readmissions within 30-days following laparoscopic retroperitoneal surgery with high-dose relaxant anesthesia and sugammadex reversal in comparison to low-dose relaxant anesthesia. Further prospective studies are needed in larger samples to corroborate our findings and additionally assess the pharmacoeconomics of high-dose relaxant anesthesia taking into account the benefits (reduced readmissions) and harm (cost of relaxants and reversal agents) of such practice.

[Absorbed doses to critical organs from full mouth dental radiography].

PubMed

Zhang, G; Yasuhiko, O; Hidegiko, Y

1999-01-01

A few studies were reported in China on radiological risk of dental radiography. The aim of this study is to evaluate the absorbed doses of patients from the full mouth radiographs, and to find out the contribution from each projection to the total absorbed dose of the organs. Absorbed doses to critical organs were measured from 14-film complete dental radiography. The organs included pituitary, optical lens, parotid glands, submandibular glands, sublingual glands, thyroid, breasts, ovary, testes and the skin in center field of each projection were studied. A-radiation analog dosimetry system (RANDO) phantom with thermoluminescent dosimeters (ILD200) was used for the study. All of the exposure parameters were fixed. The total filtration was 2 mm Al equivalent. The column collaboration was 6 cm in diameter and 20 cm in length. The absorbed doses of organs were measured three times in each projection of the full-mouth series (FMS) exposures. The absorbed dose of lenses in FMS (249 microGy) in present study was much less (10%) than the doses (2,630 microGy) reported in 1976. The doses absorbed of other organs in the present study were thyroid gland (125 microGy), pituitary gland (112 microGy), parotid gland (153 microGy), submandibular gland (629 microGy), sublingual gland (1,900 microGy), and breast gland (12 microGy). The doses of the ovary and testis were to small to further analysis. All of the results show that the radiation risk to patients in intraoral radiograph has been reduced significantly. In the pituitary, half of the dose is from both sides of the maxillary molar projection. For the lenses, the largest contribultions of radiation (60%) come from the ipsilateral molar and premolar projection of maxilla. In parotid gland, up to 57% of the dose is from the contralateral molar, pre-molar and canine of maxilla. It could be derived that about 90% of the absorbed doses could be avoided in FMS if the column collimator is 20 cm long and the filter is 2.0 mm thick. If we use the 10-film complete mouth radiograph instead of the 14-film series, more 20% of the doses would be reduced.

Low-dose estrogen therapy for prevention of osteoporosis: working our way back to monotherapy.

PubMed

Richman, Susan; Edusa, Valentine; Fadiel, Ahmed; Naftolin, Frederick

2006-01-01

The risks of low bone mineral density, osteoporosis and fractures, are major concerns in postmenopausal women. Although postmenopausal hormone therapy is effective for reducing these risks, safety issues have been raised by the results of studies such as the Women's Health Initiative. Although there are scientifically valid reasons to be wary of the general applicability of the Women's Health Initiative findings, the study has underscored the continuing need for research into new forms of menopausal hormone therapy. Low-dose transdermal estrogen monotherapy can preserve bone density while relieving vasomotor symptoms. Transdermal administration may offer advantages, including lack of first-pass liver metabolism, which permits the use of lower doses and avoids a negative impact on the lipid profile. Moreover, a recently published 2-year study of ultra-low-dose transdermal estrogen monotherapy in an older population similar to that of the WHI reported significant increases in bone mineral density, accompanied by significant reductions in markers of bone turnover, with no increased risk of endometrial hyperplasia or other side effects. Additional studies are warranted to shed further light on the possible benefits of low-dose estrogen monotherapy for the prevention of bone loss in postmenopausal women.

Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma.

PubMed

Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Seung Sook; Park, Sun Hoo; Lee, Hae June; Lee, Soong In; Lee, Chang Geun; Kim, Sung Dae; Jo, Wol Soon; Kim, Sung Ho; Shin, In Sik

2015-01-01

Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation.

SU-F-T-659: Nanoparticle-Aided Eye Plaque Radiotherapy

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

Chin, J; Ngwa, W

Purpose: Eye plaque brachytherapy is one of the approaches for radiotherapy treatment for ocular cancers: retinoblastoma and choroidal melanoma. This study, investigates the potential benefits of using gold nanoparticles to enhance therapeutic efficacy during eye plaque brachytherapy. Methods: The EYE PHYSICS Inc. Plaque Simulator program distributed by IsoAid, LLC, Port Richey, Florida was used. It is based on the superposition of dose contributions from individual seeds following the TG–43 formalism. Dose enhancement factor (DEF) values for feasible nanoparticle concentrations from previous studies was used to investigate the benefit of using nanoparticles to enhance dose to tumour or reduce dose tomore » healthy tissue. The dose enhancement factor (DEF) represents the ratio of the dose deposited in tumour with nanoparticles divided by dose deposited in the tumour without nanoparticles. The investigation was done for I–125 and Pd–103 typical sources employed for eye plaque brachytherapy. The prescription dose used is 85 Gy. Results: Lower dose enhancement values were obtained for Pd–103. With DEF of 2 due to gold nanoparticles, critical structure doses reduce by a factor of 2. Optic disc dose is 6.69 Gy and 4.571 Gy, opposite retina dose is 4.064 and 2.484 Gy, lens dose is 12.66 Gy and 9.870 Gy, and fovea dose is 9.85 Gy and 7.275 Gy. With DEF of 3 due to gold nanoparticles, critical structure doses reduce by a factor of 3. Optic disc dose is 4.352 Gy and 2.975 Gy, opposite retina dose is 2.644 Gy and 1.618 Gy, lens dose is 8.322 Gy and 6.427 Gy, and fovea dose is 4.815 Gy and 4.737 Gy. Conclusion: The results of this research predict that using gold nanoparticles will lead to major sparing of dose to critical structures. The finding provides more impetus for the development of nanoparticle–aided brachytherapy.« less

Non-Malignant Thyroid Diseases Following a Wide Range of Radiation Exposures

PubMed Central

Ron, Elaine; Brenner, Alina

2013-01-01

Background The thyroid gland is one of the most radiosensitive human organs. While it is well known that radiation exposure increases the risk of thyroid cancer, less is known about its effects in relation to non-malignant thyroid diseases. Objectives The aim of this review is to evaluate the effects of high and low dose radiation on benign structural and functional diseases of the thyroid. Methods We examined the results of major studies from cancer patients treated with high-dose radiotherapy or thyrotoxicosis patients treated with high doses of iodine-131, patients treated with moderate to high dose radiotherapy for benign diseases, persons exposed to low doses from environmental radiation and survivors of the atomic bombings who were exposed to a range of doses. We evaluated radiation effects on structural (tumors, nodules), functional (hyper- and hypothyroidism), and autoimmune thyroid diseases. Results Following a wide range of doses of ionizing radiation, an increased risk of thyroid adenomas and nodules was observed in a variety of populations and settings. The dose response appeared to be linear at low to moderate doses, but in one study there was some suggestion of a reduction in risk above 5 Gy. The elevated risk for benign tumors continues for decades following exposure. Considerably less consistent findings are available regarding functional thyroid diseases including autoimmune diseases. In general, associations for these outcomes were fairly weak and significant radiation effects were most often observed following high doses, particularly for hypothyroidism. Conclusions A significant radiation dose-response relation was demonstrated for benign nodules and follicular adenomas. The effects of radiation on functional thyroid diseases are less clear, partly due to the greater difficulties studying these diseases. PMID:21128812

A randomized, double-blind, active control, multicenter, dose-finding study of lipegfilgrastim (XM22) in breast cancer patients receiving myelosuppressive therapy.

PubMed

Buchner, Anton; Elsässer, Reiner; Bias, Peter

2014-11-01

This dose-ranging study was conducted to identify the optimal fixed dose of lipegfilgrastim compared with pegfilgrastim 6.0 mg for the provision of neutrophil support during myelosuppressive chemotherapy in patients with breast cancer. A phase 2 study was conducted in which 208 chemotherapy-naive patients were randomized to receive lipegfilgrastim 3.0, 4.5, or 6.0 mg or pegfilgrastim 6.0 mg. Study drugs were administered as a single subcutaneous injection on day 2 of each chemotherapy cycle (doxorubicin/docetaxel on day 1 for four 3-week cycles). The primary outcome measure was duration of severe neutropenia (DSN) in cycle 1. Patients treated with lipegfilgrastim experienced shorter DSN in cycle 1 with higher doses. The mean DSN was 0.76 days in the lipegfilgrastim 6.0-mg group and 0.87 days in the pegfilgrastim 6.0-mg group, with no significant differences between treatment groups. Treatment with lipegfilgrastim 6.0 mg was consistently associated with a higher absolute neutrophil count (ANC) at nadir, shorter ANC recovery time, and a similar safety and tolerability profile compared with pegfilgrastim. This phase 2 study demonstrated that lipegfilgrastim 6.0 mg is the optimal dose for patients with breast cancer and provides neutrophil support that is at least equivalent to the standard 6.0-mg fixed dose of pegfilgrastim.

[Toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na) (1). Single-dose intravenous toxicity studies in rats and dogs].

PubMed

Yanagi, H; Yamaguchi, K; Shimizu, K; Shichino, Y; Nishiyama, K; Mori, H; Shinomiya, K; Ueda, H; Suzuki, Y; Yonezawa, H; Fujita, T

1998-07-01

Single-dose toxicity studies of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel neutrophil elastase inhibitor, were conducted in Sprague-Dawley (SD) rats and beagle dogs. The rats of both sexes were administered ONO-5046.Na intravenously at a single dose of 150, 300 or 450 mg/kg. The male dogs were also given ONO-5046.Na at a single dose of 75 or 150 mg/kg. In the rat study, hypoactivity, bradypnea and paleness of limbs and pinna were observed at doses of 300 mg/kg and above. In particular, one of six female rats in the 450 mg/kg group showed clonic convulsion and died. In surviving animals, those signs disappeared within 3 hr after administration. No effect on body weight gain was seen in either group. Necropsy findings showed a slight foamy fluid in the bronchus, hemorrhage at the right knee joint muscle, tendon and lung in a dead animal. In the dog study, no effects on clinical signs, body weight, food consumption and blood biochemistry were seen in any animals of the 75 and 150 mg/kg groups. It is concluded that the approximate lethal doses are 450 mg/kg in rats and 150 mg/kg and above in dogs.

Determination of the adequate dosage of rebamipide, a gastric mucoprotective drug, to prevent low-dose aspirin-induced gastrointestinal mucosal injury.

PubMed

Ota, Kazuhiro; Takeuchi, Toshihisa; Nouda, Sadaharu; Ozaki, Haruhiko; Kawaguchi, Shinpei; Takahashi, Yoshiaki; Harada, Satoshi; Edogawa, Shoko; Kojima, Yuichi; Kuramoto, Takanori; Higuchi, Kazuhide

2016-11-01

Small intestinal mucosal injury caused by low-dose aspirin is a common cause of obscure gastrointestinal bleeding. We aimed to investigate the protective effects and optimal dose of rebamipide for low-dose aspirin-induced gastrointestinal mucosal injury. In this prospective randomized trial, 45 healthy volunteers (aged 20-65 years) were included and divided into three groups. The groups received enteric-coated aspirin 100 mg (low-dose aspirin) plus omeprazole 10 mg (Group A: proton pump inhibitor group), low-dose aspirin plus rebamipide 300 mg (Group B: standard-dose group), or low-dose aspirin plus rebamipide 900 mg (Group C: high-dose group). Esophagogastroduodenoscopy and video capsule endoscopy were performed, and the fecal occult blood reaction and fecal calprotectin levels were measured before and two weeks after drug administration. Although the fecal calprotectin levels increased significantly in Group A, they did not increase in Groups B and C. The esophagogastroduodenoscopic and video capsule endoscopic findings and the fecal occult blood test findings did not differ significantly among the three groups. In conclusion, standard-dose rebamipide is sufficient for preventing mucosal injury of the small intestine induced by low-dose aspirin, indicating that high-dose rebamipide is not necessary.

Influence of exposure and geometric parameters on absorbed doses associated with common neuro-interventional procedures.

PubMed

Safari, Mohammad Javad; Wong, Jeannie Hsiu Ding; Jong, Wei Loong; Thorpe, Nathan; Cutajar, Dean; Rosenfeld, Anatoly; Ng, Kwan Hoong

2017-03-01

The purpose of this study was to investigate the effects of routine exposure parameters on patient's dose during neuro-interventional radiology procedures. We scrutinized the routine radiological exposure parameters during 58 clinical neuro-interventional procedures such as, exposure direction, magnification, frame rate, and distance between image receptor to patient's body and evaluate their effects on patient's dose using an anthropomorphic phantom. Radiation dose received by the occipital region, ears and eyes of the phantom were measured using MOSkin detectors. DSA imaging technique is a major contributor to patient's dose (80.9%) even though they are used sparingly (5.3% of total frame number). The occipital region of the brain received high dose largely from the frontal tube constantly placed under couch (73.7% of the total KAP). When rotating the frontal tube away from under the couch, the radiation dose to the occipital reduced by 40%. The use of magnification modes could increase radiation dose by 94%. Changing the image receptor to the phantom surface distance from 10 to 40cm doubled the radiation dose received by the patient's skin at the occipital region. Our findings provided important insights into the contribution of selected fluoroscopic exposure parameters and their impact on patient's dose during neuro-interventional radiology procedures. This study showed that the DSA imaging technique contributed to the highest patient's dose and judicial use of exposure parameters might assist interventional radiologists in effective skin and eye lens dose reduction for patients undergoing neuro-interventional procedures. Copyright © 2017 Associazione Italiana di Fisica Medica. All rights reserved.

Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

PubMed Central

Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

2012-01-01

BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

Reconstruction of Absorbed Doses to Fibroglandular Tissue of the Breast of Women undergoing Mammography (1960 to the Present)

PubMed Central

Thierry-Chef, Isabelle; Simon, Steven L.; Weinstock, Robert M.; Kwon, Deukwoo; Linet, Martha S.

2013-01-01

The assessment of potential benefits versus harms from mammographic examinations as described in the controversial breast cancer screening recommendations of the U.S. Preventive Task Force included limited consideration of absorbed dose to the fibroglandular tissue of the breast (glandular tissue dose), the tissue at risk for breast cancer. Epidemiological studies on cancer risks associated with diagnostic radiological examinations often lack accurate information on glandular tissue dose, and there is a clear need for better estimates of these doses. Our objective was to develop a quantitative summary of glandular tissue doses from mammography by considering sources of variation over time in key parameters including imaging protocols, x-ray target materials, voltage, filtration, incident air kerma, compressed breast thickness, and breast composition. We estimated the minimum, maximum, and mean values for glandular tissue dose for populations of exposed women within 5-year periods from 1960 to the present, with the minimum to maximum range likely including 90% to 95% of the entirety of the dose range from mammography in North America and Europe. Glandular tissue dose from a single view in mammography is presently about 2 mGy, about one-sixth the dose in the 1960s. The ratio of our estimates of maximum to minimum glandular tissue doses for average-size breasts was about 100 in the 1960s compared to a ratio of about 5 in recent years. Findings from our analysis provide quantitative information on glandular tissue doses from mammographic examinations which can be used in epidemiologic studies of breast cancer. PMID:21988547

A dose-finding, cross-over study to evaluate the effect of a Nestorone®/Estradiol transdermal gel delivery on ovulation suppression in normal ovulating women.

PubMed

Brache, Vivian; Merkatz, Ruth; Kumar, Narender; Jesam, Cristian; Sussman, Heather; Hoskin, Elena; Roberts, Kevin; Alami, Mohcine; Taylor, Deshawn; Jorge, Aidelis; Croxatto, Horacio; Lorange, Ellen; Mishell, Daniel R; Sitruk-Ware, Regine

2015-10-01

This study aims to determine the lowest effective of three Nestorone (NES)/estradiol (E2) transdermal gel doses to ensure ovulation suppression in 90-95% of cycles. This was a randomized, open-label, three-treatment-period cross-over study to evaluate the effects of NES/E2 transdermal gel on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters. The doses were low (1.5 mg NES/0.5 mg E2), medium (3.0 mg NES/1.0 mg E2) and high (4.5 mg NES/1.5 mg E2). Participants applied gel daily to a fixed area on the abdomen for 21 consecutive days. They were interviewed regarding their experiences using the gel. Eighteen participants were randomized; 16 completed the study. Median NES C(max) values for low, medium and high dose groups at day 21 were 318.6 pmol/L, 783.0 pmol/L and 1063.8 pmol/L, respectively. Median maximum follicular diameter was higher with the lowest dose with 16.2 mm versus 10.0 and 10.4 mm with the medium and high doses, respectively. Among adherent participants, ovulation was inhibited in all dose groups, except for one participant in the medium dose (6.7%) that had luteal activity and an ultrasound image suggestive of a luteinized unruptured follicle. There were few reports of unscheduled bleeding, with more episodes reported for the lower dose. Adverse events were mild, and no skin irritation was reported from gel application. While all three doses blocked ovulation effectively and were evaluated as safe and acceptable, the medium dose was considered the lowest effective dose based on a more adequate suppression of follicular development. Further development of this novel contraceptive delivering NES and E2 is warranted and has potential for improved safety compared to ethinyl-estradiol-based methods. Copyright © 2015 Elsevier Inc. All rights reserved.

Residential Exposure to Natural Background Radiation and Risk of Childhood Acute Leukemia in France, 1990-2009.

PubMed

Demoury, Claire; Marquant, Fabienne; Ielsch, Géraldine; Goujon, Stéphanie; Debayle, Christophe; Faure, Laure; Coste, Astrid; Laurent, Olivier; Guillevic, Jérôme; Laurier, Dominique; Hémon, Denis; Clavel, Jacqueline

2017-04-01

Exposures to high-dose ionizing radiation and high-dose rate ionizing radiation are established risk factors for childhood acute leukemia (AL). The risk of AL following exposure to lower doses due to natural background radiation (NBR) has yet to be conclusively determined. AL cases diagnosed over 1990-2009 (9,056 cases) were identified and their municipality of residence at diagnosis collected by the National Registry of Childhood Cancers. The Geocap study, which included the 2,763 cases in 2002-2007 and 30,000 population controls, was used for complementary analyses. NBR exposures were modeled on a fine scale (36,326 municipalities) based on measurement campaigns and geological data. The power to detect an association between AL and dose to the red bone marrow (RBM) fitting UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) predictions was 92%, 45% and 99% for exposure to natural gamma radiation, radon and total radiation, respectively. AL risk, irrespective of subtype and age group, was not associated with the exposure of municipalities to radon or gamma radiation in terms of yearly exposure at age reached, cumulative exposure or RBM dose. There was no confounding effect of census-based socio-demographic indicators, or environmental factors (road traffic, high voltage power lines, vicinity of nuclear plants) related to AL in the Geocap study. Our findings do not support the hypothesis that residential exposure to NBR increases the risk of AL, despite the large size of the study, fine scale exposure estimates and wide range of exposures over France. However, our results at the time of diagnosis do not rule out a slight association with gamma radiation at the time of birth, which would be more in line with the recent findings in the UK and Switzerland.

Dosimetry during intramedullary nailing of the tibia.

PubMed

Kirousis, George; Delis, Harry; Megas, Panagiotis; Lambiris, Elias; Panayiotakis, George

2009-10-01

Intramedullary nailing under fluoroscopic guidance is a common operation. We studied the intraoperative radiation dose received by both the patient and the personnel. 25 intramedullary nailing procedures of the tibia were studied. All patients suffered from tibial fractures and were treated using the Grosse-Kempf intramedullary nail, with free-hand technique for fixation of the distal screws, under fluoroscopic guidance. The exposure, at selected positions, was recorded using an ion chamber, while the dose area product (DAP) was measured with a DAP meter, attached to the tube head. Thermoluminescent dosimeters (TLDs) were used to derive the occupational dose to the personnel, and also to monitor the surface dose on the gonads of some of the patients. The mean operation time was 101 (48-240) min, with a mean fluoroscopic time of 72 seconds and a mean DAP value of 75 cGy x cm(2). The surface dose to the gonads of the patients was less than 8.8 mGy during any procedure, and thus cannot be considered to be a contraindication for the use of this technique. Occupational dose differed substantially between members of the operating personnel, the maximum dose recorded being to the operator of the fluoroscopic equipment (0.11 mSv). Our findings underscore the care required by the primary operator not to exceed the dose constraint of 10 mSv per year. The rest of the operating personnel, although they do not receive very high doses, should focus on the dose optimization of the technique.

Study of visitor response to air tour and other aircraft noise in national parks

DOT National Transportation Integrated Search

2005-01-31

This document summarizes the findings of a study that considers all known aircraft noise dose and visitor response data previously collected in the National Parks. These data consist of almost 2500 visitor interviews and simultaneous acoustical measu...

Evaluation of cytotoxicity and radiation enhancement using 1.9 nm gold particles: potential application for cancer therapy

PubMed Central

Butterworth, K T; Coulter, J A; Jain, S; Forker, J; McMahon, S J; Schettino, G; Prise, K M; Currell, F J; Hirst, D G

2010-01-01

High atomic number (Z) materials such as gold preferentially absorb kilovoltage x-rays compared to soft tissue and may be used to achieve local dose enhancement in tumours during treatment with ionizing radiation. Gold nanoparticles have been demonstrated as radiation dose enhancing agents in vivo and in vitro. In the present study, we used multiple endpoints to characterize the cellular cytotoxic response of a range of cell lines to 1.9 nm gold particles and measured dose modifying effects following transient exposure at low concentrations. Gold nanoparticles caused significant levels of cell type specific cytotoxicity, apoptosis and increased oxidative stress. When used as dose modifying agents, dose enhancement factors varied between the cell lines investigated with the highest enhancement being 1.9 in AGO-1522B cells at a nanoparticle concentration of 100 μg ml−1. This study shows exposure to 1.9 nm gold particles to induce a range of cell line specific responses including decreased clonogenic survival, increased apoptosis and induction of DNA damage which may be mediated through the production of reactive oxygen species. This is the first study involving 1.9 nm nanometre sized particles to report multiple cellular responses which impact on the radiation dose modifying effect. The findings highlight the need for extensive characterization of responses to gold nanoparticles when assessing dose enhancing potential in cancer therapy. PMID:20601762

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

PubMed Central

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang

2016-01-01

Lessons Learned This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity. These findings provide clinicians with evidence for application of higher-dose icotinib. Background. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Methods. Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study. Results. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. Conclusion. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. PMID:27789778

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

2016-11-01

This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Evaluation of dose delivery accuracy of gamma knife using MRI polymer gel dosimeter in an inhomogeneous phantom

NASA Astrophysics Data System (ADS)

Pourfallah T, A.; Alam N, Riahi; M, Allahverdi; M, Ay; M, Zahmatkesh

2009-05-01

Polymer gel dosimetry is still the only dosimetry method for directly measuring three-dimensional dose distributions. MRI Polymer gel dosimeters are tissue equivalent and can act as a phantom material. Because of high dose response sensitivity, the MRI was chosen as readout device. In this study dose profiles calculated with treatment-planning software (LGP) and measurements with the MR polymer gel dosimeter for single-shot irradiations were compared. A custom-built 16 cm diameter spherical plexiglas head phantom was used in this study. Inside the phantom, there is a cubic cutout for insertion of gel phantoms and another cutout for inserting the inhomogeneities. The phantoms were scanned with a 1.5T MRI (Siemens syngo MR 2004A 4VA25A) scanner. The multiple spin-echo sequence with 32 echoes was used for the MRI scans. Calibration relations between the spin-spin relaxation rate and the absorbed dose were obtained by using small cylindrical vials, which were filled with the PAGAT polymer gel from the same batch as for the spherical phantom. 1D and 2D data obtained using gel dosimeter for homogeneous and inhomogeneous phantoms were compared with dose obtained using LGP calculation. The distance between relative isodose curves obtained for homogeneous phantom and heterogeneous phantoms exceed the accepted total positioning error (>±2mm). The findings of this study indicate that dose measurement using PAGAT gel dosimeter can be used for verifying dose delivering accuracy in GK unit in presence of inhomogeneities.

Safety of florfenicol administered in feed to tilapia (Oreochromis sp.)

USGS Publications Warehouse

Gaikowski, Mark P.; Wolf, Jeffrey C.; Schleis, Susan M.; Tuomari, Darrell; Endris, Richard G.

2013-01-01

The safety of Aquaflor® (50% w/w florfenicol [FFC]) incorporated in feed then administered to tilapia for 20 days (2x the recommended duration) at 0, 15, 45, or 75 mg/kg body weight/day (0, 1, 3, or 5x the recommended dose of 15 mg FFC/kg BW/d) was investigated. Mortality, behavioral change, feed consumption, body size, and gross and microscopic lesions were determined. Estimated delivered doses were >96.9% of target. Three unscheduled mortalities occurred but were considered incidental since FFC-related findings were not identified. Feed consumption was only affected during the last 10 dosing days when the 45 and 75 mg/kg groups consumed only 62.5% and 55.3% of the feed offered, respectively. There were significant, dose-dependent reductions in body size in the FFC-dose groups relative to the controls. Treatment-related histopathological findings included increased severity of lamellar epithelial hyperplasia, increased incidence of lamellar adhesions, decreased incidence of lamellar telangiectasis in the gills, increased glycogen-type and lipid-type hepatocellular vacuolation in the liver, decreased lymphocytes, increased blast cells, and increased individual cell necrosis in the anterior kidney, and tubular epithelial degeneration and mineralization in the posterior kidney. These changes are likely to be of minimal clinical relevance, given the lack of mortality or morbidity observed. This study has shown that FFC, when administered in feed to tilapia at the recommended dose (15 mg FFC/kg BW/day) for 10 days would be well tolerated.

Non-Target Effect for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Doses of High LET Radiation

NASA Technical Reports Server (NTRS)

Hada, Megumi; George, Kerry A.; Cucinotta, F. A.

2011-01-01

The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (.01 - 0.2 Gy) of 170 MeV/u Si-28-ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The curves for doses above 0.1 Gy were more than one ion traverses a cell showed linear dose responses. However, for doses less than 0.1 Gy, Si-28-ions showed no dose response, suggesting a non-targeted effect when less than one ion traversal occurs. Additional findings for Fe-56 will be discussed.

Collaborative work on evaluation of ovarian toxicity. 13) Two- or four-week repeated dose studies and fertility study of PPAR alpha/gamma dual agonist in female rats.

PubMed

Sato, Norihiro; Uchida, Keisuke; Nakajima, Mikio; Watanabe, Atsushi; Kohira, Terutomo

2009-01-01

The main focus of this study was to determine the optimal dosing period in a repeated dose toxicity study based on toxic effects as assessed by ovarian morphological changes. To assess morphological and functional changes induced in the ovary by a peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, the compound was administered to female rats at dose levels of 0, 4, 20, and 100 mg/kg/day in a repeated dose toxicity study for 2 or 4 weeks, and from 2 weeks prior to mating to Day 7 of pregnancy in a female fertility study. In the repeated dose toxicity study, an increase in atresia of large follicles, a decrease in corpora lutea, and an increase in stromal cells were observed in the treated groups. In addition, the granulosa cell exfoliations into antrum of large follicles and corpora lutea with retained oocyte are morphological characteristics induced by this compound, and they might be related with abnormal condition of ovulation. In the female fertility study, the pregnancy rate tended to decrease in the 100 mg/kg/day group. At necropsy, decreases in the number of corpora lutea, implantations and live embryos were noted in the 20 and 100 mg/kg/day group. No changes were observed in animals given 4 mg/kg/day. These findings indicated that histopathological changes in the ovary are important endpoints for evaluation of drugs inducing ovarian damage. In conclusion, a 2-week administration period is sufficient to detect ovarian toxicity of this test compound in the repeated dose toxicity study.

Micronucleation in the lens epithelium following in vivo exposure to physical and chemical mutagens

NASA Technical Reports Server (NTRS)

Odrich, S.; Medvedovsky, C.; Merriam, G. R. Jr; Worgul, B. V.

1988-01-01

Rats were exposed to cataractogenic doses of known physical and chemical genotoxic agents in order to study the efficacy of using micronuclei to monitor mutagenicity in the lens epithelium. The total numbers of micronuclei were counted in lens epithelia from rats exposed to graded doses of either 250 kVp X-rays or the anti-leukemic drug, 1,4 dimethanesulfonoxybutane (Myleran (R)). The results indicate a dose-dependent incidence of micronucleation in the lens epithelium following exposure. The findings are consistent with the hypothesis that the cataractogenicity of certain agents may be related to their effect on the genome of lens epithelial cells.

A prospective cohort study of exposure-response relationship for vibration-induced white finger.

PubMed

Bovenzi, M

2010-01-01

To investigate prospectively the relation between vibration-induced white finger (VWF) and measures of cumulative (lifetime) exposure to hand-transmitted vibration (HTV). Two hundred and forty-nine HTV workers and 138 control men of the same companies participated in a 3-year follow-up study. The diagnosis of VWF (Raynaud's phenomenon in the controls) was based on the medical history, the administration of colour charts and the results of a cold test. Tool vibration magnitudes were expressed as root-mean-square (r.m.s.) acceleration, frequency-weighted according to international standard ISO 5349-1 and also unweighted over the frequency range 6.3-1250 Hz. From the vibration magnitudes and exposure durations, alternative measures of cumulative vibration dose were calculated for each HTV worker, according to the expression: dose = Sigmaa(i)(m)t(i), where a(i) is the acceleration magnitude on tool i, t(i) is the lifetime exposure duration (hours) for tool i, and m = 0, 1, 2 or 4. The incidence of VWF varied from 5 to 6% in the HTV workers versus 0 to 1.5% for Raynaud's phenomenon in the controls. After adjusting for potential confounders, measures of cumulative vibration dose derived from total operating hours and high powers of unweighted acceleration (ie, , with m>1) gave better predictions of the occurrence of VWF than dose measures calculated from frequency-weighted acceleration (ie, ). These findings were observed in the entire sample of HTV workers, in those with no VWF at the initial investigation, and in those with normal cold test results at baseline. This prospective cohort study suggests that measures of cumulative vibration doses constructed from unweighted r.m.s. acceleration perform better for the prediction of VWF than dose measures calculated according to the recommendations of current standards. These findings should contribute to the improvement of the ISO frequency weighting for evaluating the severity of hand-transmitted vibration.

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.

Comparison of Chest Wall and Lymphatic Radiotherapy Techniques in Patients with Left Breast Carcinoma.

PubMed

Gültekin, Melis; Karabuğa, Mehmet; Yıldız, Ferah; Özyiğit, Gökhan; Cengiz, Mustafa; Zorlu, Faruk; Akyol, Fadıl; Gürkaynak, Murat

2014-04-01

The aim of this study was to find the most appropriate technique for postmastectomy chest wall (CW) and lymphatic irradiation. Partially wide tangent, 30/70 photon/electron mix, 20/80 photon/electron mix and CW and internal mammary en face electron field, were studied on computerized tomography (CT) scans of 10 left breast carcinoma patients and dosimetric calculations have been studied. Dose volume histograms (DVH) obtained from treatment planning system (TPS) were used for minimal, maximal and mean doses received by the clinical target volumes and critical structures. Partially wide tangent field resulted in the most homogeneous dose distribution for the CW and a significantly lower lung and heart doses compared with all other techniques. However, right breast dose was significantly higher for partially wide tangent technique than that each of the other techniques. Approximately 0.6-7.9% differences were found between thermoluminescent dosimeter (TLD) and treatment planning system (TPS). The daily surface doses calculating using Gafchromic® external beam therapy (EBT) dosimetry films were 161.8±2.7 cGy for the naked, 241.0±1.5 cGy when 0.5 cm bolus was used and 255.3±2.7 cGy when 1 cm bolus was used. As a result of this study, partially wide tangent field was found to be the most appropriate technique in terms of the dose distribution, treatment planning and set-up procedure. The main disadvantage of this technique was the higher dose to the contralateral breast comparing the other techniques.

Range-Finding Risk Assessment of Inhalation Exposure to Nanodiamonds in a Laboratory Environment

PubMed Central

Koivisto, Antti J.; Palomäki, Jaana E.; Viitanen, Anna-Kaisa; Siivola, Kirsi M.; Koponen, Ismo K.; Yu, Mingzhou; Kanerva, Tomi S.; Norppa, Hannu; Alenius, Harri T.; Hussein, Tareq; Savolainen, Kai M.; Hämeri, Kaarle J.

2014-01-01

This study considers fundamental methods in occupational risk assessment of exposure to airborne engineered nanomaterials. We discuss characterization of particle emissions, exposure assessment, hazard assessment with in vitro studies, and risk range characterization using calculated inhaled doses and dose-response translated to humans from in vitro studies. Here, the methods were utilized to assess workers’ risk range of inhalation exposure to nanodiamonds (NDs) during handling and sieving of ND powder. NDs were agglomerated to over 500 nm particles, and mean exposure levels of different work tasks varied from 0.24 to 4.96 µg·m−3 (0.08 to 0.74 cm−3). In vitro-experiments suggested that ND exposure may cause a risk for activation of inflammatory cascade. However, risk range characterization based on in vitro dose-response was not performed because accurate assessment of delivered (settled) dose on the cells was not possible. Comparison of ND exposure with common pollutants revealed that ND exposure was below 5 μg·m−3, which is one of the proposed exposure limits for diesel particulate matter, and the workers’ calculated dose of NDs during the measurement day was 74 ng which corresponded to 0.02% of the modeled daily (24 h) dose of submicrometer urban air particles. PMID:24840353

Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

PubMed

Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

2015-01-01

We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies.

The ion environment near Europa and its role in surface energetics

NASA Astrophysics Data System (ADS)

Paranicas, C.; Ratliff, J. M.; Mauk, B. H.; Cohen, C.; Johnson, R. E.

2002-03-01

This paper gives the composition, energy spectra, and time variability of energetic ions measured just upstream of Europa. From 100 keV to 100 MeV, ion intensities vary by less than a factor of ~5 among Europa passes considered between 1997 and 2000. We use the data to estimate the radiation dose rate into Europa's surface for depths 0.01 mm - 1 m. We find that in a critical fraction of the upper layer on Europa's trailing hemisphere, energetic electrons are the principal agent for radiolysis, and their bremsstrahlung photon products, not included in previous studies, dominate the dose below about 1 m. Because ion bombardment is more uniform across Europa's surface, the radiation dose on the leading hemisphere is dominated by the proton flux. Differences exist between this calculation and published doses based on the E4 wake pass. For instance, proton doses presented here are much greater below 1 mm.

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.

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.

Whole-body low-dose computed tomography in multiple myeloma staging: Superior diagnostic performance in the detection of bone lesions, vertebral compression fractures, rib fractures and extraskeletal findings compared to radiography with similar radiation exposure.

PubMed

Lambert, Lukas; Ourednicek, Petr; Meckova, Zuzana; Gavelli, Giampaolo; Straub, Jan; Spicka, Ivan

2017-04-01

The primary objective of the present prospective study was to compare the diagnostic performance of conventional radiography (CR) and whole-body low-dose computed tomography (WBLDCT) with a comparable radiation dose reconstructed using hybrid iterative reconstruction technique, in terms of the detection of bone lesions, skeletal fractures, vertebral compressions and extraskeletal findings. The secondary objective was to evaluate lesion attenuation in relation to its size. A total of 74 patients underwent same-day skeletal survey by CR and WBLDCT. In CR and WBLDCT, two readers assessed the number of osteolytic lesions at each region and stage according to the International Myeloma Working Group (IMWG) criteria. A single reader additionally assessed extraskeletal findings and their significance, the number of vertebral compressions and bone fractures. The radiation exposure was 2.7±0.9 mSv for WBLDCT and 2.5±0.9 mSv for CR (P=0.054). CR detected bone involvement in 127 out of 486 regions (26%; P<0.0001), confirmed by WBLDCT. CR underestimated the disease stage in 16% and overestimated it in 8% of the patients (P=0.0077). WBLDCT detected more rib fractures compared with CR (188 vs. 47; P<0.0001), vertebral compressions (93 vs. 67; P=0.010) and extraskeletal findings (194 vs. 52; P<0.0001). There was no correlation observed between lesion size (≥5 mm) and its attenuation (r=-0.006; P=0.93). The inter-observer agreement for the presence of osteolytic lesions was κ=0.76 for WBLDCT, and κ=0.55 for CR. The present study concluded that WBLDCT with hybrid iterative reconstruction technique demonstrates superiority to CR with an identical radiation dose in the detection of bone lesions, skeletal fractures, vertebral compressions and extraskeletal findings, which results in up- or downstaging in 24% patients according to the IMWG criteria. The attenuation of osteolytic lesions can be measured with the avoidance of the partial volume effect.

Can the Equivalent Sphere Model Approximate Organ Doses in Space?

NASA Technical Reports Server (NTRS)

Lin, Zi-Wei

2007-01-01

For space radiation protection it is often useful to calculate dose or dose,equivalent in blood forming organs (BFO). It has been customary to use a 5cm equivalent sphere to. simulate the BFO dose. However, many previous studies have concluded that a 5cm sphere gives very different dose values from the exact BFO values. One study [1] . concludes that a 9 cm sphere is a reasonable approximation for BFO'doses in solar particle event environments. In this study we use a deterministic radiation transport [2] to investigate the reason behind these observations and to extend earlier studies. We take different space radiation environments, including seven galactic cosmic ray environments and six large solar particle events, and calculate the dose and dose equivalent in the skin, eyes and BFO using their thickness distribution functions from the CAM (Computerized Anatomical Man) model [3] The organ doses have been evaluated with a water or aluminum shielding of an areal density from 0 to 20 g/sq cm. We then compare with results from the equivalent sphere model and determine in which cases and at what radius parameters the equivalent sphere model is a reasonable approximation. Furthermore, we address why the equivalent sphere model is not a good approximation in some cases. For solar particle events, we find that the radius parameters for the organ dose equivalent increase significantly with the shielding thickness, and the model works marginally for BFO but is unacceptable for the eye or the skin. For galactic cosmic rays environments, the equivalent sphere model with an organ-specific constant radius parameter works well for the BFO dose equivalent, marginally well for the BFO dose and the dose equivalent of the eye or the skin, but is unacceptable for the dose of the eye or the skin. The ranges of the radius parameters are also being investigated, and the BFO radius parameters are found to be significantly, larger than 5 cm in all cases, consistent with the conclusion of an earlier study [I]. The radius parameters for the dose equivalent in GCR environments are approximately between 10 and I I cm for the BFO, 3.7 to 4.8 cm for the eye, and 3.5 to 5.6 cm for the skin; while the radius parameters are between 10 and 13 cm for the BFO dose.

Influence of sensitization on the discriminative stimulus effects of methylphenidate in mice.

PubMed

McGovern, Robin; Luderman, Lauryn; Knecht, Kelly; Griffin, William C

2014-12-01

Methylphenidate (MPH) remains an important therapy for attention-deficit hyperactivity disorder, but aspects of its pharmacology remain unclear. In the present study, we used a regimen of MPH (8 mg/kg daily×14 days) in C57BL/6J mice to determine whether establishing locomotor sensitization to MPH influenced the acquisition and the dose-response function of MPH in a classic drug discrimination procedure. MPH-sensitized mice (SENS group) showed enhanced locomotor activity to the 8 mg/kg exposure dose as well as a 2 mg/kg dose before discrimination training. However, the SENS mice did not acquire discrimination of either a low dose (2 mg/kg) or a higher dose (4 mg/kg) of MPH any more rapidly than the CTRL mice. Further, during generalization testing, the dose-response functions for the SENS and CTRL mice were identical. Therefore, we did not find that previous exposure to MPH, which produced a sensitized locomotor response, facilitated MPH discrimination.

Effects of neutron irradiation on optical and chemical properties of CR-39: Potential application in neutron dosimetry.

PubMed

Sahoo, G S; Paul, S; Tripathy, S P; Sharma, S C; Jena, S; Rout, S; Joshi, D S; Bandyopadhyay, T

2014-12-01

Effects of high-dose neutron irradiation on chemical and optical properties of CR-39 were studied using FTIR (Fourier Transform Infrared) and UV-vis (Ultraviolet-Visible) spectroscopy. The primary goal was to find a correlation between the neutron dose and the corresponding changes in the optical and chemical properties of CR-39 resulted from the neutron irradiation. The neutrons were produced by bombarding a thick Be target with 22-MeV protons. In the FTIR spectra, prominent absorbance peaks were observed at 1735cm(-1) (C=O stretching), 1230cm(-1)(C-O-C stretching), and 783cm(-1)(=C-H bending), the intensities of which decreased with increasing neutron dose. The optical absorbance in the visible range increased linearly with the neutron dose. Empirical relations were established to estimate neutron doses from these optical properties. This technique is particularly useful in measuring high doses, where track analysis with an optical microscope is difficult because of track overlapping. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of Mangosteen juice blend on biomarkers of inflammation in obese subjects: a pilot, dose finding study.

PubMed

Udani, Jay K; Singh, Betsy B; Barrett, Marilyn L; Singh, Vijay J

2009-10-20

The ability to reduce inflammation in overweight and obese individuals may be valuable in preventing the progression to metabolic syndrome with associated risks for heart disease and diabetes. The purpose of this study was to evaluate the effect of multiple dosages of a proprietary Mangosteen Juice blend on indicators of inflammation and antioxidant levels in obese patients with elevated C-reactive protein (CRP) levels. The study was an 8 week randomized, double-blind, placebo-controlled study with a pre-study 2 week washout period. The study included four groups including placebo and three difference doses of the test product, XanGo Juice: 3, 6 or 9 oz twice daily. The primary outcome measure of this study was high-sensitivity (HS)-CRP. Secondary outcome measures included other biochemical indicators of inflammation, anthropomorphic measures and a safety evaluation. One hundred twenty two (122) persons were screened for the study, 44 were randomized and 40 completed the study. HS-CRP measurements dropped after 8 weeks treatment compared to baseline in all 3 dose groups and increased in the placebo group. The changes from baseline were not significant but the comparison of change from baseline was significant for the 18 oz group when compared to placebo (p = 0.02). Other markers of inflammation (inflammatory cytokines) and a marker for lipid peroxidation (F2 isoprostane) did not show any significant differences when compared with placebo. There was a trend towards a decrease in BMI in the juice groups. There were no side effects reported in any of the groups and none of the laboratory or EKG safety assessments indicated clinically significant changes for any subject. In this pilot, dose-finding study, a proprietary mangosteen juice blend (XanGo Juice) reduced CRP levels (increased change from baseline) compared to placebo for those taking the highest dose of 18 oz per day. Further studies with a larger population are required to confirm and further define the benefits of this juice. The juice was administered safely. ISRCTN9300027.

Evaluation of Mangosteen juice blend on biomarkers of inflammation in obese subjects: a pilot, dose finding study

PubMed Central

Udani, Jay K; Singh, Betsy B; Barrett, Marilyn L; Singh, Vijay J

2009-01-01

Background The ability to reduce inflammation in overweight and obese individuals may be valuable in preventing the progression to metabolic syndrome with associated risks for heart disease and diabetes. The purpose of this study was to evaluate the effect of multiple dosages of a proprietary Mangosteen Juice blend on indicators of inflammation and antioxidant levels in obese patients with elevated C-reactive protein (CRP) levels. Methods The study was an 8 week randomized, double-blind, placebo-controlled study with a pre-study 2 week washout period. The study included four groups including placebo and three difference doses of the test product, XanGo Juice™: 3, 6 or 9 oz twice daily. The primary outcome measure of this study was high-sensitivity (HS)-CRP. Secondary outcome measures included other biochemical indicators of inflammation, anthropomorphic measures and a safety evaluation. Results One hundred twenty two (122) persons were screened for the study, 44 were randomized and 40 completed the study. HS-CRP measurements dropped after 8 weeks treatment compared to baseline in all 3 dose groups and increased in the placebo group. The changes from baseline were not significant but the comparison of change from baseline was significant for the 18 oz group when compared to placebo (p = 0.02). Other markers of inflammation (inflammatory cytokines) and a marker for lipid peroxidation (F2 isoprostane) did not show any significant differences when compared with placebo. There was a trend towards a decrease in BMI in the juice groups. There were no side effects reported in any of the groups and none of the laboratory or EKG safety assessments indicated clinically significant changes for any subject. Conclusion In this pilot, dose-finding study, a proprietary mangosteen juice blend (XanGo Juice™) reduced CRP levels (increased change from baseline) compared to placebo for those taking the highest dose of 18 oz per day. Further studies with a larger population are required to confirm and further define the benefits of this juice. The juice was administered safely. Trial Registration ISRCTN9300027 PMID:19843321

Leukemia and other cancers following radiation treatment of pelvic disease

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

Smith, P.G.

1977-04-01

Follow-up studies of patients treated for cancer of the cervix with radiotherapy have shown such women to be at little or no increased risk of leukemia subsequent to the radiation exposure. However, women exposed to lower doses of radiation in the pelvic area, in the induction of an artificial menopause, appear to show increased risks of both leukemia and cancers of those sites directly in the radiation field. The studies of these two types of radiation exposure are reviewed. The findings may possibly be reconciled with each other on the basis of the distribution of radiation dose to the bonemore » marrow. Irradiation for cancer of the cervix delivers radiation doses to a small portion of the marrow which are probably lethal for most marrow cells. The mean dose to cells distant from the cervix may be too small to produce a detectable increase in leukemia incidence. The lower and more uniformly distributed radiation dose used to induce an artificial menopause will be less lethal for marrow cells and may consequently deliver a higher ''effective'' marrow dose to surviving cells, resulting in an increased leukemia risk.« less

Toxicity of Single-dose Intramuscular Injection of Samjeong Pharmacopuncture in Sprague-Dawley Rats.

PubMed

Kwon, Kang; Kim, Chul-Yun; Kim, Nam-Kwen; Sun, Seung-Ho; Seo, Hyung-Sik

2015-06-01

This study was carried out in order to find both the single-dose intramuscular injection toxicity and the approximate lethal dose of samjeong pharmacopuncture (SP) in Sprague-Dawley (SD) rats. The SD rats in this study were divided into four groups, one control group (1.0 mL/animal, normal saline) and three experimental groups (0.25, 0.5, and 1.0 mL/animal, SP). All groups consisted of five male and five female rats. SP was injected as a single-dose intramuscularly at the thigh. After the injection, general symptoms and weight were observed for 14 days. After the observations had ended, hematologic and serum biochemical examinations, necropsy and a local tolerance test at the injection site were performed. The experiments were carried out at the Good Laboratory Practice firm, Biotoxtech Co. (Cheongwon, Chungbuk). Animal experiments were approved by the Ethics Committee (Approval Number: 130379). No deaths occurred in any of the three experimental groups. The injection of SP had no effects on the general symptoms, body weights, results of the hematologic, and serum biochemical examinations, and necropsy findings. In local tolerance tests at the injection sites, mild inflammation was observed in the experimental group, but it did not appear to be a treatment related effect. Under the conditions of this test, the results from the injection of SP suggest that the approximate lethal dose of SP is above 1.0 mL/animal for both male and female SD rats. Therefore, the clinical use of SP is thought to be safe.

Communicating and understanding the purpose of pediatric phase I cancer trials.

PubMed

Cousino, Melissa K; Zyzanski, Stephen J; Yamokoski, Amy D; Hazen, Rebecca A; Baker, Justin N; Noll, Robert B; Rheingold, Susan R; Geyer, J Russell; Alexander, Stewart C; Drotar, Dennis; Kodish, Eric D

2012-12-10

Quality informed consent should provide a clear understanding of the purpose of the research. Given the ethical challenges of pediatric phase I cancer trials, it is important to investigate physician-parent communication during informed consent conferences (ICCs) and parental understanding of the purpose of these studies. In the multisite Informed Consent in Pediatric Phase I Cancer Trials study, 85 ICCs for phase I research between June 2008 and May 2011 were directly observed, and 60 parents were subsequently interviewed. The scientific purpose was defined as composite understanding of drug safety, dose finding, and dose escalation. We determined the frequency with which physicians explained these and other phase I-related concepts during the ICC. Parent interviews were analyzed to determine understanding. The child was present at 83 of 85 ICCs. Only 32% of parents demonstrated substantial understanding of the scientific purpose of phase I cancer trials; 35% demonstrated little or no understanding. Parents of higher socioeconomic status and racial majority status were more likely to understand the scientific purpose. Factors associated with understanding included physician explanation of the goal of the applicable phase I protocol offered (explained in 85% of ICCs) and explanation of the dose cohorts (explained in 43% of ICCs). Physicians explained drug safety in 23% of ICCs, dose finding in 52% of ICCs, and dose escalation in 53% of ICCs. Many parents of children participating in phase I trials do not understand the purpose of these trials. Physician-parent communication about the purpose of phase I research is lacking during ICCs.

Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study.

PubMed

Fukudo, S; Hongo, M; Kaneko, H; Ueno, R

2011-06-01

Lubiprostone is a prostone analog with a novel mechanism of action involving type-2 chloride channel activation. The aim of this work was to perform a dose-finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo (n=42) or 16μg (n=41), 32μg (n=43), or 48μg (n=44) of lubiprostone daily for 2weeks. There was a statistically significant and dose-dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5±0.4; 16μg: 2.3±0.4, 32μg: 3.5±0.5; and 48μg: 6.8±1.1, per week, mean±SE; P<0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS (P<0.0001). The primary endpoint in patients with IBS treated with 48μg of lubiprostone was significantly better than those given placebo (P=0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose-dependent manner with a good safety profile and tolerability in a Japanese population. © 2011 Blackwell Publishing Ltd.

Performance of toxicity probability interval based designs in contrast to the continual reassessment method

PubMed Central

Horton, Bethany Jablonski; Wages, Nolan A.; Conaway, Mark R.

2016-01-01

Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for Phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both the mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. PMID:27435150

Low-dose priming before vaccination with the phase I chloroform-methanol residue vaccine against Q fever enhances humoral and cellular immune responses to Coxiella burnetii.

PubMed

Waag, David M; England, Marilyn J; Bolt, Christopher R; Williams, Jim C

2008-10-01

Although the phase I Coxiella burnetii cellular vaccine is completely efficacious in humans, adverse local and systemic reactions may develop if immune individuals are inadvertently vaccinated. The phase I chloroform-methanol residue (CMRI) vaccine was developed as a potentially safer alternative. Human volunteers with no evidence of previous exposure to C. burnetii received a subcutaneous vaccination with the CMRI vaccine in phase I studies under protocol IND 3516 to evaluate the safety and immunogenicity of the vaccine. This clinical trial tested escalating doses of the CMRI vaccine, ranging from 0.3 to 60 microg, followed by a booster dose of 30 microg, in a placebo-controlled study. Although priming doses of the CMRI vaccine did not induce a specific antibody detectable by enzyme-linked immunosorbent assay, booster vaccination stimulated the production of significant levels of anti-C. burnetii antibody. Peripheral blood cells (PBCs) of vaccinees responded to C. burnetii cellular antigen in vitro in a vaccine dose-dependent manner. After the booster dose, PBCs were activated by recall antigen in vitro, regardless of the priming dose. These findings suggest that vaccination with the CMRI vaccine can effectively prime the immune system to mount significant anamnestic responses after infection.

Low-Dose Priming before Vaccination with the Phase I Chloroform-Methanol Residue Vaccine against Q Fever Enhances Humoral and Cellular Immune Responses to Coxiella burnetii▿

PubMed Central

Waag, David M.; England, Marilyn J.; Bolt, Christopher R.; Williams, Jim C.

2008-01-01

Although the phase I Coxiella burnetii cellular vaccine is completely efficacious in humans, adverse local and systemic reactions may develop if immune individuals are inadvertently vaccinated. The phase I chloroform-methanol residue (CMRI) vaccine was developed as a potentially safer alternative. Human volunteers with no evidence of previous exposure to C. burnetii received a subcutaneous vaccination with the CMRI vaccine in phase I studies under protocol IND 3516 to evaluate the safety and immunogenicity of the vaccine. This clinical trial tested escalating doses of the CMRI vaccine, ranging from 0.3 to 60 μg, followed by a booster dose of 30 μg, in a placebo-controlled study. Although priming doses of the CMRI vaccine did not induce a specific antibody detectable by enzyme-linked immunosorbent assay, booster vaccination stimulated the production of significant levels of anti-C. burnetii antibody. Peripheral blood cells (PBCs) of vaccinees responded to C. burnetii cellular antigen in vitro in a vaccine dose-dependent manner. After the booster dose, PBCs were activated by recall antigen in vitro, regardless of the priming dose. These findings suggest that vaccination with the CMRI vaccine can effectively prime the immune system to mount significant anamnestic responses after infection. PMID:18701647

42 CFR 82.27 - How can claimants obtain reviews of their NIOSH dose reconstruction results by NIOSH?

Code of Federal Regulations, 2011 CFR

2011-10-01

... METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION... estimated in the completed dose reconstructions; or (2) NIOSH changes a scientific element underlying dose..., the methods employed in the review, and the review findings to the claimant, DOL, and DOE. ...

42 CFR 82.27 - How can claimants obtain reviews of their NIOSH dose reconstruction results by NIOSH?

Code of Federal Regulations, 2014 CFR

2014-10-01

... METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION... estimated in the completed dose reconstructions; or (2) NIOSH changes a scientific element underlying dose..., the methods employed in the review, and the review findings to the claimant, DOL, and DOE. ...

42 CFR 82.27 - How can claimants obtain reviews of their NIOSH dose reconstruction results by NIOSH?

Code of Federal Regulations, 2012 CFR

2012-10-01

... METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION... estimated in the completed dose reconstructions; or (2) NIOSH changes a scientific element underlying dose..., the methods employed in the review, and the review findings to the claimant, DOL, and DOE. ...

42 CFR 82.27 - How can claimants obtain reviews of their NIOSH dose reconstruction results by NIOSH?

Code of Federal Regulations, 2013 CFR

2013-10-01

... METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS COMPENSATION... estimated in the completed dose reconstructions; or (2) NIOSH changes a scientific element underlying dose..., the methods employed in the review, and the review findings to the claimant, DOL, and DOE. ...

A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

ClinicalTrials.gov

2017-07-24

Primary Myelofibrosis; Thrombocythemia, Essential; Thrombocytosis; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Blood Coagulation Disorders; Blood Platelet Disorders; Hemorrhagic Disorders

The effect of low larkspur (Delphinium spp.) co-administration on the acute toxicity of death camas (Zigadenus spp.) in sheep.

PubMed

Welch, K D; Green, B T; Gardner, D R; Stonecipher, C A; Panter, K E; Pfister, J A; Cook, D

2013-12-15

In most cases where livestock are poisoned by plants in a range setting, there is more than one potential poisonous plant in the same area. Two poisonous plants that are often found growing simultaneously in the same location are death camas (Zigadenus spp.) and low larkspur (Delphinium spp.). Sheep are known to be susceptible to death camas poisoning while they are thought to be resistant to larkspur. The objective of this study was to determine if co-administration of low larkspur would exacerbate the toxicity of death camas in sheep. A dose finding study was performed to find a dose of death camas that caused minimal clinical signs of poisoning. Sheep were observed for clinical signs of poisoning as well as changes in heart rate and muscle fatigue. Sheep dosed with 1.14 g of death camas per kg BW showed slight frothing and lethargy, whereas sheep dosed with death camas and low larkspur showed slightly more noticeable clinical signs of poisoning. Sheep dosed with only low larkspur, at 7.8 g/kg BW, showed no signs of poisoning. Although we observed a qualitative difference in clinical signs of intoxication in sheep co-treated with death camas and low larkspur we did not detect any quantitative differences in heart rate, exercise-induced muscle fatigue, or differences in serum zygacine kinetics. Consequently, the results from this study suggest that low larkspur does not affect the toxicity of death camas in sheep. The results from this study increase knowledge and understanding regarding the acute toxicity of death camas and low larkspur in sheep. As combined intoxications are most likely common, this information will be useful in further developing management recommendations for ranchers and in designing additional experiments to study the toxicity of death camas to other livestock species. Published by Elsevier Ltd.

Application of Adaptive Design Methodology in Development of a Long-Acting Glucagon-Like Peptide-1 Analog (Dulaglutide): Statistical Design and Simulations

PubMed Central

Skrivanek, Zachary; Berry, Scott; Berry, Don; Chien, Jenny; Geiger, Mary Jane; Anderson, James H.; Gaydos, Brenda

2012-01-01

Background Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus. Methods To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies. Results Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design). Conclusions This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm—including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design. PMID:23294775

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

PubMed

Lensen, Sarah F; Wilkinson, Jack; Leijdekkers, Jori A; La Marca, Antonio; Mol, Ben Willem J; Marjoribanks, Jane; Torrance, Helen; Broekmans, Frank J

2018-02-01

During a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper-response are associated with increased chance of cycle cancellation. Hyper-response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes. To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. We searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies. We included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm. We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration. We included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding.Direct dose comparisons in women according to predicted responseAll evidence was low or very low quality.Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy.Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I 2 = 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences.In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study).ORT-algorithm studiesFour trials compared an ORT-based algorithm to a non-ORT control group. Rates of live birth/ongoing pregnancy and clinical pregnancy did not appear to differ by more than a few percentage points (respectively: OR 1.04, 95% CI 0.88 to 1.23; N = 2823, 4 studies; I 2 = 34%; OR 0.96, 95% CI 0.82 to 1.13, 4 studies, I 2 =0%, moderate-quality evidence). However, ORT algorithms probably reduce the likelihood of moderate or severe OHSS (Peto OR 0.58, 95% CI 0.34 to 1.00; N = 2823; 4 studies; I 2 = 0%, low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.54, 95% CI 0.14 to 1.99; N = 1494; 3 studies; I 2 = 0%, low quality evidence). Our findings suggest that if the chance of live birth with a standard dose is 26%, the chance with ORT-based dosing would be between 24% and 30%. If the chance of moderate or severe OHSS with a standard dose is 2.5%, the chance with ORT-based dosing would be between 0.8% and 2.5%. These results should be treated cautiously due to heterogeneity in the study designs. We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT), influenced rates of live birth/ongoing pregnancy but we could not rule out differences, due to sample size limitations. In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS. Moderate-quality evidence suggests that ORT-based individualisation produces similar live birth/ongoing pregnancy rates to a policy of giving all women 150 IU. However, in all cases the confidence intervals are consistent with an increase or decrease in the rate of around five percentage points with ORT-based dosing (e.g. from 25% to 20% or 30%). Although small, a difference of this magnitude could be important to many women. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions in women with a predicted high response. However, the size of the effect is unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates, and many of the included studies had a serious risk of bias.Current evidence does not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders, especially as increased dose is generally associated with greater total FSH dose and therefore greater cost. However, a decreased dose in predicted high responders may reduce OHSS.

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials.

PubMed

Atri, Alireza; Frölich, Lutz; Ballard, Clive; Tariot, Pierre N; Molinuevo, José Luis; Boneva, Neli; Windfeld, Kristian; Raket, Lars L; Cummings, Jeffrey L

2018-01-09

New therapeutic approaches for Alzheimer disease (AD) are needed. To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

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.

A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.

PubMed

Siegel, Abby B; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J; Hansen, Ryan J; Gustafson, Daniel L; Flaig, Thomas W; Tsai, Wei Yann; Wu, David P H; Lee, Valerie; Greenlee, Heather

2014-01-01

To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis

PubMed Central

Borrmann, Steffen; Tékété, Mamadou; Lefèvre, Gilbert; Hamed, Kamal; Piola, Patrice; Ursing, Johan; Kofoed, Poul Erik; Mårtensson, Andreas; Ngasala, Billy; Björkman, Anders; Friberg Hietala, Sofia; Aweeka, Francesca; Parikh, Sunil; Mwai, Leah; Davis, Timothy M. E.; Karunajeewa, Harin; Newton, Paul N.; Mayxay, Mayfong; Deloron, Philippe; van Vugt, Michele; Karbwang, Juntra; Ezzet, Farkad; Bakshi, Rajesh; Stepniewska, Kasia; Barnes, Karen I.

2018-01-01

Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. Methods and findings A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15–25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Conclusions Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment. PMID:29894518

Dose reduction in whole-body computed tomography of multiple injuries (DoReMI): protocol for a prospective cohort study

PubMed Central

2014-01-01

Background Single-pass, contrast-enhanced whole body multidetector computed tomography (MDCT) emerged as the diagnostic standard for evaluating patients with major trauma. Modern iterative image algorithms showed high image quality at a much lower radiation dose in the non-trauma setting. This study aims at investigating whether the radiation dose can safely be reduced in trauma patients without compromising the diagnostic accuracy and image quality. Methods/Design Prospective observational study with two consecutive cohorts of patients. Setting: A high-volume, academic, supra-regional trauma centre in Germany. Study population: Consecutive male and female patients who 1. had been exposed to a high-velocity trauma mechanism, 2. present with clinical evidence or high suspicion of multiple trauma (predicted Injury Severity Score [ISS] ≥16) and 3. are scheduled for primary MDCT based on the decision of the trauma leader on call. Imaging protocols: In a before/after design, a consecutive series of 500 patients will undergo single-pass, whole-body 128-row multi-detector computed tomography (MDCT) with a standard, as low as possible radiation dose. This will be followed by a consecutive series of 500 patients undergoing an approved ultra-low dose MDCT protocol using an image processing algorithm. Data: Routine administrative data and electronic patient records, as well as digital images stored in a picture archiving and communications system will serve as the primary data source. The protocol was approved by the institutional review board. Main outcomes: (1) incidence of delayed diagnoses, (2) diagnostic accuracy, as correlated to the reference standard of a synopsis of all subsequent clinical, imaging, surgical and autopsy findings, (3) patients’ safety, (4) radiation exposure (e.g. effective dose), (5) subjective image quality (assessed independently radiologists and trauma surgeons on a 100-mm visual analogue scale), (6) objective image quality (e.g., contrast-to-noise ratio). Analysis: Multivariate regression will be employed to adjust and correct the findings for time and cohort effects. An exploratory interim analysis halfway after introduction of low-dose MDCT will be conducted to assess whether this protocol is clearly inferior or superior to the current standard. Discussion Although non-experimental, this study will generate first large-scale data on the utility of imaging-enhancing algorithms in whole-body MDCT for major blunt trauma. Trial registration Current Controlled Trials ISRCTN74557102. PMID:24589310

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

PubMed

Coritsidis, George N; Maglinte, Gregory A; Acharya, Anjali; Saxena, Anjali; Chang, Chun-Lan; Hill, Jerrold; Gitlin, Matthew; Lafayette, Richard A

2014-03-01

Few data have been reported on anemia management practices in hospital-based dialysis centers (HBDCs), which are uniquely different from other freestanding dialysis centers. Examining data from HBDCs would help determine if HBDCs and the general US dialysis population have similar trends related to how anemia is managed in dialysis patients. Given recent changes in the prescribing information of erythropoiesis-stimulating agents (ESAs) and in end-stage renal disease-related health policy and reimbursement, this study describes trends in anemia management practices in HBDCs from January 2010 through March 2013. Electronic medical records of 5404 adult hemodialysis patients in 50 US-based HBDCs were analyzed retrospectively. Patients included in the study cohort were aged ≥18 years and had at least 1 hemoglobin (Hb) measurement and 1 dose of an ESA between January 2010 and March 2013. End points included Hb concentration, darbepoetin alfa dosing, epoetin alfa dosing, and iron biomarkers (transferrin saturation and ferritin) and dosing. From 2010 to 2013, mean monthly Hb levels declined from 11.4 to 10.7 g/dL; the percentage of patients with mean monthly Hb levels <10 g/dL increased from 11.3% to 24.4%; and the percentage of patients with mean monthly Hb levels >12 g/dL declined from 30.1% to 11.2%. The median darbepoetin alfa cumulative 4-week dose also declined 38.8%, and the weekly epoetin alfa dose declined 24%. From January 2010 to March 2013, the percentage of patients with transferrin saturation >30% increased from 35.8% to 43.6%, the percentage of patients with ferritin levels >500 ng/mL increased from 62.0% to 77.9%, the percentage of patients with ferritin levels ≥800 ng/mL increased from 28.9% to 47.3%, and the median cumulative 4-week intravenous iron dose increased 50%. These study results support growing evidence that meaningful changes have occurred over the last 3 years in how anemia is clinically managed in US hemodialysis patients. Study limitations include that changes in patient clinical/demographic characteristics over time were not controlled for and that study findings may not be applicable to HBDCs that have different patient populations and/or do not use an electronic medical record system. Continuing to evaluate anemia management practices in HBDCs would provide additional information on the risks and benefits of anemia care. Consistent with national data, the findings from this study indicate that from 2010 to 2013, HBDCs modified anemia management practices for dialysis patients, as evidenced by reductions in mean monthly Hb levels and ESA dosing and by increases in iron biomarkers and dosing. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study

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

Roach, Mack; Winter, Kathryn; Michalski, Jeffrey M.

2004-12-01

Purpose: To assess the relationship between the dose to the bulb of the penis and the risk of impotence in men treated on Radiation Therapy Oncology Group (RTOG) 9406. Methods and materials: Men enrolled on a Phase I/II dose-escalation study, RTOG 9406, who were reported to be potent at entry and evaluable (n = 158) were selected for inclusion. Follow-up evaluations were scheduled every 3, 4, and 6 months for the first, second, and the third through fifth years, then annually. At each follow-up visit an assessment of potency status was made. Penile structures were defined by a single observermore » blinded to the potency status, using Web-based, on-line software. The dosimetry for penile structures was calculated at the Quality Assurance Center at Washington University and provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. Results: Patients whose median penile dose was {>=}52.5 Gy had a greater risk of impotence compared with those receiving <52.5 Gy (p = 0.039). In a multivariate analysis neither age, the dose to the prostate, nor the use of hormonal therapy correlated with the risk of impotence. Conclusions: Dose to the bulb of the penis seems to be associated with the risk of radiation-induced impotence.« less

Study of crosslinking onset and hydrogen annealing of ultra-high molecular weight polyethylene irradiated with high-energy protons

NASA Astrophysics Data System (ADS)

Wilson, John Ford

1997-09-01

Ultra high molecular weight polyethylene (UHMW-PE) is used extensively in hip and knee endoprostheses. Radiation damage from the sterilization of these endoprostheses prior to surgical insertion results in polymer crosslinking and decreased oxidative stability. The motivation for this study was to determine if UHMW-PE could be crosslinked by low dose proton irradiation with minimal radiation damage and its subsequent deleterious effects. I found that low dose proton irradiation and post irradiation hydrogen annealing did crosslink UHMW-PE and limit post irradiation oxidation. Crosslinking onset was investigated for UHMW-PE irradiated with 2.6 and 30 MeV H+ ions at low doses from 5.7 × 1011-2.3 × 1014 ions/cm2. Crosslinking was determined from gel permeation chromatography (GPC) of 1,2,4 trichlorobenzene sol fractions and increased with dose. Fourier transform infrared spectroscopy (FTIR) showed irradiation resulted in increased free radicals confirmed from increased carbonyl groups. Radiation damage, especially at the highest doses observed, also showed up in carbon double bonds and increased methyl end groups. Hydrogen annealing after ion irradiation resulted in 40- 50% decrease in FTIR absorption associated with carbonyl. The hydrogen annealing prevented further oxidation after aging for 1024 hours at 80oC. Hydrogen annealing was successful in healing radiation damage through reacting with the free radicals generated during proton irradiation. Polyethylenes, polyesters, and polyamides are used in diverse applications by the medical profession in the treatment of orthopedic impairments and cardiovascular disease and for neural implants. These artificial implants are sterilized with gamma irradiation prior to surgery and the resulting radiation damage can lead to accelerated deterioration of the implant properties. The findings in this study will greatly impact the continued use of these materials through the elimination of many problems associated with radiation damage from sterilization. The higher energy transfer for proton compared to gamma irradiation greatly accelerated the radiation damage. Radiation damage increased linearly with dose over the range of doses examined. These results were consistent with findings from earlier researchers of gamma irradiation of polyethylene.

Patient doses from CT examinations in Turkey.

PubMed

Ataç, Gökçe Kaan; Parmaksız, Aydın; İnal, Tolga; Bulur, Emine; Bulgurlu, Figen; Öncü, Tolga; Gündoğdu, Sadi

2015-01-01

We aimed to establish the first diagnostic reference levels (DRLs) for computed tomography (CT) examinations in adult and pediatric patients in Turkey and compare these with international DRLs. CT performance information and examination parameters (for head, chest, high-resolution CT of the chest [HRCT-chest], abdominal, and pelvic protocols) from 1607 hospitals were collected via a survey. Dose length products and effective doses for standard patient sizes were calculated from the reported volume CT dose index (CTDIvol). The median number of protocols reported from the 167 responding hospitals (10% response rate) was 102 across five different age groups. Third quartile CTDIvol values for adult pelvic and all pediatric body protocols were higher than the European Commission standards but were comparable to studies conducted in other countries. The radiation dose indicators for adult patients were similar to those reported in the literature, except for those associated with head protocols. CT protocol optimization is necessary for adult head and pediatric chest, HRCT-chest, abdominal, and pelvic protocols. The findings from this study are recommended for use as national DRLs in Turkey.

Correlation of Noncancer Benchmark Doses in Short- and Long-Term Rodent Bioassays.

PubMed

Kratchman, Jessica; Wang, Bing; Fox, John; Gray, George

2018-05-01

This study investigated whether, in the absence of chronic noncancer toxicity data, short-term noncancer toxicity data can be used to predict chronic toxicity effect levels by focusing on the dose-response relationship instead of a critical effect. Data from National Toxicology Program (NTP) technical reports have been extracted and modeled using the Environmental Protection Agency's Benchmark Dose Software. Best-fit, minimum benchmark dose (BMD), and benchmark dose lower limits (BMDLs) have been modeled for all NTP pathologist identified significant nonneoplastic lesions, final mean body weight, and mean organ weight of 41 chemicals tested by NTP between 2000 and 2012. Models were then developed at the chemical level using orthogonal regression techniques to predict chronic (two years) noncancer health effect levels using the results of the short-term (three months) toxicity data. The findings indicate that short-term animal studies may reasonably provide a quantitative estimate of a chronic BMD or BMDL. This can allow for faster development of human health toxicity values for risk assessment for chemicals that lack chronic toxicity data. © 2017 Society for Risk Analysis.

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) balance in developmental outcomes.

PubMed

Colombo, John; Jill Shaddy, D; Kerling, Elizabeth H; Gustafson, Kathleen M; Carlson, Susan E

2017-06-01

The DHA Intake and Measurement of Neural Development (DIAMOND) trial represents one of only a few studies of the long-term dose-response effects of LCPUFA-supplemented formula feeding during infancy. The trial contrasted the effects of four formulations: 0.00% docosahexaenoic acid (DHA)/0.00% arachidonic acid (ARA), 0.32% DHA/0.64% ARA, 0.64% DHA/0.64% ARA, and 0.96% DHA/0.64% ARA against a control condition (0.00% DHA/0.00% ARA). The results of this trial have been published elsewhere, and show improved cognitive outcomes for infants fed supplemented formulas, but a common finding among many of the outcomes show a reduction of benefit for the highest DHA dose (i.e., 0.96%DHA/0.64% ARA, that is, a DHA: ARA ratio 1.5:1.0). The current paper gathers and summarizes the evidence for the reduction of benefit at this dose, and in an attempt to account for this reduced benefit, presents for the first time data from infants' red blood cell (RBC) assays taken at 4 and 12 months of age. Those assays indicate that blood DHA levels generally rose with increased DHA supplementation, although those levels tended to plateau as the DHA-supplemented level exceeded 0.64%. Perhaps more importantly, ARA levels showed a strong inverted-U function in response to increased DHA supplementation; indeed, infants assigned to the formula with the highest dose of DHA (and highest DHA/ARA ratio) showed a reduction in blood ARA relative to more intermediate DHA doses. This finding raises the possibility that reduced ARA may be responsible for the reduction in benefit on cognitive outcomes seen at this dose. The findings implicate the DHA/ARA balance as an important variable in the contribution of LCPUFAs to cognitive and behavioral development in infancy. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

PubMed Central

Azman, Andrew S.; Luquero, Francisco J.; Ciglenecki, Iza; Grais, Rebecca F.; Sack, David A.; Lessler, Justin

2015-01-01

Background In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. Methods and Findings Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%–88%) for two doses and 44% (95% CI −27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%–88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943–86,205) cases in Zimbabwe, 78,317 (95% PI 57,435–100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490–3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture uncertainty due to imperfect surveillance data and uncertainty about the transmission dynamics of cholera in each setting. Conclusions Reactive vaccination campaigns using a single dose of OCV may avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited, while at the same time reducing logistical complexity. These findings should motivate consideration of the trade-offs between one- and two-dose campaigns in resource-constrained settings, though further field efficacy data are needed and should be a priority in any one-dose campaign. PMID:26305226

General 4-week toxicity study with EMS in the rat.

PubMed

Pfister, Thomas; Eichinger-Chapelon, Anne

2009-11-12

In this subacute toxicity study, ethyl methanesulfonate (EMS) was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 20, 60 and 180/120 mg/kg body weight (bw)/day for a period of 28 days (for 19 days in the high-dose group). A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 10 animals per sex, which were sacrificed after 28 days, respectively 19 days in the high-dose group, of treatment. Additional five rats per sex and group were treated accordingly and then allowed a 14 days treatment-free recovery period. Additional six rats per sex and group (three rats per sex in the control group) were treated accordingly and used for hemoglobin adduct analysis after EMS exposure. All animals survived until their scheduled necropsy. Treatment with EMS had a direct dose-dependent effect on food consumption and consequently on body weight at doses > or =20mg/kgbw/day in male rats and at > or =60 mg/kgbw/day in females rats. Hence, treatment with the high dose of 180 mg/kgbw/day had to be interrupted for 9 days after which, the animals were re-dosed at 120 mg/kgbw/day. This dose was also poorly tolerated over the remaining two treatment weeks causing again a marked reduction in food consumption and body weight. A dose of 60 mg/kgbw/day was moderately tolerated over 4 weeks treatment with mean daily food consumption and body weight distinctly lower than in controls. Primary targets of systemic toxicity were the hematopoietic system, thymolymphatic system and sexual organs. Characteristic changes in hematology parameters were decreased red blood cell counts, hematocrit, and hemoglobin concentration. White blood cell counts were also decreased due to reduced lymphocyte and granulocyte populations of each fraction. The corresponding histopathology findings were fatty atrophy of bone marrow and minimal hypocellularity of the white pulp of the spleen. Similarly, treatment with EMS caused an involution of the thymolymphatic system characterized by decreased organ weight of thymus, lymph nodes, and spleen microscopically associated with atrophy of the thymus and hypocellularity of Peyer's patches, lymph nodes and the white pulp of the spleen. The effects on sexual organs included lower organ weight/reduced size for testes, epididymides, seminal vesicles, prostate, and uterus. Tubular atrophy, single cell necrosis of the germ cells and in epididymides reduced spermatozoa were recorded microscopically. The described findings occurred at doses of 60 and 180/120 mg/kgbw/day and were dose-dependent with regard to incidence and severity. Other target organs were the pancreas (acinar cell vacuolation), thyroid gland (follicular cell hypertrophy), and salivary gland (secretory depletion of convoluted ducts). The systemic exposure to EMS was monitored by hemoglobin ethylvaline adduct measurement. The concentration of hemoglobin ethylvaline adducts was linear with the dose and accumulated 11-26-fold over the treatment period. In summary, decreases in food consumption and body weight were the dose-limiting effects of treatment with EMS. Organ toxicity was characterized by depression of cell proliferation (hematopoiesis and spermatogenesis) and changes suggestive of reduced metabolism and/or physiological imbalances (e.g. thymolymphatic system and thyroid gland) without signs of inflammatory or necrotic lesions. For some findings, especially the effects on the thymolymphatic system and sexual organs, it cannot be excluded that starvation-like condition contributed to the occurrence of such changes. The low dose of 20 mg/kgbw/day was basically free of adverse effects despite of a clear evidence for hemoglobin adducts.

Are Ecstasy Induced Serotonergic Alterations Overestimated For The Majority Of Users?

PubMed

Szigeti, Balázs; Winstock, Adam R; Erritzoe, David; Maier, Larissa J

2018-05-01

Neuroimaging studies imply that the regular use of ±3,4-methylenedioxymethamphetamine (MDMA), the major constituent of ecstasy pills, alters the brain's serotonergic system in a dose-dependent manner. However, the relevance of these findings remains unclear due to limited knowledge about the ecstasy/MDMA use pattern of real-life users. We examined the representativeness of ecstasy users enrolled in neuroimaging studies by comparing their ecstasy use habits with the use patterns of a large, international sample. A systematic literature search revealed 10 imaging studies that compare serotonin transporter levels in recreational ecstasy users to matched controls. To characterize the ecstasy use patterns we relied on the Global Drug Survey, the world's largest self-report database on drug use. The basis of the dose comparison were the Usual Amount (pills/session), Use Frequency (sessions/month) and Dose Intensity (pills/year) variables. Both the average Usual Amount (pills/session) and Use Frequency (sessions/month) of neuroimaging study participants corresponded to the top 5-10% of the Global Drug Survey sample and imaging participants, on average, consumed 720% more pills over a year than the Global Drug Survey participants. Our findings suggest that the serotonin brain imaging literature has focused on unusually heavy ecstasy use and therefore the conclusions from these studies are likely to overestimate the extent of serotonergic alterations experienced by the majority of people who use ecstays.

Towards tracer dose reduction in PET studies: Simulation of dose reduction by retrospective randomized undersampling of list-mode data.

PubMed

Gatidis, Sergios; Würslin, Christian; Seith, Ferdinand; Schäfer, Jürgen F; la Fougère, Christian; Nikolaou, Konstantin; Schwenzer, Nina F; Schmidt, Holger

2016-01-01

Optimization of tracer dose regimes in positron emission tomography (PET) imaging is a trade-off between diagnostic image quality and radiation exposure. The challenge lies in defining minimal tracer doses that still result in sufficient diagnostic image quality. In order to find such minimal doses, it would be useful to simulate tracer dose reduction as this would enable to study the effects of tracer dose reduction on image quality in single patients without repeated injections of different amounts of tracer. The aim of our study was to introduce and validate a method for simulation of low-dose PET images enabling direct comparison of different tracer doses in single patients and under constant influencing factors. (18)F-fluoride PET data were acquired on a combined PET/magnetic resonance imaging (MRI) scanner. PET data were stored together with the temporal information of the occurrence of single events (list-mode format). A predefined proportion of PET events were then randomly deleted resulting in undersampled PET data. These data sets were subsequently reconstructed resulting in simulated low-dose PET images (retrospective undersampling of list-mode data). This approach was validated in phantom experiments by visual inspection and by comparison of PET quality metrics contrast recovery coefficient (CRC), background-variability (BV) and signal-to-noise ratio (SNR) of measured and simulated PET images for different activity concentrations. In addition, reduced-dose PET images of a clinical (18)F-FDG PET dataset were simulated using the proposed approach. (18)F-PET image quality degraded with decreasing activity concentrations with comparable visual image characteristics in measured and in corresponding simulated PET images. This result was confirmed by quantification of image quality metrics. CRC, SNR and BV showed concordant behavior with decreasing activity concentrations for measured and for corresponding simulated PET images. Simulation of dose-reduced datasets based on clinical (18)F-FDG PET data demonstrated the clinical applicability of the proposed data. Simulation of PET tracer dose reduction is possible with retrospective undersampling of list-mode data. Resulting simulated low-dose images have equivalent characteristics with PET images actually measured at lower doses and can be used to derive optimal tracer dose regimes.

Quantifying annual internal effective 137Cesium dose utilizing direct body-burden measurement and ecological dose modeling.

PubMed

Jelin, Benjamin A; Sun, Wenjie; Kravets, Alexandra; Naboka, Maryna; Stepanova, Eugenia I; Vdovenko, Vitaliy Y; Karmaus, Wilfried J; Lichosherstov, Alex; Svendsen, Erik R

2016-11-01

The Chernobyl Nuclear Power Plant (CNPP) accident represents one of the most significant civilian releases of 137 Cesium ( 137 Cs, radiocesium) in human history. In the Chernobyl-affected region, radiocesium is considered to be the greatest on-going environmental hazard to human health by radiobiologists and public health scientists. The goal of this study was to characterize dosimetric patterns and predictive factors for whole-body count (WBC)-derived radiocesium internal dose estimations in a CNPP-affected children's cohort, and cross-validate these estimations with a soil-based ecological dose estimation model. WBC data were used to estimate the internal effective dose using the International Commission on Radiological Protection (ICRP) 67 dose conversion coefficient for 137 Cs and MONDAL Version 3.01 software. Geometric mean dose estimates from each model were compared utilizing paired t-tests and intra-class correlation coefficients. Additionally, we developed predictive models for WBC-derived dose estimation in order to determine the appropriateness of EMARC to estimate dose for this population. The two WBC-derived dose predictive models identified 137 Cs soil concentration (P<0.0001) as the strongest predictor of annual internal effective dose from radiocesium validating the use of the soil-based EMARC model. The geometric mean internal effective dose estimate of the EMARC model (0.183 mSv/y) was the highest followed by the ICRP 67 dose estimates (0.165 mSv/y) and the MONDAL model estimates (0.149 mSv/y). All three models yielded significantly different geometric mean dose (P<0.05) estimates for this cohort when stratified by sex, age at time of exam and season of exam, except for the mean MONDAL and EMARC estimates for 15- and 16-year olds and mean ICRP and MONDAL estimates for children examined in Winter. Further prospective and retrospective radio-epidemiological studies utilizing refined WBC measurements and ecological model dose estimations, in conjunction with findings from animal toxicological studies, should help elucidate possible deterministic radiogenic health effects associated with chronic low-dose internal exposure to 137 Cs.

Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147), a Pan-Class I PI3K Inhibitor, in Combination With Erlotinib in Patients With Solid Tumors

PubMed Central

LoRusso, Patricia; Bahleda, Ratislav; Lager, Joanne; Liu, Li; Jiang, Jason; Martini, Jean-François; Macé, Sandrine; Burris, Howard

2015-01-01

Background. This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. Methods. In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50–600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. Results. Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. Conclusion. Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors. PMID:25669662

Mu Opioid Mediated Discriminative-Stimulus Effects of Tramadol: An Individual Subjects Analysis

PubMed Central

Strickland, Justin C.; Rush, Craig R.; Stoops, William W.

2015-01-01

Drug discrimination procedures use dose-dependent generalization, substitution, and pretreatment with selective agonists and antagonists to evaluate receptor systems mediating interoceptive effects of drugs. Despite the extensive use of these techniques in the nonhuman animal literature, few studies have used human subjects. Specifically, human studies have not routinely used antagonist administration as a pharmacological tool to elucidate the mechanisms mediating the discriminative stimulus effects of drugs. This study evaluated the discriminative-stimulus effects of tramadol, an atypical analgesic with monoamine and mu opioid activity. Three human subjects first learned to discriminate 100 mg tramadol from placebo. A range of tramadol doses (25 to 150 mg) and hydromorphone (4 mg) with and without naltrexone pretreatment (50 mg) were then administered to subjects after acquiring the discrimination. Tramadol produced dose-dependent increases in drug-appropriate responding and hydromorphone partially or fully substituted for tramadol in all subjects. These effects were attenuated by naltrexone. Individual subject records indicated a relationship between mu opioid activity (i.e., miosis) and drug discrimination performance. Our findings indicate that mu opioid activity may mediate the discriminative-stimulus effects of tramadol in humans. The correspondence of generalization, substitution, and pretreatment findings with the animal literature supports the neuropharmacological specificity of the drug discrimination procedure. PMID:25664525

Prostaglandin E2 Prevents Ovariectomy-Induced Cancellous Bone Loss in Rats

NASA Technical Reports Server (NTRS)

Ke, Hua Zhu; Li, Mei; Jee, Webster S. S.

1992-01-01

The object of this study was to determine whether prostaglandin E2, (PGE2) can prevent ovariectomy induced cancellous bone loss. Thirty-five 3-month-old female Sprague-Dawley rats were divided into two groups. The rats in the first group were ovariectomized (OVX) while the others received sham operation (sham-OVX). The OVX group was further divided into three treatment groups. The daily doses for the three groups were 0,1 and 6 mg PGE2/kg for 90 days. Bone histomorphometric analyses were performed on double-fluorescent-labeled undecalcified proximal tibial metaphysis (PTM). We confirmed that OVX induces massive cancellous bone loss (-80%) and a higher bone turnover (+143%). The new findings from the present study demonstrate that bone loss due to ovarian hormone deficiency can be prevented by a low-dose (1 mg) daily administration of PGE2. Furthermore, a higher-dose (6 mg) daily administration of PGE2 not only prevents bone loss but also adds extra bone to the proximal tibial metaphyses. PGE, at the 1-mg dose level significantly increased trabecular bone area, trabecular width, trabecular node density, density of node to node, ratio of node to free end, and thus significantly decreased trabecular separation from OVX controls. At this dose level, these same parameters did not differ significantly from sham-OVX controls. However, at the 6-mg dose level PGE2, there were significant increases in trabecular bone area, trabecular width, trabecular node density, density of node to node, and ratio of node to free end, while there was significant decrease in trabecular separation from both OVX and sham-operated controls. The changes in indices of trabecular bone microanatomical structure indicated that PGE2 prevented bone loss as well as the disconnection of existing trabeculae. In summary, PGE2, administration to OVX rats decreased bone turnover and increased bone formation parameters resulting in a positive bone balance that prevented bone loss (in both lower and higher doses) and added extra bone to metaphyses of OVX rats (in higher dose). These findings support the strategy of the use of bone stimulation agents in the prevention of estrogen depletion bone loss (postmenopausal osteoporosis).

A Phase I/II adaptive design for heterogeneous groups with application to a stereotactic body radiation therapy trial.

PubMed

Wages, Nolan A; Read, Paul W; Petroni, Gina R

2015-01-01

Dose-finding studies that aim to evaluate the safety of single agents are becoming less common, and advances in clinical research have complicated the paradigm of dose finding in oncology. A class of more complex problems, such as targeted agents, combination therapies and stratification of patients by clinical or genetic characteristics, has created the need to adapt early-phase trial design to the specific type of drug being investigated and the corresponding endpoints. In this article, we describe the implementation of an adaptive design based on a continual reassessment method for heterogeneous groups, modified to coincide with the objectives of a Phase I/II trial of stereotactic body radiation therapy in patients with painful osseous metastatic disease. Operating characteristics of the Institutional Review Board approved design are demonstrated under various possible true scenarios via simulation studies. Copyright © 2015 John Wiley & Sons, Ltd.

Dose-mass inverse optimization for minimally moving thoracic lesions

NASA Astrophysics Data System (ADS)

Mihaylov, I. B.; Moros, E. G.

2015-05-01

In the past decade, several different radiotherapy treatment plan evaluation and optimization schemes have been proposed as viable approaches, aiming for dose escalation or an increase of healthy tissue sparing. In particular, it has been argued that dose-mass plan evaluation and treatment plan optimization might be viable alternatives to the standard of care, which is realized through dose-volume evaluation and optimization. The purpose of this investigation is to apply dose-mass optimization to a cohort of lung cancer patients and compare the achievable healthy tissue sparing to that one achievable through dose-volume optimization. Fourteen non-small cell lung cancer (NSCLC) patient plans were studied retrospectively. The range of tumor motion was less than 0.5 cm and motion management in the treatment planning process was not considered. For each case, dose-volume (DV)-based and dose-mass (DM)-based optimization was performed. Nine-field step-and-shoot IMRT was used, with all of the optimization parameters kept the same between DV and DM optimizations. Commonly used dosimetric indices (DIs) such as dose to 1% the spinal cord volume, dose to 50% of the esophageal volume, and doses to 20 and 30% of healthy lung volumes were used for cross-comparison. Similarly, mass-based indices (MIs), such as doses to 20 and 30% of healthy lung masses, 1% of spinal cord mass, and 33% of heart mass, were also tallied. Statistical equivalence tests were performed to quantify the findings for the entire patient cohort. Both DV and DM plans for each case were normalized such that 95% of the planning target volume received the prescribed dose. DM optimization resulted in more organs at risk (OAR) sparing than DV optimization. The average sparing of cord, heart, and esophagus was 23, 4, and 6%, respectively. For the majority of the DIs, DM optimization resulted in lower lung doses. On average, the doses to 20 and 30% of healthy lung were lower by approximately 3 and 4%, whereas lung volumes receiving 2000 and 3000 cGy were lower by 3 and 2%, respectively. The behavior of MIs was very similar. The statistical analyses of the results again indicated better healthy anatomical structure sparing with DM optimization. The presented findings indicate that dose-mass-based optimization results in statistically significant OAR sparing as compared to dose-volume-based optimization for NSCLC. However, the sparing is case-dependent and it is not observed for all tallied dosimetric endpoints.

Re-evaluation of the reward comparison hypothesis for alcohol abuse.

PubMed

He, Alan Bo-Han; Chang, Yu-Chieh; Meng, Anna Wan Yun; Huang, Andrew Chih Wei

2017-08-14

This study examined whether various doses of ethanol induced reward or aversion and then evaluated Grigson's reward comparison hypothesis (1997). Rats were given a 0.1% saccharin solution (conditioned stimulus 1 [CS1]) 15min prior to administration of a 0, 0.05, 0.125, 0.20, 0.35, or 0.50g/kg dose of ethanol (unconditioned stimulus [US]). The rats were then exposed to a paired compartment (CS2) for 30min. The low dose of 0.05g/kg ethanol did not induce conditioned suppression (i.e., conditioned taste aversion [CTA]) or conditioned place preference (CPP). The dose of 0.125g/kg ethanol induced CPP but not CTA. High doses of ethanol, including 0.35g/kg and 0.50g/kg, produced CTA but not CPP. The middle dose of 0.20g/kg ethanol simultaneously induced CTA and CPP. As a result, the reward comparison hypothesis cannot explain the present finding that the middle dose of ethanol induced CTA and CPP. Meanwhile, the high doses of ethanol induced motivationally aversive CTA but not rewarding CPP. The reward comparison hypothesis should be updated further. Copyright © 2017 Elsevier B.V. All rights reserved.

Dose of rocuronium for rapid tracheal intubation following remifentanil 2 μg kg-1 and propofol 2 mg kg-1.

PubMed

Oh, Ah-Young; Cho, Suk-Ju; Seo, Kwang-Suk; Ryu, Jung-Hee; Han, Sung-Hee; Hwang, Jung-Won

2013-09-01

Full relaxation is not mandatory for successful tracheal intubation. We tried to find the dose of rocuronium that gave acceptable intubation conditions in a rapid sequence intubation with remifentanil and propofol. A dose-finding study of rocuronium using a modified Dixon's up-and-down method. A single tertiary care teaching hospital. Patients undergoing elective surgery under general anaesthesia. After premedication with midazolam and glycopyrrolate, anaesthesia was induced using remifentanil 2 μg kg and propofol 2 mg kg, and a predetermined dose of rocuronium was administered. The dose of rocuronium was determined by a modified Dixon's up-and-down method starting from 0.8 mg kg with an interval of 0.1 or 0.05 mg kg. Intubation was performed 60 s after the start of the rocuronium injection. Intubation conditions were graded as excellent, good or poor. Excellent or good were regarded as clinically acceptable. A dose of rocuronium needed for acceptable intubation condition in 50% of patients (ED50) during rapid tracheal intubation after induction of anaesthesia with remifentanil and propofol. Twenty-eight patients were enrolled to obtain six crossovers. The ED50 of rocuronium was 0.20 mg kg (95% confidence interval, CI 0.17 to 0.23 mg kg) by a modified Dixon's up-and-down method. After induction of anaesthesia with remifentanil 2 μg kg and propofol 2 mg kg, the ED50 of rocuronium for acceptable intubation condition was 0.20 mg kg (95% CI, 0.17 to 0.23 mg kg) for rapid sequence intubation. Thus, we recommend that the intubation dose should be 0.8 mg kg. Clinical trial registration KCT0000094.

Study of antioxidative effects and anti-inflammatory effects in mice due to low-dose X-irradiation or radon inhalation

PubMed Central

Kataoka, Takahiro

2013-01-01

Low-dose irradiation induces various stimulating effects, especially activation of the biological defense system including antioxidative and immune functions. Oxidative stress induced by reactive oxygen species (ROS) can cause cell damage and death and can induce many types of diseases. This paper reviews new insights into inhibition of ROS-related diseases with low-dose irradiation or radon inhalation. X-irradiation (0.5 Gy) before or after carbon tetrachloride (CCl4) treatment inhibits hepatopathy in mice. X-irradiation (0.5 Gy) before ischemia-reperfusion injury or cold-induced brain injury also inhibits edema. These findings suggest that low-dose X-irradiation has antioxidative effects due to blocking the damage induced by free radicals or ROS. Moreover, radon inhalation increases superoxide dismutase activity in many organs and inhibits CCl4-induced hepatic and renal damage and streptozotocin-induced type I diabetes. These findings suggest that radon inhalation also has antioxidative effects. This antioxidative effect against CCl4-induced hepatopathy is comparable to treatment with ascorbic acid (vitamin C) at a dose of 500 mg/kg weight, or α-tocopherol (vitamin E) treatment at a dose of 300 mg/kg weight, and is due to activation of antioxidative functions. In addition, radon inhalation inhibits carrageenan-induced inflammatory paw edema, suggesting that radon inhalation has anti-inflammatory effects. Furthermore, radon inhalation inhibits formalin-induced inflammatory pain and chronic constriction injury-induced neuropathic pain, suggesting that radon inhalation relieves pain. Thus, low-dose irradiation very likely activates the defense systems in the body, and therefore, contributes to preventing or reducing ROS-related injuries, which are thought to involve peroxidation. PMID:23420683

Study of antioxidative effects and anti-inflammatory effects in mice due to low-dose X-irradiation or radon inhalation.

PubMed

Kataoka, Takahiro

2013-07-01

Low-dose irradiation induces various stimulating effects, especially activation of the biological defense system including antioxidative and immune functions. Oxidative stress induced by reactive oxygen species (ROS) can cause cell damage and death and can induce many types of diseases. This paper reviews new insights into inhibition of ROS-related diseases with low-dose irradiation or radon inhalation. X-irradiation (0.5 Gy) before or after carbon tetrachloride (CCl4) treatment inhibits hepatopathy in mice. X-irradiation (0.5 Gy) before ischemia-reperfusion injury or cold-induced brain injury also inhibits edema. These findings suggest that low-dose X-irradiation has antioxidative effects due to blocking the damage induced by free radicals or ROS. Moreover, radon inhalation increases superoxide dismutase activity in many organs and inhibits CCl4-induced hepatic and renal damage and streptozotocin-induced type I diabetes. These findings suggest that radon inhalation also has antioxidative effects. This antioxidative effect against CCl4-induced hepatopathy is comparable to treatment with ascorbic acid (vitamin C) at a dose of 500 mg/kg weight, or α-tocopherol (vitamin E) treatment at a dose of 300 mg/kg weight, and is due to activation of antioxidative functions. In addition, radon inhalation inhibits carrageenan-induced inflammatory paw edema, suggesting that radon inhalation has anti-inflammatory effects. Furthermore, radon inhalation inhibits formalin-induced inflammatory pain and chronic constriction injury-induced neuropathic pain, suggesting that radon inhalation relieves pain. Thus, low-dose irradiation very likely activates the defense systems in the body, and therefore, contributes to preventing or reducing ROS-related injuries, which are thought to involve peroxidation.

The atypical excretion profile of meldonium: Comparison of urinary detection windows after single- and multiple-dose application in healthy volunteers.

PubMed

Görgens, Christian; Guddat, Sven; Bosse, Christina; Geyer, Hans; Pop, Valentin; Schänzer, Wilhelm; Thevis, Mario

2017-05-10

Following a one-year monitoring program providing unequivocal analytical evidence for a high prevalence in international elite sports, meldonium has been included in the World Anti-Doping Agency's (WADA) list of prohibited substances that came into effect on 1 January 2016. Despite of the polar and hydrophilic nature of the molecule, an unusual long detection window was observed in pilot elimination studies. Consequently, in the present study, urinary excretion profiles after single-dose (5 volunteers, 1×500mg) and multiple-dose oral application (5 volunteers; 2×500mg/day for 6days) were determined in order to facilitate the result management concerning meldonium findings in doping controls. Particularly the option to differentiate between recent use and tapering concentrations was studied. Urinary meldonium concentrations were determined using an analytical approach based on hydrophilic interaction liquid chromatography and high resolution tandem mass spectrometry. The study corroborates the hypothesis of a non-linear, dose-depended and biphasic excretion profile after oral application of meldonium and demonstrates that urinary detection windows are of considerable extent with up to 65 and 117days (concentrations>LOQ of 10ng/mL) following single- and multiple-dose applications, respectively. Copyright © 2017 Elsevier B.V. All rights reserved.

EFFECTS OF IONIZING RADIATION IN CHIMPANZEES. Final Report, February 28, 1962-October 31, 1962

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

Riopelle, A.J.; Rogers, C.M.

1963-10-31

Results are reported from studies of the psychological, hematological, and pathological effects of a second dose of radiation to a group of chimpanzees irradiated several years before. The effects of a large dose of radiation to the head alone on previously nonirradiated animals were evaluated in 4 animals. Findings are summarized for each animal. No evidence of damage to neural tissue was seen following exposure to the head to 2000 r gamma radiation. (C.H.)

Electron beam irradiation for biological decontamination of Spirulina platensis

NASA Astrophysics Data System (ADS)

Brasoveanu, Mirela; Nemtanu, Monica; Minea, R.; Grecu, Maria Nicoleta; Mazilu, Elena; Radulescu, Nora

2005-10-01

The Cyanobacterium Spirulina is commercialized for its use in health foods and for therapeutic purposes due to its valuable constituents particularly proteins and vitamins. The aim of the paper is to study the Spirulina platensis behaviour when it is electron beam irradiated for biological decontamination. Microbial load, antioxidant activity, enzymatic inhibition, electron spin resonance (ESR) and UV-Vis spectra were measured for doses up to 80 kGy. The results were correlated with doses in order to find where decontamination is efficient, keeping the Spirulina qualities.

Weight and the vitamin K expoxide reductase 1 genotype primarily contribute to the warfarin dosing in pediatric patients with Kawasaki disease.

PubMed

Wang, Zhouping; Zhang, Li; Huang, Ping; Gu, Xiaoqiong; Xie, Xiaofei; Wang, Yanfei; Li, Wei; Zeng, Qiyi

2018-05-08

Warfarin therapy is recommended in children with giant coronary artery aneurysms (GCAAs) after Kawasaki disease (KD). Large individual variability makes it difficult to predict the warfarin dose. Polymorphisms in the vitamin K expoxide reductase 1 (VKORC1) and cytochrome P4502C9 (CYP2C9) genes have been reported to influence the warfarin dose. We investigated the effects of the VKORC1 and CYP2C9 genotypes on the warfarin dose in pediatric patients with giant CAAs after KD. We attempted to create a dosing algorithm. The clinical and genetic data of patients were documented. VKORC1 (rs 9923231) and CYP2C9 *3 (rs 1057910) were genotyped using TaqMan real-time polymerase chain reaction. A linear regression analysis was performed to evaluate the contribution of clinical and genetic factors to the warfarin maintenance dose. Forty-seven patients were enrolled. Patients with the CT or CC genotype of VKORC1 had a relatively higher warfarin dose than did those with the TT genotype (p < 0.05). Three patients with CYP2C9*1/*3 had a lower warfarin dose than did those with the wild CYP2C9*1/*1 genotype, but the difference did not reach significance (p > 0.05). Weight and the VKORC1 genotype predominantly contributed to the warfarin dose, with 33.0% and 11.2% of variability, respectively. The observed warfarin dose was correlated with the predicted dose based on the algorithm used in our study (r = 0.45, p < 0.01). Weight and the VKORC1 genotype primarily determined the warfarin dose in Chinese pediatric patients with KD. Further studies are warranted to verify the findings of our study. Copyright © 2018 Elsevier Ltd. All rights reserved.

Review of proton pump inhibitors for the initial treatment of heartburn: is there a dose ceiling effect?

PubMed

Kushner, Pamela R; Peura, David A

2011-05-01

Proton pump inhibitors (PPIs) are widely used in clinical practice. However, concerns have been expressed about their long-term use, particularly with regard to bone health, Clostridium difficile infections, and drug interactions with platelet aggregation inhibitors. There has been limited guidance for clinicians concerning appropriate dose selection of PPIs for the initial treatment of heartburn. This review explored whether published clinical trials provide evidence of a ceiling above which higher PPI doses do not provide additional clinical benefit over the lowest approved dose. All articles of randomized, controlled clinical trials in nonerosive gastroesophageal reflux disease (GERD) in which the effects of two or more doses of the same PPI on symptomatic relief of heartburn were quantified as a study endpoint were identified and analyzed through PubMed searches up to the end of September 2010. The majority of trials evaluated provided no evidence that higher PPI doses were superior to the lowest approved dose for the initial treatment of heartburn. There were no clinically relevant findings with respect to dose dependence and safety outcomes in these studies. Efficacy outcomes from the trials suggest there may be a dose ceiling effect and highlight the need for further research on the use of the lowest effective PPI doses as an appropriate strategy in the initial treatment of uncomplicated heartburn. Observational studies and some meta-analyses have suggested that long-term PPI pharmacotherapy might be associated with safety concerns, which necessitate the periodic evaluation of therapeutic benefit in terms of symptom resolution and regimen tolerability. However, evidence to date suggests that use of the lowest effective dose for the indication is not associated with significant adverse events, particularly in the short term. Clinical practice suggests that patients requiring long-term treatment should be maintained on the lowest dose necessary to control symptoms, and monitored for potentially confounding factors that may lead to safety concerns.

The Impact of UV-dose, Body Surface Area Exposed and Other Factors on Cutaneous Vitamin D Synthesis Measured as Serum 25(OH)D Concentration: Systematic Review and Meta-analysis.

PubMed

Jager, Nadine; Schöpe, Jakob; Wagenpfeil, Stefan; Bocionek, Peter; Saternus, Roman; Vogt, Thomas; Reichrath, Jörg

2018-02-01

To optimize public health campaigns concerning UV exposure, it is important to characterize factors that influence UV-induced cutaneous vitamin D production. This systematic review and meta-analysis investigated the impact of different individual and environmental factors including exposed body surface area (BSA), UVB dose and vitamin D status, on serum 25(OH)D concentration. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses, and Meta-analysis of Observational studies in Epidemiology guidelines, a systematic literature search was conducted (MEDLINE; 01/1960-07/2016) investigating the impact of these factors on vitamin D status after artificial UV exposure as main outcome measure. Summary mean differences [and 95% confidence interval (CI)] were derived from random-effects meta-analysis to account for possible heterogeneity across studies. Meta-regression was conducted to account for impact of UVB dose, baseline 25(OH)D level and BSA. We identified 15 studies, with an estimated mean 25(OH)D rise per standard erythema dose (SED) of 0.19 nmol/l (95% CI 0.11-0.26 nmol/l). Results from meta-regression suggest a significant impact of UV dose and baseline 25(OH)D concentration on serum 25(OH)D level (p<0.01). Single UVB doses between 0.75 and 3 SED resulted in the highest rise of serum 25(OH)D per dose unit. BSA exposed had a smaller, non-proportional, not significant impact. Partial BSA exposure resulted in relatively higher rise compared to whole-body exposure (e.g. exposure of face and hands caused an 8-fold higher rise of serum 25(OH)D concentration/SED/1% BSA compared to whole-body exposure). Our findings support previous reports, estimating that the half-life of serum 25(OH)D varies depending on different factors. Our results indicate that partial BSA exposure (e.g. 10%) with moderate UV doses (e.g. 1 SED) is effective in generating or maintaining a healthy vitamin D status. However, due to limitations that include possible confounding factors such as skin type, which could not be considered, these findings should be interpreted with caution. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Radiation-Induced Central Nervous System Death - A study of the Pathologic Findings in Monkeys Irradiated with Massive Doses of Cobalt-60 (Gamma) Radiation

DTIC Science & Technology

1959-04-01

U.S. DEPARTMENT OF COMMERCE National Technical Information Service AD-AO36 168 RADIATION-INDUCED CENTRAL NERVOUS SYSTEM DEATH - A STUDY OF THE...ý." - ý " . :..’ýý.ý-. .. , . ý 4 ý .. -- ’ý.- -!:;:ý’,. 1,ý,-: WJiAUOK4KOUED CENTRAL NERVOUS SYSTEM NT A Study of the Pathologic Findings in...University SCHOOL OF AVIATION MEDICINE, USAF Randolph AFB, Texas April 1959 7757-. AdIAIONH-INDUCED CENTRAL NEVOUS $Y$194 DUTH A Study of the Pathologic

Ultra-low-dose Ultrasound Molecular Imaging for the Detection of Angiogenesis in a Mouse Murine Tumor Model: How Little Can We See?

PubMed Central

Wang, Shiying; Herbst, Elizabeth B.; Mauldin, F. William; Diakova, Galina B.; Klibanov, Alexander L.; Hossack, John A.

2016-01-01

Objectives The objective of this study is to evaluate the minimum microbubble dose for ultrasound molecular imaging to achieve statistically significant detection of angiogenesis in a mouse model. Materials and Methods The pre-burst minus post-burst method was implemented on a Verasonics ultrasound research scanner using a multi-frame compounding pulse inversion imaging sequence. Biotinylated lipid (distearoyl phosphatidylcholine, DSPC-based) microbubbles that were conjugated with anti-vascular endothelial growth factor 2 (VEGFR2) antibody (MBVEGFR2) or isotype control antibody (MBControl) were injected into mice carrying adenocarcinoma xenografts. Different injection doses ranging from 5 × 104 to 1 × 107 microbubbles per mouse were evaluated to determine the minimum diagnostically effective dose. Results The proposed imaging sequence was able to achieve statistically significant detection (p < 0.05, n = 5) of VEGFR2 in tumors with a minimum MBVEGFR2 injection dose of only 5 × 104 microbubbles per mouse (DSPC at 0.053 ng/g mouse body mass). Non-specific adhesion of MBControl at the same injection dose was negligible. Additionally, the targeted contrast ultrasound signal of MBVEGFR2 decreased with lower microbubble doses, while non-specific adhesion of MBControl increased with higher microbubble doses. Conclusions 5 × 104 microbubbles per animal is now the lowest injection dose on record for ultrasound molecular imaging to achieve statistically significant detection of molecular targets in vivo. Findings in this study provide us with further guidance for future developments of clinically translatable ultrasound molecular imaging applications using a lower dose of microbubbles. PMID:27654582

The Effect of High-Dose Ionizing Radiation on the Astrobiological Model Lichen Circinaria gyrosa

NASA Astrophysics Data System (ADS)

de la Torre, Rosa; Zélia Miller, Ana; Cubero, Beatriz; Martín-Cerezo, M. Luisa; Raguse, Marina; Meeßen, Joachim

2017-02-01

The lichen Circinaria gyrosa is an astrobiological model defined by its high capacity of resistance to space conditions and to a simulated martian environment. Therefore, it became part of the currently operated BIOMEX experiment on board the International Space Station and the recent STARLIFE campaign to study the effects of four types of space-relevant ionizing radiation. The samples were irradiated with helium and iron ions at doses up to 2 kGy, with X-rays at doses up to 5 kGy and with γ rays at doses from 6 to 113 kGy. Results on C. gyrosa's resistance to simulated space ionizing radiation and its post-irradiation viability were obtained by (i) chlorophyll a fluorescence of photosystem II (PSII), (ii) epifluorescence microscopy, (iii) confocal laser scanning microscopy (CLSM), and (iv) field emission scanning electron microscopy (FESEM). Results of photosynthetic activity and epifluorescence show no significant changes up to a dose of 1 kGy (helium ions), 2 kGy (iron ions), 5 kGy (X-rays) - the maximum doses applied for those radiation qualities - as well as a dose of 6 kGy of γ irradiation, which was the lowest dose applied for this low linear energy transfer (LET) radiation. Significant damage in a dose-related manner was observed only at much higher doses of γ irradiation (up to 113 kGy). These data corroborate the findings of the parallel STARLIFE studies on the effects of ionizing radiation on the lichen Circinaria gyrosa, its isolated photobiont, and the lichen Xanthoria elegans.

Dosimetry during intramedullary nailing of the tibia

PubMed Central

2009-01-01

Background Intramedullary nailing under fluoroscopic guidance is a common operation. We studied the intraoperative radiation dose received by both the patient and the personnel. Patients and methods 25 intramedullary nailing procedures of the tibia were studied. All patients suffered from tibial fractures and were treated using the Grosse-Kempf intramedullary nail, with free-hand technique for fixation of the distal screws, under fluoroscopic guidance. The exposure, at selected positions, was recorded using an ion chamber, while the dose area product (DAP) was measured with a DAP meter, attached to the tube head. Thermoluminescent dosimeters (TLDs) were used to derive the occupational dose to the personnel, and also to monitor the surface dose on the gonads of some of the patients. Results The mean operation time was 101 (48–240) min, with a mean fluoroscopic time of 72 seconds and a mean DAP value of 75 cGy·cm2. The surface dose to the gonads of the patients was less than 8.8 mGy during any procedure, and thus cannot be considered to be a contraindication for the use of this technique. Occupational dose differed substantially between members of the operating personnel, the maximum dose recorded being to the operator of the fluoroscopic equipment (0.11 mSv). Interpretation Our findings underscore the care required by the primary operator not to exceed the dose constraint of 10 mSv per year. The rest of the operating personnel, although they do not receive very high doses, should focus on the dose optimization of the technique. PMID:19916691

Coffee consumption is not associated with ovarian cancer risk: a dose-response meta-analysis of prospective cohort studies.

PubMed

Berretta, Massimiliano; Micek, Agnieszka; Lafranconi, Alessandra; Rossetti, Sabrina; Di Francia, Raffaele; De Paoli, Paolo; Rossi, Paola; Facchini, Gaetano

2018-04-17

Coffee consumption has been associated with numerous cancers, but evidence on ovarian cancer risk is controversial. Therefore, we performed a meta-analysis on prospective cohort studies in order to review the evidence on coffee consumption and risk of ovarian cancer. Studies were identified through searching the PubMed and MEDLINE databases up to March 2017. Risk estimates were retrieved from the studies, and dose-response analysis was modelled by using restricted cubic splines. Additionally, a stratified analysis by menopausal status was performed. A total of 8 studies were eligible for the dose-response meta-analysis. Studies included in the analysis comprised 787,076 participants and 3,541 ovarian cancer cases. The results showed that coffee intake was not associated with ovarian cancer risk (RR = 1.06, 95% CI: 0.89, 1.26). Stratified and subgroup analysis showed consisted results. This comprehensive meta-analysis did not find evidence of an association between the consumption of coffee and risk of ovarian cancer.

Are two doses of human papillomavirus vaccine sufficient for girls aged 15-18 years? Results from a cohort study in India.

PubMed

Bhatla, Neerja; Nene, Bhagwan M; Joshi, Smita; Esmy, Pulikottil O; Poli, Usha Rani Reddy; Joshi, Geeta; Verma, Yogesh; Zomawia, Eric; Pimple, Sharmila; Prabhu, Priya R; Basu, Partha; Muwonge, Richard; Hingmire, Sanjay; Sauvaget, Catherine; Lucas, Eric; Pawlita, Michael; Gheit, Tarik; Jayant, Kasturi; Malvi, Sylla G; Siddiqi, Maqsood; Michel, Angelika; Butt, Julia; Sankaran, Subha; Kannan, Thiraviam Pillai Rameshwari Ammal; Varghese, Rintu; Divate, Uma; Willhauck-Fleckenstein, Martina; Waterboer, Tim; Müller, Martin; Sehr, Peter; Kriplani, Alka; Mishra, Gauravi; Jadhav, Radhika; Thorat, Ranjit; Tommasino, Massimo; Pillai, M Radhakrishna; Sankaranarayanan, Rengaswamy

2018-06-01

Extending two-dose recommendations of HPV vaccine to girls between 15 and 18 years will reduce program cost and improve compliance. Immunogenicity and vaccine targeted HPV infection outcomes were compared between 1795 girls aged 15-18 years receiving two (1-180 days) and 1515 girls of same age receiving three (1-60-180 days) doses. Immunogenicity outcomes in 15-18 year old two-dose recipients were also compared with the 10-14 year old three-dose (N = 2833) and two-dose (N = 3184) recipients. The 15-18 year old two-dose recipients had non-inferior L1-binding antibody titres at seven months against vaccine-targeted HPV types compared to three-dose recipients at 15-18 years and three-dose recipients at 10-14 years of age. Neutralizing antibody titres at 18 months in 15-18 year old two-dose recipients were non-inferior to same age three-dose recipients for all except HPV 18. The titres were inferior to those in the 10-14 year old three-dose recipients for all targeted types. Frequency of incident infections from vaccine-targeted HPV types in the 15-18 year old two-dose recipients was similar to the three dose recipients. None of the girls receiving two or three doses had persistent infection from vaccine-targeted types. These findings support that two doses of HPV vaccine can be extended to girls aged 15-18 years. Copyright © 2018. Published by Elsevier B.V.

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.

PubMed

Hohloch, Karin; Zeynalova, Samira; Chapuy, Björn; Pfreundschuh, Michael; Loeffler, Markus; Ziepert, Marita; Feller, Alfred C; Trümper, Lorenz; Hasenclever, Dirk; Wulf, Gerald; Schmitz, Norbert

2016-06-01

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia

PubMed Central

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-01-01

Objective The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Methods Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. Results A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0–2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. Conclusions The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment. PMID:29142459

A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia.

PubMed

Qin, Yan; Han, Xiaohong; Wang, Lin; Du, Ping; Yao, Jiarui; Wu, Di; Song, Yuanyuan; Zhang, Shuxiang; Tang, Le; Shi, Yuankai

2017-10-01

The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 μg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 μg/kg) of PEG rhG-CSF were investigated. A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 μg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0-2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 μg/kg, 100 μg/kg and double half dose of 30 μg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment.

MO-F-CAMPUS-T-03: Continuous Dose Delivery with Gamma Knife Perfexion

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

Ghobadi,; Li, W; Chung, C

2015-06-15

Purpose: We propose continuous dose delivery techniques for stereotactic treatments delivered by Gamma Knife Perfexion using inverse treatment planning system that can be applied to various tumour sites in the brain. We test the accuracy of the plans on Perfexion’s planning system (GammaPlan) to ensure the obtained plans are viable. This approach introduces continuous dose delivery for Perefxion, as opposed to the currently employed step-and-shoot approaches, for different tumour sites. Additionally, this is the first realization of automated inverse planning on GammaPlan. Methods: The inverse planning approach is divided into two steps of identifying a quality path inside the target,more » and finding the best collimator composition for the path. To find a path, we select strategic regions inside the target volume and find a path that visits each region exactly once. This path is then passed to a mathematical model which finds the best combination of collimators and their durations. The mathematical model minimizes the dose spillage to the surrounding tissues while ensuring the prescribed dose is delivered to the target(s). Organs-at-risk and their corresponding allowable doses can also be added to the model to protect adjacent organs. Results: We test this approach on various tumour sizes and sites. The quality of the obtained treatment plans are comparable or better than forward plans and inverse plans that use step- and-shoot technique. The conformity indices in the obtained continuous dose delivery plans are similar to those of forward plans while the beam-on time is improved on average (see Table 1 in supporting document). Conclusion: We employ inverse planning for continuous dose delivery in Perfexion for brain tumours. The quality of the obtained plans is similar to forward and inverse plans that use conventional step-and-shoot technique. We tested the inverse plans on GammaPlan to verify clinical relevance. This research was partially supported by Elekta, Sweden (vendor of Gamma Knife Perfexion)« less

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients

PubMed Central

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-01-01

Aim This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. Patients & methods A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. Results The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better ‘ideal dose’ estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R2 = 51%). Conclusion Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients. PMID:23215886

β-blocker dosage and outcomes after acute coronary syndrome.

PubMed

Allen, Jason E; Knight, Stacey; McCubrey, Raymond O; Bair, Tami; Muhlestein, Joseph Brent; Goldberger, Jeffrey J; Anderson, Jeffrey L

2017-02-01

Although β-blockers increase survival in acute coronary syndrome (ACS) patients, the doses used in trials were higher than doses used in practice, and recent data do not support an advantage of higher doses. We hypothesized that rates of major adverse cardiac events (MACE), all-cause death, myocardial infarction, and stroke are equivalent for patients on low-dose and high-dose β-blocker. Patients admitted to Intermountain Healthcare with ACS and diagnosed with ≥70% coronary stenosis between 1994 and 2013 were studied (N = 7,834). We classified low dose as ≤25% and high dose as ≥50% of an equivalent daily dose of 200 mg of metoprolol. Multivariate analyses were used to test association between low-dose versus high-dose β-blocker dosage and MACE at 0-6 months and 6-24 months. A total of 5,287 ACS subjects were discharged on β-blockers (87% low dose, 12% high dose, and 1% intermediate dose). The 6-month MACE outcomes rates for the β-blocker dosage (low versus high) were not equivalent (P = .18) (hazard ratio [HR] = 0.76; 95% CI, 0.52-1.10). However, subjects on low-dose β-blocker therapy did have a significantly decreased risk of myocardial infarction for 0-6 months (HR = 0.53; 95% CI, 0.33-0.86). The rates of MACE events during the 6-24 months after presentation with ACS were equivalent for the 2 doses (P = .009; HR = 1.03 [95% CI, 0.70-1.50]). In ACS patients, rates of MACE for high-dose and low-dose β-blocker doses are similar. These findings question the importance of achieving a high dose of β-blocker in ACS patients and highlight the need for further investigation of this clinical question. Copyright © 2016 Elsevier Inc. All rights reserved.

LEUKEMIA, LYMPHOMA AND MULTIPLE MYELOMA MORTALITY (1950–1999) AND INCIDENCE (1969–1999) IN THE ELDORADO URANIUM WORKERS COHORT

PubMed Central

Zablotska, Lydia B.; Lane, Rachel S.D.; Frost, Stanley E.; Thompson, Patsy A.

2014-01-01

Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932–1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months and the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation. PMID:24583244

Effective doses to family members of patients treated with radioiodine-131

NASA Astrophysics Data System (ADS)

Zdraveska Kocovska, M.; Vaskova, O.; Majstorov, V.; Kuzmanovska, S.; Pop Gjorceva, D.; Spasic Jokic, V.

2011-09-01

The purpose of this study was to evaluate the effective dose to family members of thyroid cancer and hyperthyroid patients treated with radioiodine-131, and also to compare the results with dose constraints proposed by the International Commission of Radiological Protection (ICRP) and the Basic Safety Standards (BSS) of the International Atomic Energy Agency (IAEA). For the estimation of the effective doses, sixty family members of sixty patients, treated with radioiodine-131, and thermoluminiscent dosimeters (Model TLD 100) were used. Thyroid cancer patients were hospitalized for three days, while hyperthyroid patients were treated on out-patient basis. The family members wore TLD in front of the torso for seven days. The radiation doses to family members of thyroid cancer patients were well below the recommended dose constraint of 1 mSv. The mean value of effective dose was 0.21 mSv (min 0.02 - max 0.51 mSv). Effective doses, higher than 1 mSv, were detected for 11 family members of hyperthyroid patients. The mean value of effective dose of family members of hyperthyroid patients was 0.87 mSv (min 0.12 - max 6.79). The estimated effective doses to family members of hyperthyroid patients were higher than the effective doses to family members of thyroid carcinoma patients. These findings may be considered when establishing new national guidelines concerning radiation protection and release of patients after a treatment with radioiodine therapy.

Comparative assessment of onion and garlic extracts on endogenous hepatic and renal antioxidant status in rat.

PubMed

Suru, Stephen M; Ugwu, Chidiebere E

2015-07-01

Despite growing claims of functional health benefits in folkloric medicine, the safety of chronic/elevated intakes of onion and garlic cannot be assumed. Therefore, this study assesses oral administration of varied doses of onion and garlic on some biomarkers of hepatic and renal functions in rats. Animals were divided into five groups: control group received vehicle and extract-treated groups received varied doses of onion or garlic extract (0.5 mL and 1.0 mL/100 g bwt/day) for 6 weeks. Both doses of onion caused marked (p<0.05) increase in hepatic and renal levels of glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and marked (p<0.05) decrease in malondialdehyde (MDA). Treatment with low dose of garlic elicited similar trend except in hepatic CAT, renal SOD and GST levels. A high dose of garlic only caused marked (p<0.05) increase in hepatic GST, renal GST, and SOD. Both doses of onion and low dose of garlic significantly (p<0.05) enhanced renal Na+/K+-ATPase activity. Only a high dose of onion caused significant (p<0.05) increase in hepatic aspartate transaminase (AST), alkaline phosphatase (ALP), and decrease in plasma AST activities. These findings suggest antioxidant enhancing capability for both doses of onion and low dose of garlic, while high dose of garlic elicited pro-oxidant conditions.

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.

Estimating the uncertainty of calculated out-of-field organ dose from a commercial treatment planning system.

PubMed

Wang, Lilie; Ding, George X

2018-06-12

Therapeutic radiation to cancer patients is accompanied by unintended radiation to organs outside the treatment field. It is known that the model-based dose algorithm has limitation in calculating the out-of-field doses. This study evaluated the out-of-field dose calculated by the Varian Eclipse treatment planning system (v.11 with AAA algorithm) in realistic treatment plans with the goal of estimating the uncertainties of calculated organ doses. Photon beam phase-space files for TrueBeam linear accelerator were provided by Varian. These were used as incident sources in EGSnrc Monte Carlo simulations of radiation transport through the downstream jaws and MLC. Dynamic movements of the MLC leaves were fully modeled based on treatment plans using IMRT or VMAT techniques. The Monte Carlo calculated out-of-field doses were then compared with those calculated by Eclipse. The dose comparisons were performed for different beam energies and treatment sites, including head-and-neck, lung, and pelvis. For 6 MV (FF/FFF), 10 MV (FF/FFF), and 15 MV (FF) beams, Eclipse underestimated out-of-field local doses by 30%-50% compared with Monte Carlo calculations when the local dose was <1% of prescribed dose. The accuracy of out-of-field dose calculations using Eclipse is improved when collimator jaws were set at the smallest possible aperture for MLC openings. The Eclipse system consistently underestimates out-of-field dose by a factor of 2 for all beam energies studied at the local dose level of less than 1% of prescribed dose. These findings are useful in providing information on the uncertainties of out-of-field organ doses calculated by Eclipse treatment planning system. © 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

PubMed

Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

2017-09-12

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

Supplemental computational phantoms to estimate out-of-field absorbed dose in photon radiotherapy

NASA Astrophysics Data System (ADS)

Gallagher, Kyle J.; Tannous, Jaad; Nabha, Racile; Feghali, Joelle Ann; Ayoub, Zeina; Jalbout, Wassim; Youssef, Bassem; Taddei, Phillip J.

2018-01-01

The purpose of this study was to develop a straightforward method of supplementing patient anatomy and estimating out-of-field absorbed dose for a cohort of pediatric radiotherapy patients with limited recorded anatomy. A cohort of nine children, aged 2-14 years, who received 3D conformal radiotherapy for low-grade localized brain tumors (LBTs), were randomly selected for this study. The extent of these patients’ computed tomography simulation image sets were cranial only. To approximate their missing anatomy, we supplemented the LBT patients’ image sets with computed tomography images of patients in a previous study with larger extents of matched sex, height, and mass and for whom contours of organs at risk for radiogenic cancer had already been delineated. Rigid fusion was performed between the LBT patients’ data and that of the supplemental computational phantoms using commercial software and in-house codes. In-field dose was calculated with a clinically commissioned treatment planning system, and out-of-field dose was estimated with a previously developed analytical model that was re-fit with parameters based on new measurements for intracranial radiotherapy. Mean doses greater than 1 Gy were found in the red bone marrow, remainder, thyroid, and skin of the patients in this study. Mean organ doses between 150 mGy and 1 Gy were observed in the breast tissue of the girls and lungs of all patients. Distant organs, i.e. prostate, bladder, uterus, and colon, received mean organ doses less than 150 mGy. The mean organ doses of the younger, smaller LBT patients (0-4 years old) were a factor of 2.4 greater than those of the older, larger patients (8-12 years old). Our findings demonstrated the feasibility of a straightforward method of applying supplemental computational phantoms and dose-calculation models to estimate absorbed dose for a set of children of various ages who received radiotherapy and for whom anatomies were largely missing in their original computed tomography simulations.

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

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

PubMed

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

1982-12-01

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

Monitoring exposure to atomic bomb radiation by somatic mutation

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

Akiyama, Mitoshi; Kyoizumi, Seishi; Kusunoki, Yoichiro

Atomic bomb survivors are a population suitable for studying the relationship between somatic mutation and cancer risk because their exposure doses are relatively well known and their dose responses in terms of cancer risk have also been thoroughly studied. An analysis has been made of erythrocyte glycophorin A (GPA) gene mutations in 1,226 atomic bomb survivors in Hiroshima and Nagasaki. The GPA mutation frequency (Mf) increased slightly but significantly with age at the time of measurement and with the number of cigarettes smoked. After adjustment for the effect of smoking, the Mf was significantly higher in males than in femalesmore » and higher in Hiroshima than in Nagasaki. All of these characteristics of the background GPA Mf were in accord with those of solid tumor incidence obtained from an earlier epidemiological study of A-bomb survivors. Analysis of the dose effect on Mf revealed the doubling dose to be about 1.20 Sv and the minimum dose for detection of a significant increase to be about 0.24 Sv. No significant dose effect for difference in sex, city, or age at the time of bombing was observed. Interestingly, the doubling dose for the GPA Mf approximated that for solid cancer incidence (1.59 Sv). And the minimum dose for detection was not inconsistent with the data for solid cancer incidence. The dose effect was significantly higher in those diagnosed with cancer before or after measurement than in those without a history of cancer. These findings are consistent with the hypothesis that somatic mutations are the main cause of excess cancer risk from radiation exposure. 27 refs., 2 figs.« less

Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

PubMed Central

Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

2017-01-01

Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and recorded, and at the end of experiments, tumor xenografts were removed for Western blot and immunohistochemical analyses. Compared to control groups (negative control, regular-dose icotinib [IcoR], high-dose icotinib [IcoH], and docetaxel [DTX]) and regular icotinib dose (60 mg/kg) with docetaxel, treatment of mice with a high-dose (1200 mg/kg) of icotinib plus sequential docetaxel for 3 weeks (IcoH-DTX) had an additive effect on suppression of tumor xenograft size and volume (P < 0.05). Icotinib-containing treatments markedly reduced phosphorylation of EGFR, mitogen activated protein kinase (MAPK), and protein kinase B (Akt), but only the high-dose icotinib-containing treatments showed an additive effect on CD34 inhibition (P < 0.05), an indication of reduced microvessel density in tumor xenografts. Moreover, high-dose icotinib plus docetaxel had a similar effect on mouse weight loss (a common way to measure adverse reactions in mice), compared to the other treatment combinations. The study indicate that the high dose of icotinib plus sequential docetaxel (IcoH-DTX) have an additive effect on suppressing the growth of wild-type EGFR NSCLC cell nude mouse xenografts, possibly through microvessel density reduction. Future clinical trials are needed to confirm the findings of this study. PMID:27852073

A Cohort Study of Metformin and Colorectal Cancer Risk among Patients with Diabetes Mellitus.

PubMed

Bradley, Marie C; Ferrara, Assiamira; Achacoso, Ninah; Ehrlich, Samantha F; Quesenberry, Charles P; Habel, Laurel A

2018-05-01

Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases. Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose). Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk. Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies. Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525-30. ©2018 AACR See related commentary by Jackson and García-Albéniz, p. 520 . ©2018 American Association for Cancer Research.

Developability assessment of clinical drug products with maximum absorbable doses.

PubMed

Ding, Xuan; Rose, John P; Van Gelder, Jan

2012-05-10

Maximum absorbable dose refers to the maximum amount of an orally administered drug that can be absorbed in the gastrointestinal tract. Maximum absorbable dose, or D(abs), has proved to be an important parameter for quantifying the absorption potential of drug candidates. The purpose of this work is to validate the use of D(abs) in a developability assessment context, and to establish appropriate protocol and interpretation criteria for this application. Three methods for calculating D(abs) were compared by assessing how well the methods predicted the absorption limit for a set of real clinical candidates. D(abs) was calculated for these clinical candidates by means of a simple equation and two computer simulation programs, GastroPlus and an program developed at Eli Lilly and Company. Results from single dose escalation studies in Phase I clinical trials were analyzed to identify the maximum absorbable doses for these compounds. Compared to the clinical results, the equation and both simulation programs provide conservative estimates of D(abs), but in general D(abs) from the computer simulations are more accurate, which may find obvious advantage for the simulations in developability assessment. Computer simulations also revealed the complex behavior associated with absorption saturation and suggested in most cases that the D(abs) limit is not likely to be achieved in a typical clinical dose range. On the basis of the validation findings, an approach is proposed for assessing absorption potential, and best practices are discussed for the use of D(abs) estimates to inform clinical formulation development strategies. Copyright © 2012 Elsevier B.V. All rights reserved.

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

PubMed

Richardson, Paul G; Soiffer, Robert J; Antin, Joseph H; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L; Steinbach, Gideon; Murray, Karen F; Vogelsang, Georgia B; Chen, Allen R; Krishnan, Amrita; Kernan, Nancy A; Avigan, David E; Spitzer, Thomas R; Shulman, Howard M; Di Salvo, Donald N; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L J; Iacobelli, Massimo; McDonald, George B; Guinan, Eva C

2010-07-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

Radiation Dose-Volume Effects and the Penile Bulb

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

Roach, Mack, E-mail: mroach@radonc.ucsf.ed; Nam, Jiho; Gagliardi, Giovanna

2010-03-01

The dose, volume, and clinical outcome data for penile bulb are reviewed for patients treated with external-beam radiotherapy. Most, but not all, studies find an association between impotence and dosimetric parameters (e.g., threshold doses) and clinical factors (e.g., age, comorbid diseases). According to the data available, it is prudent to keep the mean dose to 95% of the penile bulb volume to <50 Gy. It may also be prudent to limit the D70 and D90 to 70 Gy and 50 Gy, respectively, but coverage of the planning target volume should not be compromised. It is acknowledged that the penile bulbmore » may not be the critical component of the erectile apparatus, but it seems to be a surrogate for yet to be determined structure(s) critical for erectile function for at least some techniques.« less

Evaluation of the sterility of single-dose medications used in a multiple-dose fashion

PubMed Central

Martin, Elizabeth P.; Mukherjee, Jean; Sharp, Claire R.; Sinnott-Stutzman, Virginia B.

2017-01-01

Bacterial proliferation was evaluated in single-dose medications used in a multi-dose fashion and when medications were intentionally inoculated with bacteria. Of 5 experimentally punctured medications, 1 of 75 vials (50% dextrose) became contaminated. When intentionally inoculated, hydroxyethyl starch and heparinized saline supported microbial growth. Based on these findings, it is recommended that hydroxyethyl starch and heparinized saline not be used in a multi-dose fashion. PMID:29089656

Study of pharmacological activities of methanol extract of Jatropha gossypifolia fruits.

PubMed

Apu, Apurba Sarker; Hossain, Faruq; Rizwan, Farhana; Bhuyan, Shakhawat Hossan; Matin, Maima; Jamaluddin, A T M

2012-12-01

The present study was carried out to investigate the possible in vivo analgesic, neuropharmacological and anti-diarrheal activities of the methanol extract of Jatropha gossypifolia fruits. The analgesic activity was measured by acetic acid induced writhing inhibition test. The neuropharmacological activities were evaluated by hole cross, hole-board, and elevated plus-maze (EPM) tests and the anti-diarrheal activity was assessed by castor oil induced diarrhea inhibition method. The extract showed highly significant (P < 0.001) analgesic activity with % inhibitions of writhing response at doses 200 and 400 mg/kg body weight were 77.86% and 71.25%, respectively. The extract at both doses showed significant (P < 0.05) sedative effect in-hole cross test. In-hole board test, the extract showed highly significant (P < 0.001) anxiolytic activity at lower dose whereas this activity was observed at higher dose in EPM test. The extract also showed highly significant (P < 0.001) anti-diarrheal activity. The findings of the study clearly indicate the presence of significant analgesic, neuropharmacological and anti-diarrheal properties of the plant, which demands further investigation including, compound isolation.

Caffeine is a risk factor for osteopenia of prematurity in preterm infants: a cohort study.

PubMed

Ali, Ebtihal; Rockman-Greenberg, Cheryl; Moffatt, Michael; Narvey, Michael; Reed, Martin; Jiang, Depeng

2018-01-22

Caffeine, the most commonly used medication in Neonatal Intensive Care Units, has calciuric and osteoclastogenic effects. To examine the association between the cumulative dose and duration of therapy of caffeine and osteopenia of prematurity, a retrospective cohort study was conducted including premature infants less than 31 weeks and birth weight less than 1500 g. Osteopenia of prematurity was evaluated using chest X-rays on a biweekly basis over 12 weeks of hospitalization. The cohort included 109 infants. 51% had osteopenia of prematurity and 8% had spontaneous rib fractures. Using the generalized linear mixed model, caffeine dose and duration of caffeine therapy showed a strong association with osteopenia of prematurity. Steroids and vitamin D were also significantly correlated with osteopenia of prematurity while diuretic use did not show a statistically significant effect. The cumulative dose and duration of therapy of caffeine, as well as steroid are associated with osteopenia of prematurity in this cohort. Future studies are needed to confirm these findings and determine the lowest dose of caffeine needed to treat effectively apnea of prematurity.

Luteal phase support in intrauterine insemination cycles: a prospective randomized study of 300 mg versus 600 mg intravaginal progesterone tablet.

PubMed

Biberoglu, Ebru H; Tanrıkulu, Filiz; Erdem, Mehmet; Erdem, Ahmet; Biberoglu, Kutay Omer

2016-01-01

Vaginal progesterone (P) has been suggested to be used for luteal phase support (LPS) in controlled ovarian stimulation (COH)-intrauterine insemination (IUI) cycles, however, no concensus exists about the best P dose. Therefore, considering the fecundability rate as the primary end point, our main objective was to find the optimal dose of P in COH-IUI cycles, comparing the two groups of women, each of which comprised of 100 women either on 300 mg or 600 mg of intravaginal P tablets, in a prospective randomized study design. The mean age of the women, duration of infertility, basal and day of hCG injection hormone levels in the female and sperm parameters were similar in the two study groups. Also, duration and dose of gonadotropin given, number of follicles, endometrial thickness, the total, ongoing and multiple pregnancy rates were comparable in both groups. We, therefore, claim that 300 mg of intravaginal micronized P should be the maximum dose of LPS in IUI cycles.

Oral toxicity of 3-nitro-1,2,4-triazol-5-one in rats.

PubMed

Crouse, Lee C B; Lent, Emily May; Leach, Glenn J

2015-01-01

3-Nitro-1,2,4-triazol-5-one (NTO), an insensitive explosive, was evaluated to assess potential environmental and human health effects. A 14-day oral toxicity study in Sprague-Dawley rats was conducted with NTO in polyethylene glycol -200 by gavage at doses of 0, 250, 500, 1000, 1500, or 2000 mg/kg-d. Body mass and food consumption decreased in males (2000 mg/kg-d), and testes mass was reduced at doses of 500 mg/kg-d and greater. Based on the findings in the 14-day study, a 90-day study was conducted at doses of 0, 30, 100, 315, or 1000 mg/kg-d NTO. There was no effect on food consumption, body mass, or neurobehavioral parameters. Males in the 315 and 1000 mg/kg-d groups had reduced testes mass with associated tubular degeneration and atrophy. The testicular effects were the most sensitive adverse effect and were used to derive a benchmark dose (BMD) of 70 mg/kg-d with a 10% effect level (BMDL10) of 40 mg/kg-d. © The Author(s) 2015.

Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

PubMed

Flick, Burkhard; Schneider, Steffen; Melching-Kollmuss, Stephanie; Fussell, Karma C; Gröters, Sibylle; Buesen, Roland; Strauss, Volker; van Ravenzwaay, Bennard

2017-04-01

The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.

Use of Severity Grades to Characterize Histopathologic Changes

EPA Science Inventory

The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should...

No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

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

Sheehan, Daniel M.

2006-01-15

We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated onmore » a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.« less

The safety of green tea and green tea extract consumption in adults - Results of a systematic review.

PubMed

Hu, Jiang; Webster, Donna; Cao, Joyce; Shao, Andrew

2018-06-01

A systematic review of published toxicology and human intervention studies was performed to characterize potential hazards associated with consumption of green tea and its preparations. A review of toxicological evidence from laboratory studies revealed the liver as the target organ and hepatotoxicity as the critical effect, which was strongly associated with certain dosing conditions (e.g. bolus dose via gavage, fasting), and positively correlated with total catechin and epigallocatechingallate (EGCG) content. A review of adverse event (AE) data from 159 human intervention studies yielded findings consistent with toxicological evidence in that a limited range of concentrated, catechin-rich green tea preparations resulted in hepatic AEs in a dose-dependent manner when ingested in large bolus doses, but not when consumed as brewed tea or extracts in beverages or as part of food. Toxico- and pharmacokinetic evidence further suggests internal dose of catechins is a key determinant in the occurrence and severity of hepatotoxicity. A safe intake level of 338 mg EGCG/day for adults was derived from toxicological and human safety data for tea preparations ingested as a solid bolus dose. An Observed Safe Level (OSL) of 704 mg EGCG/day might be considered for tea preparations in beverage form based on human AE data. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2012-04-01

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

A forced titration study of the antioxidant and immunomodulatory effects of Ambrotose AO supplement

PubMed Central

2010-01-01

Background Oxidative stress plays a role in acute and chronic inflammatory disease and antioxidant supplementation has demonstrated beneficial effects in the treatment of these conditions. This study was designed to determine the optimal dose of an antioxidant supplement in healthy volunteers to inform a Phase 3 clinical trial. Methods The study was designed as a combined Phase 1 and 2 open label, forced titration dose response study in healthy volunteers (n = 21) to determine both acute safety and efficacy. Participants received a dietary supplement in a forced titration over five weeks commencing with a no treatment baseline through 1, 2, 4 and 8 capsules. The primary outcome measurement was ex vivo changes in serum oxygen radical absorbance capacity (ORAC). The secondary outcome measures were undertaken as an exploratory investigation of immune function. Results A significant increase in antioxidant activity (serum ORAC) was observed between baseline (no capsules) and the highest dose of 8 capsules per day (p = 0.040) representing a change of 36.6%. A quadratic function for dose levels was fitted in order to estimate a dose response curve for estimating the optimal dose. The quadratic component of the curve was significant (p = 0.047), with predicted serum ORAC scores increasing from the zero dose to a maximum at a predicted dose of 4.7 capsules per day and decreasing for higher doses. Among the secondary outcome measures, a significant dose effect was observed on phagocytosis of granulocytes, and a significant increase was also observed on Cox 2 expression. Conclusion This study suggests that Ambrotose AO® capsules appear to be safe and most effective at a dosage of 4 capsules/day. It is important that this study is not over interpreted; it aimed to find an optimal dose to assess the dietary supplement using a more rigorous clinical trial design. The study achieved this aim and demonstrated that the dietary supplement has the potential to increase antioxidant activity. The most significant limitation of this study was that it was open label Phase 1/Phase 2 trial and is subject to potential bias that is reduced with the use of randomization and blinding. To confirm the benefits of this dietary supplement these effects now need to be demonstrated in a Phase 3 randomised controlled trial (RCT). Trial Registration Australian and New Zealand Clinical Trials Register: ACTRN12605000258651 PMID:20433711

Acute toxicity evaluation of proliferol: a dose-escalating, placebo-controlled study in swine.

PubMed

Dagenais, Simon; Wooley, James; Hite, Mark; Green, Robert; Mayer, John

2009-01-01

Prolotherapy is one of the many treatments available for chronic musculoskeletal disorders. A commonly used drug contains dextrose 12.5%, glycerin 12.5%, phenol 1.0%, and lidocaine hydrochloride 0.25% in aqueous solution (recently termed Proliferol). For chronic low back pain, this is injected into lumbosacral ligaments to stimulate connective tissue repair. Despite generally positive clinical results, the toxicity of this drug is not well characterized and was assessed in 48 (24 male, 24 female) Yucatan miniature swine randomly assigned to low (1x), medium (5x), or high (10x) dose or saline placebo. Outcomes included clinical observations, clinical chemistry, hematology, coagulation, urinalysis, toxicokinetics, and full gross and microscopic histopathology after 24 hours or 14 days. Findings attributable to Proliferol after 24 hours included dose-response elevations in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase, which returned to normal after 14 days. There were no remarkable findings in hematology, coagulation, or urinalysis. Urine concentrations of lidocaine and phenol both peaked after 8 hours. Histopathology findings after 24 hours included hemorrhage, inflammation, necrosis, and vascular changes in the ligaments and adjacent soft tissues at the sites of injection. After 14 days, there was evidence of repair under way, with fibrosis and skeletal muscle regeneration at the injection sites.

Dosimetry in differentiated thyroid carcinoma (12-1402R)

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

Minguez, Pablo; Genolla, Jose; Celeiro, Jose Javier

2013-01-15

Purpose: The aim of this study has been to perform a dosimetric study in the treatments of differentiated thyroid cancer (DTC) performed in our center in order to find a dose-effect correlation. Methods: Thirty patients treated for DTC with 3700 MBq of {sup 131}I have been included in this study. For reasons of radiological protection all of them spent two nights as inpatients. Dose rate at 1 m from all patients was measured approximately 20 and 44 h after the administration of the radioiodine and a whole body scan in the gamma camera was performed approximately 1 week later. Withmore » those measurements and by using a model of two compartments the activities in thyroid bed remnants and in the whole body were calculated as a function of time. The integration of both activities yields the corresponding cumulated activities. Absorbed doses to thyroid bed remnants and to the whole body can be calculated following the MIRDOSE method-that is, by multiplying the corresponding cumulated activities by the corresponding S factors. Results: The absorbed doses to thyroid bed remnants calculated in this study fall into a very wide range (13-1161 Gy) and showed the highest correlation factors with the following parameters: the absorbed dose rate to thyroid bed remnants, the cumulated activity in thyroid bed remnants, and the maximum radioiodine uptake in thyroid bed remnants. The absorbed doses to the whole body range from 0.12 to 0.23 Gy. The ablation was successful in all patients, and in spite of the wide range of absorbed doses to thyroid bed remnants obtained, no dose-effect correlation could be obtained. Conclusions: Facing DTC treatments from a dosimetric viewpoint in which a predosimetry to calculate the activity of {sup 131}I to be administered is performed is a subject difficult to handle. This statement is based on the fact that although a very wide range of absorbed doses to thyroid bed remnants was obtained (including several absorbed doses well below some dose thresholds previously published to achieve ablation of thyroid bed remnants), ablation of thyroid bed remnants was successful for all patients and therefore no dose-effect correlation could be determined.« less

Is there a necessity for multiple doses of surfactant for respiratory distress syndrome of premature infants?

PubMed

Tsakalidis, Christos; Giougki, Evangelia; Karagianni, Paraskevi; Dokos, Charalampos; Rallis, Dimitrios; Nikolaidis, Nikolaos

2012-01-01

Both prophylactic and early surfactant (SF) replacement therapy reduce pulmonary complications and mortality in ventilated infants with respiratory distress syndrome (RDS). The effectiveness of one or more doses and the impact on morbidity and mortality of premature neonates with RDS need to be further clarified. The objective of this study was to investigate the necessity of repeated surfactant replacement therapy in premature infants ≤32 weeks of gestational age and the possibility of an underlying pathology. This study included 126 premature neonates of 24-32 weeks of gestation. We used 200 mg/kg per dose of porcine surfactant (Curosurf®) as primary treatment and 100 mg/kg in cases that required retreatment. The subjects were classified into two groups: the first group (Group 1) received a single dose of surfactant (n=98) and the second group (Group 2) included infants who required more than one dose (n=28). The 1st dose was administered in the first 20 minutes after birth while the second was given six hours later. In four cases, a 3rd dose was required, that was provided 12 hours after birth. Recorded data included: clinical and radiological classification of RDS, extubation time, oxygenation estimation indexes (OI: oxygenation index, A-aDO2: alveolar-arterial oxygen difference, a/APO2: arterial-alveolar ratio of partial oxygen pressure), requirement and duration of oxygen administration, total duration of mechanical ventilation, and survival rate. Patient Group 1 did not present any radiological findings of RDS of grade 3 or 4 six hours after SF administration, whereas such findings were recorded in three neonates of Group 2. Therefore, we assumed that failure of a single-dosing treatment indicates a more severe RDS and might reflect an underlying pathology. The impact of maternal chorioamnionitis in the neonates that necessitated further replacement therapy was statistically significant (p=0.045); moreover, infection markers were positive in the majority of the patient population of the second group. Twenty-two neonates (22%) of the first group needed intubation in the delivery room compared to 16 (57%) of the second group (p=0.0001). In conclusion, premature infants treated with a single dose of surfactant can usually be successfully extubated. Requirement of retreatment could be attributed to other pathogenetic mechanisms. A positive history of maternal chorioamnionitis was the commonest reason.

A double-blind, randomized pilot trial of chromium picolinate for binge eating disorder: results of the Binge Eating and Chromium (BEACh) study.

PubMed

Brownley, Kimberly A; Von Holle, Ann; Hamer, Robert M; La Via, Maria; Bulik, Cynthia M

2013-07-01

Chromium treatment has been shown to improve mood, appetite, and glucose regulation in various psychiatric and medical patient populations. The authors propose that chromium may be useful in the treatment of binge eating disorder (BED). Twenty-four overweight adults with BED were enrolled in a 6-month double-blind placebo-controlled trial and randomly assigned to receive either 1000mcg chromium/day ("high dose"; n=8) or 600mcg chromium/day ("moderate dose"; n=9) as chromium picolinate or placebo (n=7). Mixed linear regression models were used to estimate mean change in binge frequency and related psychopathology, weight, symptoms of depression, and fasting glucose. Fasting glucose was significantly reduced in both chromium groups compared to the placebo group; similarly, numerically, but not significantly, greater reductions in binge frequency, weight, and symptoms of depression were observed in those treated with chromium versus placebo, although statistical power was limited in this pilot trial. For fasting glucose, the findings suggest a dose response with larger effects in the high dose compared to moderate dose group. These initial findings support further larger trials to determine chromium's efficacy in maintaining normal glucose regulation, reducing binge eating and related psychopathology, promoting modest weight loss, and reducing symptoms of depression in individuals with BED. Studies designed to link the clinical effects of chromium with changes in underlying insulin, serotonin, and dopamine pathways may be especially informative. If efficacious, chromium supplementation may provide a useful, low-cost alternative to or augmentation strategy for selective serotonin reuptake inhibitors, which have partial efficacy in BED. ClinicalTrials.gov NCT00904306. Copyright © 2013 Elsevier Inc. All rights reserved.

Relieved residual damage in the hematopoietic system of mice rescued by radiation-induced adaptive response (Yonezawa Effect)

PubMed Central

Wang, Bing; Tanaka, Kaoru; Ninomiya, Yasuharu; Maruyama, Kouichi; VarèS, Guillaume; Eguchi-Kasai, Kiyomi; Nenoi, Mitsuru

2013-01-01

Existence of adaptive response (AR) was previously demonstrated in C57BL/6J mice. Irradiations were performed by delivering a priming low dose of X-rays (0.50 Gy) in combination with a challenge high dose of accelerated carbon or neon ion particles. AR was characterized by significantly decreased mortality in the 30-day survival test. This mouse AR model (‘Yonezawa Effect’) was originally established by using X-rays as both the priming and challenge irradiations. The underlying mechanism was due to radio-resistance occurring in blood-forming tissues. In this study, we verified the existence of AR and further investigated residual damage in the hematopoietic system in surviving animals. Results showed that the priming low dose of X-rays could relieve the detrimental effects on the hematopoietic system. We observed both an improvement in the blood platelet count and the ratio of polychromatic erythrocytes (PCEs) to the sum of PCEs and normochromatic erythrocytes (NCEs) and a marked reduction of the incidences of micronucleated PCEs and micronucleated NCEs. These findings suggest that the priming low dose of low linear energy transfer (LET) X-rays induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (residual anhematopoiesis and delayed genotoxic effects) caused by exposure to a high challenge dose from low-LET (X-ray) or high-LET (carbon and neon ion) irradiations. These findings provide new knowledge of the characterization of the Yonezawa Effect by providing new insight into the mechanistic study of AR in vivo. PMID:22923746

Theoretical study of the influence of a heterogeneous activity distribution on intratumoral absorbed dose distribution.

PubMed

Bao, Ande; Zhao, Xia; Phillips, William T; Woolley, F Ross; Otto, Randal A; Goins, Beth; Hevezi, James M

2005-01-01

Radioimmunotherapy of hematopoeitic cancers and micrometastases has been shown to have significant therapeutic benefit. The treatment of solid tumors with radionuclide therapy has been less successful. Previous investigations of intratumoral activity distribution and studies on intratumoral drug delivery suggest that a probable reason for the disappointing results in solid tumor treatment is nonuniform intratumoral distribution coupled with restricted intratumoral drug penetrance, thus inhibiting antineoplastic agents from reaching the tumor's center. This paper describes a nonuniform intratumoral activity distribution identified by limited radiolabeled tracer diffusion from tumor surface to tumor center. This activity was simulated using techniques that allowed the absorbed dose distributions to be estimated using different intratumoral diffusion capabilities and calculated for tumors of varying diameters. The influences of these absorbed dose distributions on solid tumor radionuclide therapy are also discussed. The absorbed dose distribution was calculated using the dose point kernel method that provided for the application of a three-dimensional (3D) convolution between a dose rate kernel function and an activity distribution function. These functions were incorporated into 3D matrices with voxels measuring 0.10 x 0.10 x 0.10 mm3. At this point fast Fourier transform (FFT) and multiplication in frequency domain followed by inverse FFT (iFFT) were used to effect this phase of the dose calculation process. The absorbed dose distribution for tumors of 1, 3, 5, 10, and 15 mm in diameter were studied. Using the therapeutic radionuclides of 131I, 186Re, 188Re, and 90Y, the total average dose, center dose, and surface dose for each of the different tumor diameters were reported. The absorbed dose in the nearby normal tissue was also evaluated. When the tumor diameters exceed 15 mm, a much lower tumor center dose is delivered compared with tumors between 3 and 5 mm in diameter. Based on these findings, the use of higher beta-energy radionuclides, such as 188Re and 90Y is more effective in delivering a higher absorbed dose to the tumor center at tumor diameters around 10 mm.

Higher anti-depressant dose and major adverse outcomes in moderate chronic kidney disease: a retrospective population-based study

PubMed Central

2014-01-01

Background Many older patients have chronic kidney disease (CKD), and a lower dose of anti-depressants paroxetine, mirtazapine and venlafaxine is recommended in patients with CKD to prevent drug accumulation from reduced elimination. Using information available in large population-based healthcare administrative databases, we conducted this study to determine if ignoring the recommendation and prescribing a higher versus lower dose of anti-depressants associates with a higher risk of adverse events. Methods We conducted a population-based cohort study to describe the 30-day risk of delirium in older adults who initiated a higher vs. lower dose of these three anti-depressants in routine care. We defined delirium using the best proxy available in our data sources - hospitalization with an urgent head computed tomography (CT) scan. We determined if CKD status modified the association between anti-depressant dose and outcome, and examined the secondary outcome of 30 day all-cause mortality. We used multivariable logistic regression analyses to estimate adjusted odds ratios (relative risk (RR)) and 95% confidence intervals. Results We identified adults (mean age 75) in Ontario who started a new study anti-depressant at a higher dose (n = 36,651; 31%) or lower dose (n = 81,160; 69%). Initiating a higher vs. lower dose was not associated with an increased risk of hospitalization with head CT (1.09% vs. 1.27% (adjusted RR 0.90; 95% CI, 0.80 to 1.02), but was associated with a lower risk of all-cause mortality (0.76% vs. 0.97% RR 0.82; 95% CI, 0.71 to 0.95). Neither of these relative risks were modified by the presence of CKD (p = 0.16, 0.68, respectively). Conclusions We did not observe an increase in two adverse outcomes when study anti-depressants were initiated at a higher dose in elderly patients with moderate CKD. Contrary to our hypothesis, the 30-day risk of mortality was lower when a higher versus lower dose of anti-depressant was initiated in these patients, a finding which requires corroboration and further study. PMID:24884589

Longitudinal trends of total white blood cell and differential white blood cell counts of atomic bomb survivors.

PubMed

Hsu, Wan-Ling; Tatsukawa, Yoshimi; Neriishi, Kazuo; Yamada, Michiko; Cologne, John; Fujiwara, Saeko

2010-01-01

In studying the late health effects of atomic-bomb (A-bomb) survivors, earlier findings were that white blood cell (WBC) count increased with radiation dose in cross-sectional studies. However, a persistent effect of radiation on WBC count and other risk factors has yet to be confirmed. The objectives of the present study were 1) to examine the longitudinal relationship between A-bomb radiation dose and WBC and differential WBC counts among A-bomb survivors and 2) to investigate the potential confounding risk factors (such as age at exposure and smoking status) as well as modification of the radiation dose-response. A total of 7,562 A-bomb survivors in Hiroshima and Nagasaki were included in this study from 1964-2004. A linear mixed model was applied using the repeated WBC measurements. During the study period, a secular downward trend of WBC count was observed. Radiation exposure was a significant risk factor for elevated WBC and differential WBC counts over time. A significant increase of WBC counts among survivors with high radiation dose (> 2 Gy) was detected in men exposed below the age of 20 and in women regardless of age at exposure. Effects on WBC of low dose radiation remain unclear, however. Cigarette smoking produced the most pronounced effect on WBC counts and its impact was much larger than that of radiation exposure.

Metabolomics reveals dose effects of low-dose chronic exposure to uranium in rats: identification of candidate biomarkers in urine samples.

PubMed

Grison, Stéphane; Favé, Gaëlle; Maillot, Matthieu; Manens, Line; Delissen, Olivia; Blanchardon, Éric; Dublineau, Isabelle; Aigueperse, Jocelyne; Bohand, Sandra; Martin, Jean-Charles; Souidi, Maâmar

2016-01-01

Data are sparse about the potential health risks of chronic low-dose contamination of humans by uranium (natural or anthropogenic) in drinking water. Previous studies report some molecular imbalances but no clinical signs due to uranium intake. In a proof-of-principle study, we reported that metabolomics is an appropriate method for addressing this chronic low-dose exposure in a rat model (uranium dose: 40 mg L -1 ; duration: 9 months, n = 10). In the present study, our aim was to investigate the dose-effect pattern and identify additional potential biomarkers in urine samples. Compared to our previous protocol, we doubled the number of rats per group (n = 20), added additional sampling time points (3 and 6 months) and included several lower doses of natural uranium (doses used: 40, 1.5, 0.15 and 0.015 mg L -1 ). LC-MS metabolomics was performed on urine samples and statistical analyses were made with SIMCA-P+ and R packages. The data confirmed our previous results and showed that discrimination was both dose and time related. Uranium exposure was revealed in rats contaminated for 9 months at a dose as low as 0.15 mg L -1 . Eleven features, including the confidently identified N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide and 4-hydroxyphenylacetylglycine, discriminated control from contaminated rats with a specificity and a sensitivity ranging from 83 to 96 %, when combined into a composite score. These findings show promise for the elucidation of underlying radiotoxicologic mechanisms and the design of a diagnostic test to assess exposure in urine, in a dose range experimentally estimated to be above a threshold between 0.015 and 0.15 mg L -1 .

Pharmacokinetics of nicorandil in dogs with mild mitral regurgitation.

PubMed

Fukunaga, K; Fujii, Y; Chiba, N; Ueshima, A; Wakao, Y; Mishima, K; Fujiwara, M; Orito, K

2011-02-01

The aim of this study was to examine the pharmacokinetics of nicorandil, a hybrid of an adenosine triphosphate-sensitive potassium channel opener and a nitrate, and to estimate its clinical doses in dogs with mild mitral valve regurgitation (MR). Nicorandil (0.1, 0.3, and 1.0 mg/kg) was administered orally to normal dogs and those with experimentally-induced MR, and its plasma concentrations were analyzed using high-performance liquid chromatography. Plasma concentrations increased dose-dependently after the administration of nicorandil, and were not different between normal dogs and those with MR. Similar to the effective plasma values obtained in cardiac disease in humans, the findings of this pharmacokinetic study may indicate that a dose of 0.3-1.0 mg/kg has the same effectiveness in dogs with cardiac dysfunction. Copyright © 2010. Published by Elsevier India Pvt Ltd.

Spatial features of dose-surface maps from deformably-registered plans correlate with late gastrointestinal complications

NASA Astrophysics Data System (ADS)

Moulton, Calyn R.; House, Michael J.; Lye, Victoria; Tang, Colin I.; Krawiec, Michele; Joseph, David J.; Denham, James W.; Ebert, Martin A.

2017-05-01

This study investigates the associations between spatial distribution of dose to the rectal surface and observed gastrointestinal toxicities after deformably registering each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate brachytherapy (HDRBT) prostate cancer treatment. The study contains data for 118 patients where the HDRBT CT was deformably-registered to the EBRT CT. The EBRT and registered HDRBT TG43 dose distributions in a reference 2 Gy/fraction were 3D-summed. Rectum dose-surface maps (DSMs) were obtained by virtually unfolding the rectum surface slice-by-slice. Associations with late peak gastrointestinal toxicities were investigated using voxel-wise DSM analysis as well as parameterised spatial patterns. The latter were obtained by thresholding DSMs from 1-80 Gy (increment  =  1) and extracting inferior-superior extent, left-right extent, area, perimeter, compactness, circularity and ellipse fit parameters. Logistic regressions and Mann-Whitney U-tests were used to correlate features with toxicities. Rectal bleeding, stool frequency, diarrhoea and urgency/tenesmus were associated with greater lateral and/or longitudinal spread of the high doses near the anterior rectal surface. Rectal bleeding and stool frequency were also influenced by greater low-intermediate doses to the most inferior 20% of the rectum and greater low-intermediate-high doses to 40-80% of the rectum length respectively. Greater low-intermediate doses to the superior 20% and inferior 20% of the rectum length were associated with anorectal pain and urgency/tenesmus respectively. Diarrhoea, completeness of evacuation and proctitis were also related to greater low doses to the posterior side of the rectum. Spatial features for the intermediate-high dose regions such as area, perimeter, compactness, circularity, ellipse eccentricity and confinement to ellipse fits were strongly associated with toxicities other than anorectal pain. Consequently, toxicity is related to the shape of isodoses as well as dose coverage. The findings indicate spatial constraints on doses to certain sections of the rectum may be important for reducing toxicities and optimising dose.

Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

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

Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, andmore » percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.« less

Preclinical toxicity profile of oral bilastine.

PubMed

Lucero, María Luisa; Arteche, Joseba K; Sommer, E W; Casadesus, Agustín

2012-06-01

As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastine-associated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage.

Gender differences in gastrointestinal disturbances and plasma concentrations of tafenoquine in healthy volunteers after tafenoquine administration for post-exposure vivax malaria prophylaxis.

PubMed

Edstein, M D; Nasveld, P E; Kocisko, D A; Kitchener, S J; Gatton, M L; Rieckmann, K H

2007-03-01

In an open-label sequential cohort study, we compared gastrointestinal (GI) disturbances and plasma tafenoquine concentrations after administration of single-dose (400mg daily x 3 days; n=76 males, 11 females) and split-dose (200 mg twice daily x 3 days; n=73 males, 13 females) tafenoquine regimens in healthy Australian Defence Force volunteers for post-exposure malaria prophylaxis. The female and male volunteers had comparable demographic characteristics (age, weight, height) in the single- and split-dose treatment groups. GI disturbances were generally mild and self-limiting for both groups. The frequency of nausea and abdominal distress was over two-fold higher in females than in males for both treatment groups. Reporting of GI disturbances in the single-dose group differed significantly between males and females, but this gender difference was not seen for the split-dose group. In those volunteers who experienced GI disturbances, the mean plasma tafenoquine concentrations 12 h after the last dose of tafenoquine were approximately 1.3-fold higher in females than in males (means+/-SD: 737+/-118 ng/ml vs. 581+/-113 ng/ml). These preliminary findings suggest that further studies are required in a larger number of females to determine whether there is a need to reduce the dose of tafenoquine to minimise GI disturbances in females.

Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study

PubMed Central

Cirak, Sebahattin; Arechavala-Gomeza, Virginia; Guglieri, Michela; Feng, Lucy; Torelli, Silvia; Anthony, Karen; Abbs, Stephen; Garralda, Maria Elena; Bourke, John; Wells, Dominic J; Dickson, George; Wood, Matthew JA; Wilton, Steve D; Straub, Volker; Kole, Ryszard; Shrewsbury, Stephen B; Sewry, Caroline; Morgan, Jennifer E; Bushby, Kate; Muntoni, Francesco

2011-01-01

Summary Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. Method We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. Findings 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1–10·6) to 16·4% (10·8–22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. Interpretation The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. Funding UK Medical Research Council; AVI BioPharma. PMID:21784508

A Phase I Dose-Finding Study of Silybin Phosphatidylcholine (Milk Thistle) in Patients With Advanced Hepatocellular Carcinoma

PubMed Central

Siegel, Abby B.; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S.; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.; Flaig, Thomas W.; Tsai, Wei Yann; Wu, David P. H.; Lee, Valerie; Greenlee, Heather

2013-01-01

Purpose To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Experimental Design Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Results Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Conclusion Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests. PMID:23757319

Evaluation of Genotoxicity and 28-day Oral Dose Toxicity on Freeze-dried Powder of Tenebrio molitor Larvae (Yellow Mealworm).

PubMed

Han, So-Ri; Yun, Eun-Young; Kim, Ji-Young; Hwang, Jae Sam; Jeong, Eun Ju; Moon, Kyoung-Sik

2014-06-01

The larval form of Tenebrio molitor (T. molitor) has been eaten in many countries and provides benefits as a new food source of protein for humans. However, no information exists regarding its safety for humans. The objective of the present study was to evaluate the genotoxicity and repeated dose oral toxicity of the freeze-dried powder of T. molitor larvae. The genotoxic potential was evaluated by a standard battery testing: bacterial reverse mutation test, in vitro chromosome aberration test, and in vivo micronucleus test. To assess the repeated dose toxicity, the powder was administered once daily by oral gavage to Sprague-Dawley (SD) rats at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 28 days. The parameters which were applied to the study were mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination. The freezedried powder of T. molitor larvae was not mutagenic or clastogenic based on results of in vitro and in vivo genotoxicity assays. Furthermore, no treatment-related changes or findings were observed in any parameters in rats after 28 days oral administration. In conclusion, the freeze-dried powder of T. molitor larvae was considered to be non-genotoxic and the NOAEL (No Observed Adverse Effect Level) was determined to be 3000 mg/kg/day in both sexes of SD rats under our experimental conditions.

Evaluation of Genotoxicity and 28-day Oral Dose Toxicity on Freeze-dried Powder of Tenebrio molitor Larvae (Yellow Mealworm)

PubMed Central

Han, So-Ri; Yun, Eun-Young; Kim, Ji-Young; Hwang, Jae Sam; Jeong, Eun Ju

2014-01-01

The larval form of Tenebrio molitor (T. molitor) has been eaten in many countries and provides benefits as a new food source of protein for humans. However, no information exists regarding its safety for humans. The objective of the present study was to evaluate the genotoxicity and repeated dose oral toxicity of the freeze-dried powder of T. molitor larvae. The genotoxic potential was evaluated by a standard battery testing: bacterial reverse mutation test, in vitro chromosome aberration test, and in vivo micronucleus test. To assess the repeated dose toxicity, the powder was administered once daily by oral gavage to Sprague-Dawley (SD) rats at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 28 days. The parameters which were applied to the study were mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination. The freezedried powder of T. molitor larvae was not mutagenic or clastogenic based on results of in vitro and in vivo genotoxicity assays. Furthermore, no treatment-related changes or findings were observed in any parameters in rats after 28 days oral administration. In conclusion, the freeze-dried powder of T. molitor larvae was considered to be non-genotoxic and the NOAEL (No Observed Adverse Effect Level) was determined to be 3000 mg/kg/day in both sexes of SD rats under our experimental conditions. PMID:25071922

Tactile massage reduces rescue doses for pain and anxiety: an observational study.

PubMed

Pedersen, Karina; Björkhem-Bergman, Linda

2018-03-01

The aim of this study was to evaluate the effect of tactile massage (TM) on palliative care patients. An observational study at a hospice ward in Sweden was carried out. Forty-one palliative patients were offered TM, at an average of three treatments per patient. Before and after every treatment, self-assessed pain, well-being and anxiety according to the Edmonton Symptom Assessment Scale (0-10) were recorded. In addition, the number of rescue doses for pain and anxiety was monitored 24 hours before and after the treatment and in two consecutive days before the patients were offered TM (control data). TM resulted in improvement of self-assessed pain by 1.7 points (SD 1.6), anxiety by 2.3 points (SD 2.0) and well-being by 2.6 points (SD 1.4). The number of rescue doses for pain was reduced from 1.6 to 0.84 doses/patient (P<0.001) and for anxiety from 0.52 to 0.24 doses/patient (P<0.01). The number of rescue doses was not changed in the same patients in two consecutive days before the patients were offered TM. The effect was evident already after the first treatment and did not increase further with repeated treatments. No patients reported any harmful effects of the treatment. TM reduced the need for administration of rescue doses for pain and anxiety and improved well-being in palliative care patients. Larger randomised studies with parallel control groups are needed to confirm the findings from this observational pilot study. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Radiation Dose Reduction by Indication-Directed Focused z-Direction Coverage for Neck CT.

PubMed

Parikh, A K; Shah, C C

2016-06-01

The American College of Radiology-American Society of Neuroradiology-Society for Pediatric Radiology Practice Parameter for a neck CT suggests that coverage should be from the sella to the aortic arch. It also recommends using CT scans judiciously to achieve the clinical objective. Our purpose was to analyze the potential dose reduction by decreasing the scan length of a neck CT and to assess for any clinically relevant information that might be missed from this modified approach. This retrospective study included 126 children who underwent a neck CT between August 1, 2013, and September 30, 2014. Alteration of the scan length for the modified CT was suggested on the topographic image on the basis of the indication of the study, with the reader blinded to the images and the report. The CT dose index volume of the original scan was multiplied by the new scan length to calculate the dose-length product of the modified study. The effective dose was calculated for the original and modified studies by using age-based conversion factors from the American Association of Physicists in Medicine Report No. 96. Decreasing the scan length resulted in an average estimated dose reduction of 47%. The average reduction in scan length was 10.4 cm, decreasing the overall coverage by 48%. The change in scan length did not result in any missed findings that altered management. Of the 27 abscesses in this study, none extended to the mediastinum. All of the lesions in question were completely covered. Decreasing the scan length of a neck CT according to the indication provides a significant savings in radiation dose, while not altering diagnostic ability or management. © 2016 by American Journal of Neuroradiology.

Trends in opioid use and dosing among socio-economically disadvantaged patients

PubMed Central

Gomes, Tara; Juurlink, David N; Dhalla, Irfan A; Mailis-Gagnon, Angela; Paterson, J Michael; Mamdani, Muhammad M

2011-01-01

Background Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality. Methods Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality. Results Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions. Interpretation Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed. PMID:22046214

Stimulation versus inhibition--bioactivity of parthenin, a phytochemical from Parthenium hysterophorus L.

PubMed

Belz, Regina G

2007-09-30

Parthenium hysterophorus L. is an invasive weed that biosynthesizes several phytochemicals. The sesquiterpene lactone parthenin receives most attention regarding allelopathy of the plant or potential herbicidal properties. Since parthenin exhibits dose-dependent phytotoxicity with low dose stimulation, this study investigated the occurrence and temporal features of parthenin hormesis in Sinapis arvensis L. sprayed with parthenin under semi-natural conditions. Dose/response studies showed that the occurrence and the magnitude of hormesis depended on climatic conditions and the parameter measured. Within the tested dose range, stimulatory responses were only observed under less-stressful conditions and were most pronounced for leaf area growth [138 % of control; 13 days after treatment (DAT)]. Temporal assessment of leaf area development showed that doses causing a stimulatory response at the end of the experiment (< 0.42 +/- 0.04 kg/ha; 13 DAT) were initially inhibitory up to ED(50) values (2 DAT). This clearly demonstrated an over-compensatory response. Inhibition of leaf area at 13 DAT reached ED(50) values on average at 0.62 +/-0.12 kg/ha, and S. arvensis was completely inhibited at doses exceeding 1.81 +/-0.56 kg/ha (ED(90)). Based on these findings, implications of parthenin hormesis are discussed with respect to allelopathy of P. hysterophorus and exploitation of growth stimulatory responses in agriculture.

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Sub-Chronic Oral Exposure to Iridium (III) Chloride Hydrate in Female Wistar Rats: Distribution and Excretion of the Metal

PubMed Central

Iavicoli, Ivo; Fontana, Luca; Bergamaschi, Antonio; Conti, Marcelo Enrique; Pino, Anna; Mattei, Daniela; Bocca, Beatrice; Alimonti, Alessandro

2012-01-01

Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure. PMID:22942873

Evaluation of scattered radiation emitted from X-ray security scanners on occupational dose to airport personnel

NASA Astrophysics Data System (ADS)

Dalah, Entesar; Fakhry, Angham; Mukhtar, Asma; Al Salti, Farah; Bader, May; Khouri, Sara; Al-Zahmi, Reem

2017-06-01

Based on security issues and regulations airports are provided with luggage cargo scanners. These scanners utilize ionizing radiation that in principle present health risks toward humans. The study aims to investigate the amount of backscatter produced by passenger luggage and cargo toward airport personnel who are located at different distances from the scanners. To approach our investigation a Thermo Electron Radeye-G probe was used to quantify the backscattered radiation measured in terms of dose-rate emitted from airport scanners, Measurements were taken at the entrance and exit positions of the X-ray tunnel at three different distances (0, 50, and 100 cm) for two different scanners; both scanners include shielding curtains that reduce scattered radiation. Correlation was demonstrated using the Pearson coefficient test. Measurements confirmed an inverse relationship between dose rate and distance. An estimated occupational accumulative dose of 0.88 mSv/y, and 2.04 mSv/y were obtained for personnel working in inspection of carry-on, and cargo, respectively. Findings confirm that the projected dose of security and engineering staff are being well within dose limits.

Reprint of 'Evaluation of Scattered Radiation Emitted From X-ray Security Scanners on Occupational Dose to Airport Personnel'

NASA Astrophysics Data System (ADS)

Dalah, Entesar; Fakhry, Angham; Mukhtar, Asma; Al Salti, Farah; Bader, May; Khouri, Sara; Al-Zahmi, Reem

2017-11-01

Based on security issues and regulations airports are provided with luggage cargo scanners. These scanners utilize ionizing radiation that in principle present health risks toward humans. The study aims to investigate the amount of backscatter produced by passenger luggage and cargo toward airport personnel who are located at different distances from the scanners. To approach our investigation a Thermo Electron Radeye-G probe was used to quantify the backscattered radiation measured in terms of dose-rate emitted from airport scanners, Measurements were taken at the entrance and exit positions of the X-ray tunnel at three different distances (0, 50, and 100 cm) for two different scanners; both scanners include shielding curtains that reduce scattered radiation. Correlation was demonstrated using the Pearson coefficient test. Measurements confirmed an inverse relationship between dose rate and distance. An estimated occupational accumulative dose of 0.88 mSv/y, and 2.04 mSv/y were obtained for personnel working in inspection of carry-on, and cargo, respectively. Findings confirm that the projected dose of security and engineering staff are being well within dose limits.

Hormesis associated with a low dose of methylmercury injected into mallard eggs

USGS Publications Warehouse

Heinz, Gary H.; Hoffman, David J.; Klimstra, Jon D.; Stebbins, Katherine R.; Kondrad, Shannon L.; Erwin, Carol A.

2012-01-01

We injected mallard (Anas platyrhynchos) eggs with methylmercury chloride at doses of 0, 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 μg mercury/g egg contents on a wet-weight basis. A case of hormesis seemed to occur because hatching success of eggs injected with 0.05 μg mercury (the lowest dose) was significantly greater (93.3%) than that of controls (72.6%), whereas hatching success decreased at progressively greater doses of mercury. Our finding of hormesis when a low dose of methylmercury was injected into eggs agrees with a similar observation in a study in which a group of female mallards was fed a low dietary concentration of methylmercury and hatching of their eggs was significantly better than that of controls. If methylmercury has a hormetic effect at low concentrations in avian eggs, these low concentrations may be important in a regulatory sense in that they may represent a no-observed adverse effect level (NOAEL).

Quality and efficiency of statin prescribing across countries with a special focus on South Africa: findings and future implications.

PubMed

Godman, Brian; Bishop, Iain; Campbell, Stephen M; Malmström, Rickard E; Truter, Ilse

2015-04-01

Statins are recommended first-line treatment for hyperlipidemia, with published studies suggesting limited differences between them. However, there are reports of under-dosing. South Africa has introduced measures to enhance generic utilization. Part one documents prescribed doses of statins in 2011. Part two determines the extent of generics versus originator and single-sourced statins in 2011 and their costs. Underdosing of simvastatin in 2011 with average prescribed dose of 23.7 mg; however, not for atorvastatin (20.91 mg) or rosuvastatin (15.02 mg). High utilization of generics versus originators at 93-99% for atorvastatin and simvastatin, with limited utilization of single-sourced statins (22% of total statins - defined daily dose basis), mirroring Netherlands, Sweden and UK. Generics priced 33-51% below originator prices. Opportunity to increase simvastatin dosing through education, prescribing targets and incentives. Opportunity to lower generic prices with generic simvastatin 96-98% below single-sourced prices in some European countries.

Pathology in rabbits treated with leukocyte-degraded meningococci in combination with meningococcal endotoxin.

PubMed Central

DeVoe, I W; Gilka, F; Gilchrist, J E; Yu, E

1977-01-01

The effects of a preparative dose of the leukocyte egesta containing degraded meningococci and a provocative dose of the meningococcal lipopolysaccharide on development of pathological lesions associated with disseminated intravascular coagulation were studied in tissues of 32 rabbits. These effects were compared with effects of a single dose of meningococcal lipopolysaccharide as well as leukocyte egesta containing degraded Staphylococcus epidermidis. Rabbits injected subcutaneously with egesta containing degraded meningococci followed after 12 h with meningococcal endotoxin (intravenously) exhibited heterophilic leukocytosis and disseminated intravascular coagulation mainly in the pulmonary capillaries and venules; focal necroses occurred in myocardium, lungs, and liver, whereas, cortical renal necrosis developed in lethal cases. Similar lesions, however, but less severe and with less frequency, developed even after a single dose of meningococcal endotoxin or after endotoxin that followed a dose of supernatant fluid from normal leukocytes. Our findings suggest that meningococcal material from polymorphonuclear degradation plays a role in the pathology characteristic of meningococcal septicemia. Images PMID:406202

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Background Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. PMID:27073327

Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses.

PubMed

Honkalammi, Johanna; Niemi, Mikko; Neuvonen, Pertti J; Backman, Janne T

2011-10-01

Gemfibrozil 1-O-β-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of gemfibrozil dose on CYP2C8 activity in humans using repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of repaglinide 1 h after different doses of gemfibrozil or placebo. Concentrations of plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. A single gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P < 0.001), and its peak concentration 1.4-, 1.7-, 2.1-, and 2.4-fold (P < 0.05), compared with placebo, respectively. Gemfibrozil pharmacokinetics was characterized by a slightly more than dose-proportional increase in the area under the curve of gemfibrozil and its glucuronide. The gemfibrozil-repaglinide interaction could be mainly explained by gemfibrozil 1-O-β-glucuronide concentration-dependent, mechanism-based inhibition of CYP2C8, with a minor contribution by competitive inhibition of organic anion-transporting polypeptide 1B1 at the highest gemfibrozil dose. The findings are consistent with ∼50% inhibition of CYP2C8 already with a single 30-mg dose of gemfibrozil and >95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.

Study Shows Aspirin Reduces Colorectal Cancer in Those at High Risk

Cancer.gov

Findings from the first large clinical trial of its kind indicate that taking high doses of aspirin daily for at least 2 years substantially reduces the risk of colorectal cancer among people at increased risk of the disease.

Glyphosate rodent carcinogenicity bioassay expert panel review.

PubMed

Williams, Gary M; Berry, Colin; Burns, Michele; de Camargo, Joao Lauro Viana; Greim, Helmut

2016-09-01

Glyphosate has been rigorously and extensively tested for carcinogenicity by administration to mice (five studies) and to rats (nine studies). Most authorities have concluded that the evidence does not indicate a cancer risk to humans. The International Agency for Research on Cancer (IARC), however, evaluated some of the available data and concluded that glyphosate probably is carcinogenic to humans. The expert panel convened by Intertek assessed the findings used by IARC, as well as the full body of evidence and found the following: (1) the renal neoplastic effects in males of one mouse study are not associated with glyphosate exposure, because they lack statistical significance, strength, consistency, specificity, lack a dose-response pattern, plausibility, and coherence; (2) the strength of association of liver hemangiosarcomas in a different mouse study is absent, lacking consistency, and a dose-response effect and having in high dose males only a significant incidence increase which is within the historical control range; (3) pancreatic islet-cell adenomas (non-significant incidence increase), in two studies of male SD rats did not progress to carcinomas and lacked a dose-response pattern (the highest incidence is in the low dose followed by the high dose); (4) in one of two studies, a non-significant positive trend in the incidence of hepatocellular adenomas in male rats did not lead to progression to carcinomas; (5) in one of two studies, the non-significant positive trend in the incidence of thyroid C-cell adenomas in female rats was not present and there was no progression of adenomas to carcinomas at the end of the study. Application of criteria for causality considerations to the above mentioned tumor types and given the overall weight-of-evidence (WoE), the expert panel concluded that glyphosate is not a carcinogen in laboratory animals.

Dose-dependent response of Trichoderma harzianum in improving drought tolerance in rice genotypes.

PubMed

Pandey, Veena; Ansari, Mohammad W; Tula, Suresh; Yadav, Sandep; Sahoo, Ranjan K; Shukla, Nandini; Bains, Gurdeep; Badal, Shail; Chandra, Subhash; Gaur, A K; Kumar, Atul; Shukla, Alok; Kumar, J; Tuteja, Narendra

2016-05-01

This study demonstrates a dose-dependent response of Trichoderma harzianum Th-56 in improving drought tolerance in rice by modulating proline, SOD, lipid peroxidation product and DHN / AQU transcript level, and the growth attributes. In the present study, the effect of colonization of different doses of T. harzianum Th-56 strain in rice genotypes were evaluated under drought stress. The rice genotypes treated with increasing dose of T. harzianum strain Th-56 showed better drought tolerance as compared with untreated control plant. There was significant change in malondialdehyde, proline, higher superoxide dismutase level, plant height, total dry matter, relative chlorophyll content, leaf rolling, leaf tip burn, and the number of scorched/senesced leaves in T. harzianum Th-56 treated rice genotypes under drought stress. This was corroborated with altered expression of aquaporin and dehydrin genes in T. harzianum Th-56 treated rice genotypes. The present findings suggest that a dose of 30 g/L was the most effective in improving drought tolerance in rice, and its potential exploitation will contribute to the advancement of rice genotypes to sustain crop productivity under drought stress. Interaction studies of T. harzianum with three aromatic rice genotypes suggested that PSD-17 was highly benefitted from T. harzianum colonization under drought stress.

[Personalized drug therapy-directed clinical pharmacology research based on genetic polymorphisms and pharmacokinetics analysis].

PubMed

Hayashi, Hideki

2013-01-01

In this decade, the field of pharmacogenomics (PGx), which is related to pharmacokinetics (PK) or pharmacodynamics (PD), has attracted much attention because it may provide a possible explanation for individual differences in the clinical efficacy of drugs. For the development of personalized drug therapy, it is important to accumulate evidence from PK/PD/PGx analysis in clinical trials. Warfarin (WF) is one of the most widely prescribed anticoagulants for the prevention and treatment of venous and arterial thromboembolism. However, large interindividual and interethnic differences have been observed in the WF dose required to elicit the anticoagulant effect. We investigated the factors influencing the WF maintenance dose in Japanese patients. Our study confirmed a large interindividual variability in the WF maintenance dose that was due to a VKORC1 1639 G>A polymorphism and differences in body weight, age, and serum albumin. In addition, we found that the CYP4F2 genotype affects the plasma concentration of menaquinone-4, and that this finding was correlated with the WF sensitivity index in Japanese pediatric patients. Methotrexate (MTX) is an antifolate that is widely used to treat rheumatoid arthritis (RA) and cancer. The response to low-dose MTX demonstrated wide interpatient variability; however, the contributing factors remain unclear. We found that the frequency of the RFC1 80A allele was higher in RA patients treated with MTX alone compared with patients who received biological disease-modifying antirheumatic drugs (bDMARDs). This finding may support the combined use of bDMARDs and MTX. Further large-scale prospective clinical trials are required to confirm these findings.

Selection of the initial design for the two-stage continual reassessment method.

PubMed

Jia, Xiaoyu; Ivanova, Anastasia; Lee, Shing M

2017-01-01

In the two-stage continual reassessment method (CRM), model-based dose escalation is preceded by a pre-specified escalating sequence starting from the lowest dose level. This is appealing to clinicians because it allows a sufficient number of patients to be assigned to each of the lower dose levels before escalating to higher dose levels. While a theoretical framework to build the two-stage CRM has been proposed, the selection of the initial dose-escalating sequence, generally referred to as the initial design, remains arbitrary, either by specifying cohorts of three patients or by trial and error through extensive simulations. Motivated by a currently ongoing oncology dose-finding study for which clinicians explicitly stated their desire to assign at least one patient to each of the lower dose levels, we proposed a systematic approach for selecting the initial design for the two-stage CRM. The initial design obtained using the proposed algorithm yields better operating characteristics compared to using a cohort of three initial design with a calibrated CRM. The proposed algorithm simplifies the selection of initial design for the two-stage CRM. Moreover, initial designs to be used as reference for planning a two-stage CRM are provided.

The Impact of Azilsartan Medoxomil Treatment (Capsule Formulation) at Doses Ranging From 10 to 80 mg: Significant, Rapid Reductions in Clinic Diastolic and Systolic Blood Pressure.

PubMed

Perez, Alfonso; Cao, Charlie

2017-03-01

In this phase 2, multicenter, parallel-group, double-blind, dose-ranging study, hypertensive adults (n=449) were randomized to receive one of five doses of a capsule formulation of azilsartan medoxomil (AZL-M; 5, 10, 20, 40, 80 mg), olmesartan medoxomil (OLM) 20 mg, or placebo once daily. The primary endpoint was change in trough clinic diastolic blood pressure (DBP) at week 8. AZL-M provided rapid statistically and clinically significant reductions in DBP and systolic blood pressure (SBP) vs placebo at all doses except 5 mg. Placebo-subtracted changes were greatest with the 40 mg dose (DBP, -5.7 mm Hg; SBP, -12.3 mm Hg). Clinic changes with AZL-M (all doses) were statistically indistinguishable vs OLM, although there were greater reductions with AZL-M 40 mg using 24-hour ambulatory blood pressure. Adverse event frequency was similar in the AZL-M and placebo groups. Based on these and other findings, subsequent trials investigated the commercial AZL-M tablet in the dose range of 20 to 80 mg/d. ©2016 Wiley Periodicals, Inc.

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

PubMed

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

2013-02-01

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

Biphasic Effects of Alcohol on Delay and Probability Discounting

PubMed Central

Bidwell, L. Cinnamon; MacKillop, James; Murphy, James G.; Grenga, Andrea; Swift, Robert M.; McGeary, John E.

2014-01-01

Delay discounting and probability discounting are behavioral economic indices of impulsive and risky decision making that have been associated with addictive behavior, but the acute biphasic effects of alcohol on these decision-making processes are not well understood. This study sought to investigate the biphasic effects of alcohol on delay and probability discounting across the ascending and descending limbs of the breath alcohol concentration (BAC) curve, which are respectively characterized by the stimulant and sedative effects of alcohol. Delay and probability discounting were measured at four time points (Baseline, Ascending, Descending, and Endpoint) across the BAC curve at two target alcohol doses (40 mg/dl and 80 mg/dl) in healthy adults (N = 23 and 27, for both doses, respectively). There was no significant effect of alcohol on delay discounting at either dose. Alcohol significantly affected probability discounting, such that reduced discounting for uncertain rewards was evident during the descending limb of the BAC curve at the lower dose (p<.05) and during both the ascending and descending limb of the BAC curve at the higher dose (p<.05). Thus, alcohol resulted in increased risky decision making, particularly during the descending limb which is primarily characterized by the sedative effects of alcohol. These findings suggest that the biphasic effects of alcohol across the ascending and descending limbs of the BAC have differential effects on behavior related to decision-making for probabilistic, but not delayed, rewards. Parallels to and distinctions from previous findings are discussed. PMID:23750692

42 CFR 82.31 - How can the public recommend changes to scientific elements underlying the dose reconstruction...

Code of Federal Regulations, 2010 CFR

2010-10-01

... SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES METHODS FOR CONDUCTING DOSE RECONSTRUCTION UNDER THE ENERGY EMPLOYEES OCCUPATIONAL ILLNESS... elements underlying the dose reconstruction process, based on relevant new research findings and...

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects.

PubMed

Iitsuka, Hiromi; van Gelderen, Marcel; Katashima, Masataka; Takusagawa, Shin; Sawamoto, Taiji

2015-05-01

The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. In total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. After administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0-∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. Our studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Low-voltage chest CT: another way to reduce the radiation dose in asbestos-exposed patients.

PubMed

Macía-Suárez, D; Sánchez-Rodríguez, E; Lopez-Calviño, B; Diego, C; Pombar, M

2017-09-01

To assess whether low voltage chest computed tomography (CT) can be used to successfully diagnose disease in patients with asbestos exposure. Fifty-six former employees of the shipbuilding industry, who were candidates to receive a standard-dose chest CT due to their occupational exposure to asbestos, underwent a routine CT. Immediately after this initial CT, they underwent a second acquisition using low-dose chest CT parameters, based on a low potential (80 kV) and limited tube current. The findings of the two CT protocols were compared based on typical diseases associated with asbestos exposure. The kappa coefficient for each parameter and for an overall rating (grouping them based on mediastinal, pleural, and pulmonary findings) were calculated in order to test for correlations between the two protocols. A good correlation between routine and low-dose CT was demonstrated for most parameters with a mean radiation dose reduction of up to 83% of the effective dose based on the dose-length product between protocols. Low-dose chest CT, based on a limited tube potential, is useful for patients with an asbestos exposure background. Low-dose chest CT can be successfully used to minimise the radiation dose received by patients, as this protocol produced an estimated mean effective dose similar to that of an abdominal or pelvis plain film. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

DELAYED PREPUTIAL SEPARATION (PPS) AND SP22 MEASUREMENT IN RATS ADMINISTERED BROMOCHLOROACETIC ACID (BCA) IN DRINKING WATER

EPA Science Inventory

Reproductive effects of BCA were determined in a dose range finding study (DRFS) and definitive two-generational study. Adult male and female CD� (SD) rats were administered BCA in drinking water for two weeks in the DRFS (10/sex/group) and ten weeks in the definitive study (25/s...

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

Background The pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. PMID:24353445

In Vivo Dosimetry of High-Dose-Rate Interstitial Brachytherapy in the Pelvic Region: Use of a Radiophotoluminescence Glass Dosimeter for Measurement of 1004 Points in 66 Patients With Pelvic Malignancy

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

Nose, Takayuki; Department of Physics, Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo; Koizumi, Masahiko

2008-02-01

Purpose: To perform the largest in vivo dosimetry study for interstitial brachytherapy yet to be undertaken using a new radiophotoluminescence glass dosimeter (RPLGD) in patients with pelvic malignancy and to study the limits of contemporary planning software based on the results. Patients and Methods: Sixty-six patients with pelvic malignancy were treated with high-dose-rate interstitial brachytherapy, including prostate (n = 26), gynecological (n = 35), and miscellaneous (n = 5). Doses for a total of 1004 points were measured by RPLGDs and calculated with planning software in the following locations: rectum (n = 549), urethra (n = 415), vagina (n =more » 25), and perineum (n = 15). Compatibility (measured dose/calculated dose) was analyzed according to dosimeter location. Results: The compatibility for all dosimeters was 0.98 {+-} 0.23, stratified by location: rectum, 0.99 {+-} 0.20; urethra, 0.96 {+-} 0.26; vagina, 0.91 {+-} 0.08; and perineum, 1.25 {+-} 0.32. Conclusions: Deviations between measured and calculated doses for the rectum and urethra were greater than 20%, which is attributable to the independent movements of these organs and the applicators. Missing corrections for inhomogeneity are responsible for the 9% negative shift near the vaginal cylinder (specific gravity = 1.24), whereas neglect of transit dose contributes to the 25% positive shift in the perineal dose. Dose deviation of >20% for nontarget organs should be taken into account in the planning process. Further development of planning software and a real-time dosimetry system are necessary to use the current findings and to achieve adaptive dose delivery.« less

Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study)

PubMed Central

Hegarty, Joanne Elizabeth; Harding, Jane Elizabeth; Gamble, Gregory David; Crowther, Caroline Anne; Edlin, Richard; Alsweiler, Jane Marie

2016-01-01

Background Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk. Methods and Findings We conducted a randomised, double-blind, placebo-controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47–0.99, p = 0.04) but was not significantly different between dose groups (p = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64–0.98, p = 0.03; number needed to treat = 10, 95% CI 5–115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33–1.25, p = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21–1.01, p = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups. Conclusions The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12613000322730 PMID:27780197

The effect of grape seed extract on estrogen levels of postmenopausal women: a pilot study.

PubMed

Wahner-Roedler, Dietlind L; Bauer, Brent A; Loehrer, Laura L; Cha, Stephen S; Hoskin, Tanya L; Olson, Janet E

2014-06-01

The role of estrogens in breast cancer (BC) development is widely accepted, leading to the development of selective estrogen receptor modulators and aromatase inhibitors for BC treatment and prevention. However, because of potential adverse effects, healthy women with high risk of BC are hesitant to take them. Preliminary evidence from animal studies shows that grapes may have an aromatase-inhibiting effect, decreasing estrogen synthesis and increasing androgen precursors. We conducted a randomized, double-blind, dose-finding early-phase trial on the effect of grape seed extract (GSE) on estrogen levels. Postmenopausal women who met study inclusion criteria (N = 46) were randomly assigned to daily GSE at a dose of 200, 400, 600, or 800 mg for 12 weeks. Primary outcome was change in plasma levels of estrogen conjugates from baseline to 12 weeks posttreatment. Thirty-nine participants (84.8%) completed the study. GSE in the 4 daily doses did not significantly decrease estrogen or increase androgen precursors.

Randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of three doses of co-suspension delivery technology glycopyrronium MDI in Japanese patients with moderate-to-severe COPD.

PubMed

Fukushima, Yasushi; Nakatani, Yuji; Ide, Yumiko; Sekino, Hisakuni; St Rose, Earl; Siddiqui, Shahid; Maes, Andrea; Reisner, Colin

Due to the burden of COPD in Japan, new pharmacologic treatments are needed to meet patient requirements. This study assessed the efficacy and safety of glycopyrronium (GP) delivered via metered dose inhaler (MDI) in Japanese patients with moderate-to-severe COPD. This Phase IIb, multicenter, randomized, double-blind, 7-day, crossover study compared GP MDI 28.8, 14.4, and 7.2 μg with placebo MDI (all administered as two inhalations, twice daily). The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV 1 ) on Day 8. Secondary endpoints included FEV 1 area under the curve from 0 to 2 hours (AUC 0-2 ) and peak change from baseline in FEV 1 on Days 1 and 8 and forced vital capacity AUC 0-2 on Day 8. Safety was also assessed. ClinicalTrials.gov Identifier: NCT03256552; http://www.ClinicalTrials.gov. Sixty-six patients were randomized and 62 were included in the modified intent-to-treat population (mean age 67.5 years). All three GP MDI doses significantly improved change from baseline in morning pre-dose trough FEV 1 on Day 8 compared with placebo MDI (least squares mean differences 108-131 mL; all p <0.0001). Significant improvements in secondary efficacy endpoints were also observed for all three GP MDI doses compared with placebo MDI (all p <0.0001). Dose-response plateaued at GP MDI 14.4 μg. No significant safety findings were observed with any GP MDI dose or placebo MDI. The results of this study suggest that GP MDI 14.4 μg (7.2 μg per inhalation) is the most appropriate dose for use in Phase III studies in Japanese patients with moderate-to-severe COPD.

Risk of Radiation Retinopathy in Patients With Orbital and Ocular Lymphoma

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

Kaushik, Megha; Pulido, Jose S.; Schild, Steven E.

2012-12-01

Purpose: Radiation retinopathy is a potential long-term complication of radiation therapy to the orbit. The risk of developing this adverse effect is dose dependent; however, the threshold is unclear. The aim of this study was to identify the risk of developing radiation retinopathy at increasing radiation doses. Methods and Materials: A 40-year retrospective review was performed of patients who received external beam radiation therapy for ocular/orbital non-Hodgkin lymphoma (NHL). Results: Sixty-seven patients who had at least one ophthalmic follow-up examination were included in this study. Most patients (52%) were diagnosed with NHL involving the orbit. Patients received external beam radiationmore » therapy at doses between 1886 and 5400 cGy (mean, 3033 {+-} 782 cGy). Radiation retinopathy developed in 12% of patients, and the median time to diagnosis was 27 months (range, 15-241months). The mean prescribed radiation dose in patients with retinopathy was 3309 {+-} 585 cGy, and the estimated retinal dose (derived by reviewing the dosimetry) was 3087 {+-} 1030 cGy. The incidence of retinopathy increased with dose. The average prescribed daily fractionated dose was higher in patients who developed retinopathy than in patients who did not (mean, 202 cGy vs 180 cGy, respectively; P = .04). More patients with radiation retinopathy had comorbid diabetes mellitus type 2 than patients without retinopathy (P = .015). In our study, the mean visual acuity of the eyes that received radiation was worse than that of the eyes that did not (P = .027). Other postradiotherapy ocular findings included keratitis (6%), dry eyes (39%), and cataract (33%). Conclusions: Radiation retinopathy, a known complication of radiotherapy for orbital tumors, relates to vascular comorbidities and dose. Higher total doses and larger daily fractions (>180 cGy) appear to be related to higher rates of retinopathy. Future larger studies are required to identify a statistically significant threshold for the development of retinopathy.« less

Fish intake and risk of heart failure: A meta-analysis of five prospective cohort studies

PubMed Central

HOU, LI-NA; LI, FEI; ZHOU, YOU; NIE, SHI-HUAI; SU, LIANG; CHEN, PING-AN; TAN, WAN-LONG; XU, DING-LI

2012-01-01

The findings on the association between fish intake and the risk of heart failure (HF) have been inconsistent. The purpose of this study was to clarify this potential association. We searched for relevant studies in the PubMed database through January 2012 and manually reviewed references. Five independent prospective cohort studies involving 5,273 cases and 144,917 participants were included. The summary relative risk estimates (SRRE) based on the highest compared with the lowest category of fish consumption were estimated by variance-based meta-analysis. In addition, we performed sensitivity and dose-response analyses to examine the association. Overall, an absence of an association between fish intake and HF was observed (SRRE=1.00; 95% CI, 0.81–1.24). However, fried fish intake positively associated with HF (SRRE=1.40; 95% CI, 1.22–1.61). In addition, dose-response analysis of fried fish suggested that each increment of six fried fish per month corresponded to a 37% increase of HF rate (RR=1.37; 95% CI, 1.20–1.56). In conclusion, our findings suggest that there is no significant association between fish intake and risk of HF, with the exception of a possible positive correlation with individuals comsuming fried fish, based on a limited number of studies. Future studies are required to confirm these findings. PMID:23181122

Can we use the equivalent sphere model to approximate organ doses in space radiation environments?

NASA Astrophysics Data System (ADS)

Lin, Zi-Wei

For space radiation protection one often calculates the dose or dose equivalent in blood forming organs (BFO). It has been customary to use a 5cm equivalent sphere to approximate the BFO dose. However, previous studies have concluded that a 5cm sphere gives a very different dose from the exact BFO dose. One study concludes that a 9cm sphere is a reasonable approximation for the BFO dose in solar particle event (SPE) environments. In this study we investigate the reason behind these observations and extend earlier studies by studying whether BFO, eyes or the skin can be approximated by the equivalent sphere model in different space radiation environments such as solar particle events and galactic cosmic ray (GCR) environments. We take the thickness distribution functions of the organs from the CAM (Computerized Anatomical Man) model, then use a deterministic radiation transport to calculate organ doses in different space radiation environments. The organ doses have been evaluated with a water or aluminum shielding from 0 to 20 g/cm2. We then compare these exact doses with results from the equivalent sphere model and determine in which cases and at what radius parameters the equivalent sphere model is a reasonable approximation. Furthermore, we propose to use a modified equivalent sphere model with two radius parameters to represent the skin or eyes. For solar particle events, we find that the radius parameters for the organ dose equivalent increase significantly with the shielding thickness, and the model works marginally for BFO but is unacceptable for eyes or the skin. For galactic cosmic rays environments, the equivalent sphere model with one organ-specific radius parameter works well for the BFO dose equivalent, marginally well for the BFO dose and the dose equivalent of eyes or the skin, but is unacceptable for the dose of eyes or the skin. The BFO radius parameters are found to be significantly larger than 5 cm in all cases, consistent with the conclusion of an earlier study. The radius parameters for the dose equivalent in GCR environments are approximately between 10 and 11 cm for the BFO, 3.7 to 4.8 cm for eyes, and 3.5 to 5.6 cm for the skin; while the radius parameters are between 10 and 13 cm for the BFO dose. In the proposed modified equivalent sphere model, the range of each of the two radius parameters for the skin (or eyes) is much tighter than that in the equivalent sphere model with one radius parameter. Our results thus show that the equivalent sphere model works better in galactic cosmic rays environments than in solar particle events. The model works well or marginally well for BFO but usually does not work for eyes or the skin. A modified model with two radius parameters works much better in approximating the dose and dose equivalent in eyes or the skin.

Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study.

PubMed

Sankaranarayanan, Rengaswamy; Joshi, Smita; Muwonge, Richard; Esmy, Pulikottil Okkuru; Basu, Partha; Prabhu, Priya; Bhatla, Neerja; Nene, Bhagwan M; Shaw, Janmesh; Poli, Usha Rani Reddy; Verma, Yogesh; Zomawia, Eric; Pimple, Sharmila; Tommasino, Massimo; Pawlita, Michael; Gheit, Tarik; Waterboer, Tim; Sehr, Peter; Pillai, Madhavan Radhakrishna

2018-03-15

Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to 'no vaccination'. In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10-18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women. Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is 'no intervention'. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Safety of fluralaner oral solution, a novel systemic antiparasitic treatment for chickens, in laying hens after oral administration via drinking water.

PubMed

Prohaczik, Angella; Menge, Monika; Huyghe, Bruno; Flochlay-Sigognault, Annie; Traon, Gaëlle Le

2017-08-08

Poultry mites are the most significant pest affecting production systems in the egg-laying industry. Fluralaner is a novel systemic insecticide and acaricide that is effective against poultry mites (Dermanyssus gallinae, Ornithonyssus sylviarum) in chickens after oral administration. This study investigated the safety of oral administration of a 1% solution of fluralaner in drinking water to laying hens at the recommended treatment dose and at multiples of this dose. One hundred-twenty healthy 28-week-old laying hens, weighing 1.4-2.1 kg at first administration, were included in the study, and allocated to 4 treatment groups of 30 hens each receiving daily doses of 0, 0.5, 1.5 and 2.5 mg fluralaner/kg body weight, equivalent to 0, 1, 3, and 5 times the recommended dose of fluralaner. The product was administered via drinking water on a total of six occasions, as 3-day treatment periods twice with an interval of 4 days with no treatment (treatment on days 1, 2, 3 and 8, 9, 10), representing 3 times the recommended number of administrations. Hens supplied with non-medicated drinking water served as controls. During the study, all hens were clinically observed, and their health was carefully monitored including body weight, food and water consumption, hematology, clinical chemistry, and withdrawal reflex test. Eggs laid over the study were evaluated for main characteristics (e.g. weight, shape, strength, shell thickness and soundness, albumen height, yolk color, Haugh unit and presence of blood and/or meat spots). Following euthanasia of the hens at the end of the second treatment period (day 11) or 18 days later (day 29), complete gross post-mortem examination, including organ weight determination, and histopathological examination of multiple tissues were conducted. There were no clinical findings related to fluralaner treatment. Statistically significant differences between the treated groups and the control group were observed for some clinical pathology parameters; none of these findings were considered to be of clinical nor zootechnical relevance. Organ weights, gross post mortem and histopathological examinations did not reveal any finding associated with treatment with fluralaner. Oral administration of fluralaner via drinking water at the recommended treatment dose (0.5 mg/kg body weight twice at 1-week interval), is well tolerated and has a high safety margin up to an overall dose of 15 times the recommended one (5 times the daily dose given 3 times the number of days) in healthy adult laying hens. Based on the present results, the use of the new mite treatment based on fluralaner administered via drinking water is expected to be safe for laying hens under industrial conditions, and to have no negative impact on their egg quality and production.

Oral desensitization to milk: how to choose the starting dose!

PubMed Central

Mori, Francesca; Pucci, Neri; Rossi, Maria Elisabetta; de Martino, Maurizio; Azzari, Chiara; Novembre, Elio

2010-01-01

Mori F, Pucci N, Rossi ME, de Martino M, Azzari C, Novembre E. Oral desensitization to milk: how to choose the starting dose! Pediatr Allergy Immunol 2010: 21: e450–e453. © 2009 John Wiley & Sons A/S A renewed interest in oral desensitization as treatment for food allergy has been observed in the last few years. We studied a novel method based on the end point skin prick test procedure to establish the starting dose for oral desensitization in a group of 30 children higly allergic to milk. The results (in terms of reactions to the first dose administered) were compared with a group of 20 children allergic to milk as well. Such control group started to swallow the same dose of 0.015 mg/ml of milk. None reacted to the first dose when administered according to the end point skin prick test. On the other side, ten out of 20 children (50%) from the control group showed mild allergic reactions to the first dose of milk. In conclusion the end point skin prick test procedure results safe and easy to be performed in each single child in order to find out the starting dose for oral desensitization to milk, also by taking into account the individual variability. PMID:19624618

Subinhibitory Doses of Aminoglycoside Antibiotics Induce Changes in the Phenotype of Mycobacterium abscessus

PubMed Central

Tsai, Sheng-Hui; Lai, Hsin-Chih

2015-01-01

Subinhibitory doses of antibiotics have been shown to cause changes in bacterial morphology, adherence ability, and resistance to antibiotics. In this study, the effects of subinhibitory doses of aminoglycoside antibiotics on Mycobacterium abscessus were investigated. The treatment of M. abscessus cells with subinhibitory doses of amikacin was found to change their colony from a smooth to a rough morphotype and increase their ability to adhere to a polyvinylchloride plate, aggregate in culture, and resist phagocytosis and killing by macrophages. M. abscessus cells treated with a subinhibitory dose of amikacin also became more potent in Toll-like receptor 2 (TLR-2) stimulation, leading to increased tumor necrosis factor alpha (TNF-α) production by macrophages. The MAB_3508c gene was shown to play a role in mediating these phenotypic changes, as its expression in M. abscessus cells was increased when they were treated with a subinhibitory dose of amikacin. In addition, overexpression of MAB_3508c in M. abscessus cells caused changes similar to those induced by subinhibitory doses of amikacin, including a switch from smooth to rough colony morphology, increased ability to aggregate in liquid culture, decreased motility, and increased resistance to killing by macrophages. These findings suggest the importance of using sufficient doses of antibiotics for the treatment of M. abscessus infections. PMID:26195529

Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

PubMed

Warzecha, Zygmunt; Sendur, Paweł; Ceranowicz, Piotr; Cieszkowski, Jakub; Dembiński, Marcin; Sendur, Ryszard; Bonior, Joanna; Jaworek, Jolanta; Ambroży, Tadeusz; Olszanecki, Rafał; Kuśnierz-Cabala, Beata; Tomasz, Kaczmarzyk; Tomaszewska, Romana; Dembiński, Artur

2017-04-21

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

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

Wyrobek, A. J.; Manohar, C. F.; Nelson, D. O.

We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues. Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of {approx}80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, moleculemore » transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.« less

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

PubMed Central

Shen, Jie; Goodkin, Margot L; Tong, Warren; Attar, Mayssa

2017-01-01

Purpose Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. Methods New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. Results Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. Conclusion Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties), formulations of bimatoprost 0.01% can be administered once or twice daily. These findings support development of bimatoprost 0.01%-based fixed-dose combination therapies administered twice daily for patients who require multiple adjunctive medications to control their IOP. PMID:29026287

Double-blind, placebo-controlled, multiple-ascending-dose study on the pharmacodynamics of ABIO-08/01, a new CNS drug with potential anxiolytic activity. 2. EEG-tomography findings based on LORETA (low-resolution brain electromagnetic tomography).

PubMed

Saletu, Bernd; Anderer, Peter; Wolzt, Michael; Nosiska, Dorothea; Assandri, Alessandro; Noseda, Emanuele; Nannipieri, Fabrizio; Saletu-Zyhlarz, Gerda M

2009-01-01

Effects of ABIO-08/01, a new potentially anxiolytic isoxazoline, on regional electrical brain generators were investigated by 3-dimensional EEG tomography. In a double- blind, placebo-controlled, multiple-ascending-dose study, 16 healthy males (30.2 +/- 5.7 years) received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (8-day wash-out) in a randomized non-balanced design for phase-1 studies. A 3-min vigilance-controlled (V) EEG, a 4-min resting (R) EEG with eyes closed, a 1-min eyes-open (EO) EEG and psychometric tests were performed 0, 1 and 6 h after taking the drug on days 1 and 5. Low-resolution brain electromagnetic tomography (LORETA) was computed from the spectrally analyzed EEG data, and differences between drug and placebo were displayed as statistical parametric maps. Data were registered to the Talairach-Tournoux Human Brain Atlas available as a digitized MRI. An overall omnibus significance test followed by a voxel-by-voxel t test demonstrated significant regional EEG changes after ABIO-08/01 versus placebo, dependent on recording condition, dose and time. While in the EO-EEG specifically the lowest dose of ABIO-08/01 induced pronounced sedative effects (delta/theta and beta increase) 1 h after acute and slightly less so after superimposed administration, in the 6th hour a decrease in alpha and beta activity signaled less sedative and more relaxant action. In the V-EEG these changes were less pronounced, in the R-EEG partly opposite. Hemisphere-specific changes were observed, suggesting increases in LORETA power over the left temporal, parietal, superior frontal regions and decreases over the right prefrontal, temporal pole and occipital regions. These LORETA changes are discussed in the light of neuroimaging findings on anxiety and anxiolytics. 2009 S. Karger AG, Basel.

Influence of the intestinal microbiota on the immunogenicity of oral rotavirus vaccine given to infants in south India.

PubMed

Parker, Edward P K; Praharaj, Ira; Zekavati, Anna; Lazarus, Robin P; Giri, Sidhartha; Operario, Darwin J; Liu, Jie; Houpt, Eric; Iturriza-Gómara, Miren; Kampmann, Beate; John, Jacob; Kang, Gagandeep; Grassly, Nicholas C

2018-01-04

Oral rotavirus vaccines have consistently proven to be less immunogenic among infants in developing countries. Discrepancies in the intestinal microbiota, including a greater burden of enteropathogens and an altered commensal community composition, may contribute to this trend by inhibiting the replication of vaccine viruses. To test this possibility, we performed a nested case-control study in Vellore, India, in which we compared the intestinal microbiota of infants who responded serologically or not after two doses of Rotarix delivered at 6 and 10 weeks of age as part of a clinical trial (CTRI/2012/05/002677). The prevalence of 40 bacterial, viral, and eukaryotic pathogen targets was assessed in pre-vaccination stool samples from 325 infants using singleplex real-time PCR on a Taqman array card (TAC). In a subset of 170 infants, we assessed bacterial microbiota composition by sequencing the 16S rRNA gene V4 region. Contrary to expectations, responders were more likely than non-responders to harbor ≥1 bacterial enteropathogen at dose 1 (26% [40/156] vs 13% [21/157] of infants with TAC results who completed the study per protocol; χ 2 , P = .006), although this was not apparent at dose 2 (24% [38/158] vs 23% [36/158]; P = .790). Rotavirus shedding after dose 1 was negatively correlated with the replication of co-administered oral poliovirus vaccine (OPV). We observed no consistent differences in composition or diversity of the 16S bacterial microbiota according to serological response, although rotavirus shedding was associated with slightly more bacterial taxa pre-vaccination. Overall, our findings demonstrate an inhibitory effect of co-administered OPV on the first dose of Rotarix, consistent with previous studies, but in the context of OPV co-administration we did not find a strong association between other components of the intestinal microbiota at the time of vaccination and Rotarix immunogenicity. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Dose Escalation of Whole-Brain Radiotherapy for Brain Metastases From Melanoma

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

Rades, Dirk, E-mail: Rades.Dirk@gmx.ne; Heisterkamp, Christine; Huttenlocher, Stefan

2010-06-01

Purpose: The majority of patients with brain metastases from melanoma receive whole-brain radiotherapy (WBRT). However, the results are poor. Hypofractionation regimens failed to improve the outcome of these patients. This study investigates a potential benefit from escalation of the WBRT dose beyond the 'standard' regimen 30 Gy in 10 fractions (10x3 Gy). Methods and Materials: Data from 51 melanoma patients receiving WBRT alone were retrospectively analyzed. A dosage of 10x3 Gy (n = 33) was compared with higher doses including 40 Gy/20 fractions (n = 11) and 45 Gy/15 fractions (n = 7) for survival (OS) and local (intracerebral) controlmore » (LC). Additional potential prognostic factors were evaluated: age, gender, performance status, number of metastases, extracerebral metastases, and recursive partitioning analysis (RPA) class. Results: At 6 months, OS rates were 27% after 10x3 Gy and 50% after higher doses (p = 0.009). The OS rates at 12 months were 4% and 20%. On multivariate analysis, higher WBRT doses (p = 0.010), fewer than four brain metastases (p = 0.012), no extracerebral metastases (p = 0.006), and RPA class 1 (p = 0.005) were associated with improved OS. The LC rates at 6 months were 23% after 10x3 Gy and 50% after higher doses (p = 0.021). The LC rates at 12 months were 0% and 13%. On multivariate analysis, higher WBRT doses (p = 0.020) and fewer than brain metastases (p = 0.002) were associated with better LC. Conclusions: Given the limitations of a retrospective study, the findings suggest that patients with brain metastases from melanoma receiving WBRT alone may benefit from dose escalation beyond 10x3 Gy. The hypothesis generated by this study must be confirmed in a randomized trial stratifying for significant prognostic factors.« less

Leukemia, lymphoma and multiple myeloma mortality (1950-1999) and incidence (1969-1999) in the Eldorado uranium workers cohort.

PubMed

Zablotska, Lydia B; Lane, Rachel S D; Frost, Stanley E; Thompson, Patsy A

2014-04-01

Uranium workers are chronically exposed to low levels of radon decay products (RDP) and gamma (γ) radiation. Risks of leukemia from acute and high doses of γ-radiation are well-characterized, but risks from lower doses and dose-rates and from RDP exposures are controversial. Few studies have evaluated risks of other hematologic cancers in uranium workers. The purpose of this study was to analyze radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932-1980 in relation to cumulative RDP exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months and the average cumulative whole-body γ-radiation dose was 52.2 millisievert. We identified 101 deaths and 160 cases of hematologic cancers in the cohort. Overall, male workers had lower mortality and cancer incidence rates for all outcomes compared with the general Canadian male population, a likely healthy worker effect. No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found. We observed consistent but non-statistically significant increases in risks of chronic lymphocytic leukemia (CLL) and Hodgkin lymphoma (HL) incidence and non-Hodgkin lymphoma (NHL) mortality with increasing γ-ray doses. These findings are consistent with recent studies of increased risks of CLL and NHL incidence after γ-radiation exposure. Further research is necessary to understand risks of other hematologic cancers from low-dose exposures to γ-radiation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Toxicity of dietary Heliotropium circinatum to rats.

PubMed

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

2003-08-01

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

Specific immunotherapy for rhinitis and asthma with a subcutaneous hypoallergenic high-dose house dust mite extract: results of a 9-month therapy.

PubMed

El-Qutob, David; Moreno, Francisco; Subtil-Rodríguez, Alicia

2016-07-01

Effectiveness of a 9-month specific immunotherapy with a subcutaneous hypoallergenic high-dose house dust mite extract to reduce allergic symptoms as perceived by patients and physicians was assessed. An observational, retrospective, multicenter study was carried out in patients diagnosed with asthma and/or rhinitis caused by house dust mites having started specific immunotherapy with Acaroid(®). Primary end point was perceived effectiveness. A total of 409 patients were included. According to physician-completed visual analogue scale, a 58.1% clinical improvement was observed. Patient-completed visual analogue scale showed a 69.8% clinical improvement. The need for unscheduled/emergency healthcare, as an indication of poor quality of life, showed a significant reduction. Our results confirm in a real-world setting the findings from randomized clinical trials of high-dose house dust mites allergoid immunotherapy with a subcutaneous hypoallergenic high-dose house dust mite extract.

Managing nuclear power plant induced disasters.

PubMed

Kyne, Dean

2015-01-01

To understand the management process of nuclear power plant (NPP) induced disasters. The study shields light on phases and issues associated with the NPP induced disaster management. This study uses Palo Verde Nuclear Generation Station as study subject and Arizona State as study area. This study uses the Radiological Assessment System for Consequence Analysis (RASCAL) Source Term to Dose (STDose) of the Nuclear Regulatory Commission, a computer software to project and assess the source term dose and release pathway. This study also uses ArcGIS, a geographic information system to analyze geospatial data. A detailed case study of Palo Verde Nuclear Power Generation (PVNPG) Plant was conducted. The findings reveal that the NPP induced disaster management process is conducted by various stakeholders. To save lives and to minimize the impacts, it is vital to relate planning and process of the disaster management. Number of people who expose to the radioactive plume pathway and level of radioactivity could vary depending on the speed and direction of wind on the day the event takes place. This study findings show that there is a need to address the burning issue of different racial and ethnic groups' unequal exposure and unequal protection to potential risks associated with the NPPs.

Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study.

PubMed

Perlis, Michael; Grandner, Michael; Zee, Jarcy; Bremer, Erin; Whinnery, Julia; Barilla, Holly; Andalia, Priscilla; Gehrman, Phil; Morales, Knashawn; Thase, Michael; Bootzin, Richard; Ader, Robert

2015-09-01

At present, there is no consensus regarding how to medically manage chronic insomnia in the long term. The unstated standard of practice is for patients to use hypnotics intermittently. The present study aimed to compare a partial reinforcement strategy with nightly and intermittent dosing strategies for its potential as a maintenance therapy. A mixed model was used in the study. One between-subjects factor: group (n = 4). One repeated-measures factor: time (12 weekly assessments). A total of 74 subjects with chronic Insomnia were treated with 10 mg zolpidem for 4 weeks. Treatment respondents were randomized to nightly dosing with 10 mg or 5 mg (QHS-10 and QHS-5), intermittent dosing with 10 mg (IDS-10 [3-5 days weekly]), or partial reinforcement dosing with 10 mg (PRS-10 [nightly pill use with 50% active medication and 50% placebos]) for 12 weeks. It was found, in compliant subjects (n = 55), that all four strategies evaluated maintained treatment response over time (ie, prevented or delayed relapse). For the subjects that remained in remission, the subjects in the intermittent dosing group (IDS-10) group exhibited poorer sleep continuity. While best considered a preliminary study, the present findings suggest that the partial reinforcement strategy may be a viable means toward maintaining treatment gains over time with less active medication. Copyright © 2015. Published by Elsevier B.V.

Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study

PubMed Central

Perlis, Michael; Grandner, Michael; Zee, Jarcy; Bremer, Erin; Whinnery, Julia; Barilla, Holly; Andalia, Priscilla; Gehrman, Phil; Morales, Knashawn; Thase, Michael; Bootzin, Richard; Ader, Robert

2015-01-01

Background and aim At present, there is no consensus regarding how to medically manage chronic insomnia in the long term. The unstated standard of practice is for patients to use hypnotics intermittently. The present study aimed to compare a partial reinforcement strategy with nightly and intermittent dosing strategies for its potential as a maintenance therapy. Methods A mixed model was used in the study. One between-subjects factor: group (n = 4). One repeated-measures factor: time (12 weekly assessments). A total of 74 subjects with chronic Insomnia were treated with 10 mg zolpidem for 4 weeks. Treatment respondents were randomized to nightly dosing with 10 mg or 5 mg (QHS-10 and QHS-5), intermittent dosing with 10 mg (IDS-10 [3–5 days weekly]), or partial reinforcement dosing with 10 mg (PRS-10 [nightly pill use with 50% active medication and 50% placebos]) for 12 weeks. Results It was found, in compliant subjects (n = 55), that all four strategies evaluated maintained treatment response over time (ie, prevented or delayed relapse). For the subjects that remained in remission, the subjects in the intermittent dosing group (IDS-10) group exhibited poorer sleep continuity. Conclusions While best considered a preliminary study, the present findings suggest that the partial reinforcement strategy may be a viable means toward maintaining treatment gains over time with less active medication. PMID:26298795

Sanitation of chicken eggs by ionizing radiation: HACCP and inactivation studies

NASA Astrophysics Data System (ADS)

Verde, S. Cabo; Tenreiro, R.; Botelho, M. L.

2004-09-01

The aim of this study is to develop the application of irradiation technology to chicken eggs in order to get a product free of pathogenic microorganisms. Bioburden values of eggs from chickens of different ages ( n=150) were found to not be significantly different ( p<0.05) and an average value of (2.0±0.3). 10 5 cfu/egg was obtained for the shell. Two major microbial groups were characterized in the egg's natural microbiota, no Salmonella or Campylobacter were detected. HACCP studies indicated the feed as a critical point. Dosimetry studies were carried out in a γ facility to find the best geometry and dose rate for irradiation. Whole eggs were artificially contaminated with reference strains of Salmonella typhimurium, Salmonella enteritidis, Campylobacter coli and Campylobacter jejuni and irradiated in the γ facility at sub-lethal doses (0.2-1 kGy) with a dose rate of 1.0 kGy/h. Dvalue varied between 0.31-0.26 kGy and 0.20-0.19 kGy in S. typhimurium and S. enteritidis, and between 0.21-0.18 kGy and 0.07-0.09 in C. coli and C. jejuni, for shell and yolk+white. Using sub-lethal doses up to 5 kGy, the Dvalue of natural microbiota in whole eggs was 1.29 kGy. Results show that low irradiation doses could guarantee egg sanitation.

IND-directed safety and biodistribution study of intravenously injected cetuximab-IRDye800 in cynomolgus macaques.

PubMed

Zinn, Kurt R; Korb, Melissa; Samuel, Sharon; Warram, Jason M; Dion, David; Killingsworth, Cheryl; Fan, Jinda; Schoeb, Trenton; Strong, Theresa V; Rosenthal, Eben L

2015-02-01

The use of receptor-targeted antibodies conjugated to fluorophores is actively being explored for real-time imaging of disease states; however, the toxicity of the bioconjugate has not been assessed in non-human primates. To this end, the in vivo toxicity and pharmacokinetics of IRDye800 conjugated to cetuximab (cetuximab-IRDye800; 21 mg/kg; equivalent to 250 mg/m(2) human dose) were assessed in male cynomolgus monkeys over 15 days following intravenous injection and compared with an unlabeled cetuximab-dosed control group. Cetuximab-IRDye800 was well tolerated. There were no infusion reactions, adverse clinical signs, mortality, weight loss, or clinical histopathology findings. The plasma half-life for the cetuximab-IRDye800 and cetuximab groups was equivalent (2.5 days). The total recovered cetuximab-IRDye800 in all tissues at study termination was estimated to be 12 % of the total dose. Both cetuximab-IRDye800 and cetuximab groups showed increased QTc after dosing. The QTc for the cetuximab-dosed group returned to baseline by day 15, while the QTc of the cetuximab-IRDye800 remained elevated compared to baseline. IRDye800 in low molar ratios does not significantly impact cetuximab half-life or result in organ toxicity. These studies support careful cardiac monitoring (ECG) for human studies using fluorescent dyes.

Evidence of chromosomal instability in neurofibromatosis

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

Hafez, M.; Sharaf, L.; Abd el-Nabi, S.M.

Blood lymphocytes from six unrelated patients with neurofibromatosis and three normal controls were examined for their response to different doses (0, 75, 150, 300, 400 rad) of x-radiation, as measured by chromosome aberrations (gaps, breaks, dicentrics, centric rings, acentric ring, fragments, and minutes). Cytogenetic studies on phytohemagglutinin-stimulated cells revealed chromosomal instability in the neurofibromatosis lymphocytes as shown by the significant increase in the in the incidence of gaps, breaks and dicentrics. This increase paralleled the increase in the dose of irradiation. The significance of these findings is discussed.

LDEF satellite radiation study

NASA Technical Reports Server (NTRS)

Armstrong, T. W.; Colborn, B. L.

1994-01-01

Some early results are summarized from a program under way to utilize LDEF satellite data for evaluating and improving current models of the space radiation environment in low earth orbit. Reported here are predictions and comparisons with some of the LDEF dose and induced radioactivity data, which are used to check the accuracy of current models describing the magnitude and directionality of the trapped proton environment. Preliminary findings are that the environment models underestimate both dose and activation from trapped protons by a factor of about two, and the observed anisotropy is higher than predicted.

Pharmacokinetics of Lopinavir in HIV-Infected Adults Receiving Rifampin with Adjusted Doses of Lopinavir-Ritonavir Tablets▿

PubMed Central

Decloedt, Eric H.; McIlleron, Helen; Smith, Peter; Merry, Concepta; Orrell, Catherine; Maartens, Gary

2011-01-01

Rifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C0) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC0-12), C0, C12, maximum concentration of drug in serum (Cmax), or half-life (t1/2) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies. PMID:21537021

Robotic path-finding in inverse treatment planning for stereotactic radiosurgery with continuous dose delivery

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

Vandewouw, Marlee M., E-mail: marleev@mie.utoronto

Purpose: Continuous dose delivery in radiation therapy treatments has been shown to decrease total treatment time while improving the dose conformity and distribution homogeneity over the conventional step-and-shoot approach. The authors develop an inverse treatment planning method for Gamma Knife® Perfexion™ that continuously delivers dose along a path in the target. Methods: The authors’ method is comprised of two steps: find a path within the target, then solve a mixed integer optimization model to find the optimal collimator configurations and durations along the selected path. Robotic path-finding techniques, specifically, simultaneous localization and mapping (SLAM) using an extended Kalman filter, aremore » used to obtain a path that travels sufficiently close to selected isocentre locations. SLAM is novelly extended to explore a 3D, discrete environment, which is the target discretized into voxels. Further novel extensions are incorporated into the steering mechanism to account for target geometry. Results: The SLAM method was tested on seven clinical cases and compared to clinical, Hamiltonian path continuous delivery, and inverse step-and-shoot treatment plans. The SLAM approach improved dose metrics compared to the clinical plans and Hamiltonian path continuous delivery plans. Beam-on times improved over clinical plans, and had mixed performance compared to Hamiltonian path continuous plans. The SLAM method is also shown to be robust to path selection inaccuracies, isocentre selection, and dose distribution. Conclusions: The SLAM method for continuous delivery provides decreased total treatment time and increased treatment quality compared to both clinical and inverse step-and-shoot plans, and outperforms existing path methods in treatment quality. It also accounts for uncertainty in treatment planning by accommodating inaccuracies.« less

Model-Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms.

PubMed

Reinecke, Isabel; Schultze-Mosgau, Marcus-Hillert; Nave, Rüdiger; Schmitz, Heinz; Ploeger, Bart A

2017-05-01

Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects. Population PK models for ATZ and LNG were established where the interaction of LNG with sex hormone-binding globulin (SHBG) as well as a stimulating effect of estradiol on SHBG were considered. Furthermore, simulations showed that doses of 40 μg/d LNG combined with 300, 600, or 1050 μg/d ATZ reached anticipated exposure levels for both drugs, facilitating selection of ATZ and LNG doses in the phase 2 dose-finding study. The main driver for the effect on maximum follicle size appears to be unbound LNG exposure. A 50% probability of maximum follicle size ≥30 mm was estimated for 40 μg/d LNG based on the exposure-response analysis. ATZ in the dose range investigated does not increase the risk for ovarian cysts as occurs with LNG at a dose that does not inhibit ovulation. © 2016, The American College of Clinical Pharmacology.

Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

PubMed

Coric, Vladimir; van Dyck, Christopher H; Salloway, Stephen; Andreasen, Niels; Brody, Mark; Richter, Ralph W; Soininen, Hilkka; Thein, Stephen; Shiovitz, Thomas; Pilcher, Gary; Colby, Susan; Rollin, Linda; Dockens, Randy; Pachai, Chahin; Portelius, Erik; Andreasson, Ulf; Blennow, Kaj; Soares, Holly; Albright, Charles; Feldman, Howard H; Berman, Robert M

2012-11-01

To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD). Randomized, double-blind, placebo-controlled,24-week phase 2 study. Global, multicenter trial. A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups. Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily. Safety and tolerability of avagacestat. Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients. Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD. clinicaltrials.gov Identifier: NCT00810147

Clinical impact of (99m)Tc-MAA SPECT/CT-based dosimetry in the radioembolization of liver malignancies with (90)Y-loaded microspheres.

PubMed

Garin, Etienne; Rolland, Yan; Laffont, Sophie; Edeline, Julien

2016-03-01

Radioembolization with (90)Y-loaded microspheres is increasingly used in the treatment of primary and secondary liver cancer. Technetium-99 m macroaggregated albumin (MAA) scintigraphy is used as a surrogate of microsphere distribution to assess lung or digestive shunting prior to therapy, based on tumoral targeting and dosimetry. To date, this has been the sole pre-therapeutic tool available for such evaluation. Several dosimetric approaches have been described using both glass and resin microspheres in hepatocellular carcinoma (HCC) and liver metastasis. Given that each product offers different specific activities and numbers of spheres injected, their radiobiological properties are believed to lightly differ. This paper summarizes and discusses the available studies focused on MAA-based dosimetry, particularly concentrating on potential confounding factors like clinical context, tumor size, cirrhosis, previous or concomitant therapy, and product used. In terms of the impact of tumoral dose in HCC, the results were concordant and a response relationship and tumoral threshold dose was clearly identified, especially in studies using glass microspheres. Tumoral dose has also been found to influence survival. The concept of treatment intensification has recently been introduced, yet despite several studies publishing interesting findings on the tumor dose-metastasis relationship, no consensus has been reached, and further clarification is thus required. Nor has the maximal tolerated dose to the liver been well documented, requiring more accurate evaluation. Lung dose was well described, despite recently identified factors influencing its evaluation, requiring further assessment. Conclusion: MAA SPECT/CT dosimetry is accurate in HCC and can now be used in order to achieve a fully customized approach, including treatment intensification. Yet further studies are warranted for the metastasis setting and evaluating the maximal tolerated liver dose.

Interpretation of Gamma Index for Quality Assurance of Simultaneously Integrated Boost (SIB) IMRT Plans for Head and Neck Carcinoma

NASA Astrophysics Data System (ADS)

Atiq, Maria; Atiq, Atia; Iqbal, Khalid; Shamsi, Quratul ain; Andleeb, Farah; Buzdar, Saeed Ahmad

2017-12-01

Objective: The Gamma Index is prerequisite to estimate point-by-point difference between measured and calculated dose distribution in terms of both Distance to Agreement (DTA) and Dose Difference (DD). This study aims to inquire what percentage of pixels passing a certain criteria assure a good quality plan and suggest gamma index as efficient mechanism for dose verification of Simultaneous Integrated Boost Intensity Modulated Radiotherapy plans. Method: In this study, dose was calculated for 14 head and neck patients and IMRT Quality Assurance was performed with portal dosimetry using the Eclipse treatment planning system. Eclipse software has a Gamma analysis function to compare measured and calculated dose distribution. Plans of this study were deemed acceptable when passing rate was 95% using tolerance for Distance to agreement (DTA) as 3mm and Dose Difference (DD) as 5%. Result and Conclusion: Thirteen cases pass tolerance criteria of 95% set by our institution. Confidence Limit for DD is 9.3% and for gamma criteria our local CL came out to be 2.0% (i.e., 98.0% passing). Lack of correlation was found between DD and γ passing rate with R2 of 0.0509. Our findings underline the importance of gamma analysis method to predict the quality of dose calculation. Passing rate of 95% is achieved in 93% of cases which is adequate level of accuracy for analyzed plans thus assuring the robustness of SIB IMRT treatment technique. This study can be extended to investigate gamma criteria of 5%/3mm for different tumor localities and to explore confidence limit on target volumes of small extent and simple geometry.

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

PubMed

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

2017-05-01

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

Vitamin C, a Multi-Tasking Molecule, Finds a Molecular Target in Killing Cancer Cells.

PubMed

Li, Robert

2016-03-01

Early work in the 1970s by Linus Pauling, a twice-honored Nobel laureate, led to his proposal of using high-dose vitamin C to treat cancer patients. Over the past several decades, a number of studies in animal models as well as several small-scale clinical studies have provided substantial support of Linus Pauling's early proposal. Production of reactive oxygen species (ROS) via oxidation of vitamin C appears to be a major underlying event, leading to the selective killing of cancer cells. However, it remains unclear how vitamin C selectively kills cancer cells while sparing normal cells and what the molecular targets of high-dose vitamin C are. In a recent article published in Science (2015 December 11; 350(6266):1391-6. doi: 10.1126/science.aaa5004), Yun et al. reported that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) through an ROS-dependent mechanism. This work by Yun et al. along with other findings advances our current understanding of the molecular basis of high-dose vitamin C-mediated cancer cell killing, which will likely give an impetus to the continued research efforts aiming to further decipher the novel biochemistry of vitamin C and its unique role in cancer therapy.

Estrogen Replacement Regulates Vaginal Innervations in Ovariectomized Adult Virgin Rats: A Histological Study.

PubMed

Li, Ting; Ma, Yuanyuan; Zhang, Hong; Yan, Ping; Huo, Lili; Hu, Yongyan; Chen, Xi; Li, Ting; Zhang, Miao; Liu, Zhaohui

2017-01-01

Background . Our previous Gräfenberg spot findings confirmed that the distal-third areas of the anterior vaginal wall bore a significantly greater number of nerves and sexual hormone may have certain degree of influence on these significant differences. However, the role of estrogen in vaginal innervations remains controversial. Methods . To investigate whether hormonal-neural interactions occur in the vagina, sixty rats were randomly divided into six groups: Sham-operated, ovariectomy, and 4 treatment groups. After 2 weeks of treatment, vaginal biopsies were prepared with hematoxylin and eosin and PGP9.5 using immunohistochemistry. Results . The density of small nerve fibers was significantly higher in the distal-half areas of intact vaginal walls than the proximal-half areas ( P = 0.001). In contrast, the overall PGP 9.5-ir fiber innervation density was significantly decreased in the OVX rats subjected to surgical menopause. Sustained estrogen administration for 2 weeks resulted in nerve fiber proliferation, with values reaching normal levels in the low-dose estradiol valerate group. Conclusion . Our findings indicate that systemic hormonal therapy with low-dose estradiol valerate is effective and safe for treating deficient vaginal innervation caused by low level of estrogen activity in menopausal women and may aid studies to identify an optimal estradiol dose to provide relief from vaginal discomfort.

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study

PubMed Central

Rosenblad, Carl; af Edholm Arvidsson, Karolina; Wictorin, Klas; Keywood, Charlotte; Shankar, Bavani; Lowe, David A.; Björklund, Anders; Widner, Håkan

2015-01-01

In advanced stages of Parkinson’s disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson’s disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson’s disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson’s Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [–1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [–0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [–1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson’s Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson’s disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias. PMID:25669730

Kawasaki disease in Sicily: clinical description and markers of disease severity.

PubMed

Maggio, Maria Cristina; Corsello, Giovanni; Prinzi, Eugenia; Cimaz, Rolando

2016-11-02

Kawasaki disease (KD) is an acute systemic vasculitis of small and middle size arteries; 15-25 % of untreated patients and 5 % of patients treated with intravenous immunoglobulin (IVIG) develop coronary artery lesions (CAL). Many studies tried to find the most effective treatment in the management of resistant KD and to select the risk factors for CAL. Our data are assessed on children from west Sicily, characterized by a genetic heterogeneity. We studied the clinical data of 70 KD Sicilian children (36 males: 51 %; 34 females: 49 %), analysed retrospectively, including: demographic and laboratory parameters; echocardiographic findings at diagnosis, at 2, 6 and 8 weeks, and at 1 year after the onset of the illness. Forty-seven had Typical KD, three Atypical KD and twenty Incomplete KD. Age at the disease onset ranged from 0.1 to 8.9 years. IVIG were administered 5 ± 2 days after the fever started. Defervescence occurred 39 ± 26 hours after the first IVIG infusion. Fifty-six patients (80 %) received 1 dose of IVIG (responders); 14 patients (20 %) had a resistant KD, with persistent fever after the first IVIG dose (non responders). Ten (14 %) non responders responded to the second dose, 4 (5 %) responded to three doses; one needed treatment with high doses of steroids and Infliximab. Cardiac involvement was documented in twenty-two cases (eighteen with transient dilatation/ectasia, fifteen with aneurysms). Pericardial effusion, documented in eleven, was associated with coronaritis and aneurysms, and was present earlier than coronary involvement in seven. Hypoalbuminemia, D-dimer pre-IVIG, gamma-GT pre-IVIG showed a statistically significant direct correlation with IVIG doses, highlighting the role of these parameters as predictor markers of refractory disease. The persistence of elevated CRP, AST, ALT levels, a persistent hyponatremia and hypoalbuminemia after IVIG therapy, also had a statistical significant correlation with IVIG doses. Non responders showed higher levels of D-dimer and gamma-GT pre-IVIG, persistent high levels of D-dimer, CRP, AST, ALT, hypoalbuminemia and hyponatremia after IVIG. This is the first study on KD in Sicily. We suggest some laboratory parameters as predictive criteria for resistant KD. Patients who show early pericarditis need careful surveillance for coronary lesions.

Modulatory effects of naringin on hepatic key enzymes of carbohydrate metabolism in high-fat diet/low-dose streptozotocin-induced diabetes in rats.

PubMed

Pari, Leelavinothan; Chandramohan, Ramasamy

2017-07-01

We evaluated the modulatory effects of naringin on altered hepatic key enzymes of carbohydrate metabolism in high-fat diet/low-dose streptozotocin-induced diabetic rats. Oral treatment of naringin at a doses of 20, 40 and 80 mg/kg body weight to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, blood glycosylated hemoglobin and increase in the levels of plasma insulin and blood hemoglobin. The altered activities of the hepatic key enzymes of carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase, glycogen phosphorylase and glycogen content of diabetic rats were significantly reverted to near normal levels by the treatment of naringin in a dose-dependent manner. Naringin at a dose of 80 mg/kg body weight showed the highest significant effect than the other two doses (20 and 40 mg/kg). Further, immunohistochemical observation of pancreas revealed that naringin-treated diabetic rats showed the increased number of insulin immunoreactive β-cells, which confirmed the biochemical findings. These findings revealed that naringin has potential antihyperglycemic activity in high-fat diet/low-dose streptozotocin-induced diabetic rats.

Effects of Gamma Irradiation on Bacterial Microflora Associated with Human Amniotic Membrane

PubMed Central

Binte Atique, Fahmida; Ahmed, Kazi Tahsin; Asaduzzaman, S. M.; Hasan, Kazi Nadim

2013-01-01

Human amniotic membrane is considered a promising allograft material for the treatment of ocular surface reconstruction, burns, and other skin defects. In order to avoid the transmission of any diseases, grafts should be perfectly sterile. Twenty-five amniotic sacs were collected to determine the microbiological quality of human amniotic membrane, to analyze the radiation sensitivity pattern of the microorganism, and to detect the radiation decimal reduction dose (D10) values. All the samples were found to be contaminated, and the bioburden was ranged from 3.4 × 102 to 1.2 × 105 cfu/g. Initially, a total fifty bacterial isolates were characterized according to their cultural, morphological, and biochemical characteristics and then tested for the radiation sensitivity in an incremental series of radiation doses from 1 to 10 KGy. The results depict gradual decline in bioburden with incline of radiation doses. Staphylococcus spp. were the most frequently isolated bacterial contaminant in tissue samples (44%). The D10 values of the bacterial isolates were ranged from 0.6 to 1.27 KGy. Streptococcus spp. were found to be the highest radioresistant strain with the radiation sterilization dose (RSD) of 11.4 KGy for a bioburden level of 1000. To compare the differences, D10 values were also calculated by graphical evaluations of the data with two of the representative isolates of each bacterial species which showed no significant variations. Findings of this study indicate that lower radiation dose is quite satisfactory for the sterilization of amniotic membrane grafts. Therefore, these findings would be helpful to predict the efficacy of radiation doses for the processing of amniotic membrane for various purposes. PMID:24063009

Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease and Multiorgan Failure after Stem Cell Transplantation: A Multicenter, Randomized, Dose-Finding Trial

PubMed Central

Richardson, Paul G.; Soiffer, Robert J.; Antin, Joseph H.; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L.; Steinbach, Gideon; Murray, Karen F.; Vogelsang, Georgia B.; Chen, Allen R.; Krishnan, Amrita; Kernan, Nancy A.; Avigan, David E.; Spitzer, Thomas R.; Shulman, Howard M.; Di Salvo, Donald N.; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L. J.; Iacobelli, Massimo; McDonald, George B.; Guinan, Eva C.

2010-01-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for ≥ 14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day + 100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day + 100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD. PMID:20167278

mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats.

PubMed

Potucek, Peter; Radik, Michal; Doka, Gabriel; Kralova, Eva; Krenek, Peter; Klimas, Jan

2017-01-01

Chronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups. After short-term treatment, only morning dosing resulted in significant blood pressure (BP) control (measured by tail-cuff method) when compared to placebo, while after long-term treatment, both dosing groups gained similar superior results in BP control against placebo. However, mRNA levels of Bmal1 and Per2 (measured by RT-PCR) exhibited an independent pattern, with similar alterations in left and right ventricle, kidney as well as in aorta predominantly in groups with evening dosing in both, short-term and also long-term settings. This was accompanied by increased cardiac mRNA expression of plasminogen activator inhibitor-1. In summary, morning dosing proved to be advantageous due to earlier onset of antihypertensive action; however, long-term treatment was demonstrated to be effective regardless of administration time. Our findings also suggest that combination of VA may serve as an independent modulator of circadian clock and might influence disease progression beyond the primary BP lowering effect.

Evaluation of the patients with Grave's ophthalmopathy after the corticosteroids treatment.

PubMed

Petrović, Mirjana Janićijević; Sarenac, Tatjana; Srećković, Suncica; Petrović, Marko; Vulović, Dejan; Janićijević, Katarina

2012-03-01

Graves' ophthalmopthy is one of the most common causes of exophthalmos as well as the most common manifestation of Graves' disease. The treatment of Graves' ophthalmopathy includes ophthalmological and endocrinological therapy. The aim of this study was to clinically evaluate the patients with Graves' ophthalmopathy treated with corticosteroids. Evaluation of 21 patients was performed in the Ophthalmology Clinic and Endocrinology Clinic, Clinical Centre Kragujevac, in the period from 2009 to 2010. They were treated with pulse doses of intravenous corticosteroids. They were referred to ophthalmologist by endocrinologist in euthyroid condition in the active phase of Graves' ophthalmopathy (ultrasonography of orbit findings and positive findings of antithyroid stimulating hormone receptor antibody--anti-TSH R Ab). The clinical activity score (CAS) and NO SPECS classification for evaluation of disease severity were used. Ophthalmological examination includes: best corrected visual acuity, slit-lamp exam, Hertels' test, direct ophthalmoscopy and ultrasonography of the orbit. According to our results 76.19% of the patients were female; mean age of the patients was 35.2 +/- 5.6 years. According to CAS classification after 6 months of the treatment recovery was shown in 23.81% of the patients, partial amelioration in 47.62% and no clinical amelioration in 28.57% of the patients. We achieved better results with male, young patients with high clinical activity score. Good results were observed after the first dose of corticosteroids, much better CAS after the third dose, which maintained until 6 months after the first treatment. Our results signify that intravenous pulse dose of corticosteroids treatment of the patients with Graves' ophthalmopthy is safe, comfortable, clinically justified and accessible for the clinicians and patients. Positive results are achieved after the first dose with increasing trend up to the third dose, which was maintained for the next three months.

Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study.

PubMed

van Velzen, A S; Eckhardt, C L; Peters, M; Leebeek, F W G; Escuriola-Ettingshausen, C; Hermans, C; Keenan, R; Astermark, J; Male, C; Peerlinck, K; le Cessie, S; van der Bom, J G; Fijnvandraat, K

2017-07-01

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg -1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically. © 2017 International Society on Thrombosis and Haemostasis.

Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities

PubMed Central

Ezzalfani, Monia; Zohar, Sarah; Qin, Rui; Mandrekar, Sumithra J; Deley, Marie-Cécile Le

2013-01-01

The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose–toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents. PMID:23335156

Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

PubMed Central

Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

2014-01-01

The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330 PMID:24841795

Estimated fluoride doses from toothpastes should be based on total soluble fluoride.

PubMed

Oliveira, Maria José L; Martins, Carolina C; Paiva, Saul M; Tenuta, Livia M A; Cury, Jaime A

2013-11-01

The fluoride dose ingested by young children may be overestimated if based on levels of total fluoride (TF) rather than levels of bioavailable fluoride (total soluble fluoride-TSF) in toothpaste. The aim of the present study was to compare doses of fluoride intake based on TF and TSF. Fluoride intake in 158 Brazilian children aged three and four years was determined after tooth brushing with their usual toothpaste (either family toothpaste (n = 80) or children's toothpaste (n = 78)). The estimated dose (mg F/day/Kg of body weight) of TF or TSF ingested was calculated from the chemical analysis of the toothpastes. Although the ingested dose of TF from the family toothpastes was higher than that from the children's toothpastes (0.074 ± 0.007 and 0.039 ± 0.003 mg F/day/Kg, respectively; p < 0.05), no difference between types of toothpaste was found regarding the ingested dose based on TSF (0.039 ± 0.005 and 0.039 ± 0.005 mg F/day/Kg, respectively; p > 0.05). The fluoride dose ingested by children from toothpastes may be overestimated if based on the TF of the product. This finding suggests that the ingested dose should be calculated based on TSF. Dose of TSF ingested by children is similar whether family or children's toothpaste is used.

Estimated Fluoride Doses from Toothpastes Should be Based on Total Soluble Fluoride

PubMed Central

Oliveira, Maria José L.; Martins, Carolina C.; Paiva, Saul M.; Tenuta, Livia M. A.; Cury, Jaime A.

2013-01-01

The fluoride dose ingested by young children may be overestimated if based on levels of total fluoride (TF) rather than levels of bioavailable fluoride (total soluble fluoride—TSF) in toothpaste. The aim of the present study was to compare doses of fluoride intake based on TF and TSF. Fluoride intake in 158 Brazilian children aged three and four years was determined after tooth brushing with their usual toothpaste (either family toothpaste (n = 80) or children’s toothpaste (n = 78)). The estimated dose (mg F/day/Kg of body weight) of TF or TSF ingested was calculated from the chemical analysis of the toothpastes. Although the ingested dose of TF from the family toothpastes was higher than that from the children’s toothpastes (0.074 ± 0.007 and 0.039 ± 0.003 mg F/day/Kg, respectively; p < 0.05), no difference between types of toothpaste was found regarding the ingested dose based on TSF (0.039 ± 0.005 and 0.039 ± 0.005 mg F/day/Kg, respectively; p > 0.05). The fluoride dose ingested by children from toothpastes may be overestimated if based on the TF of the product. This finding suggests that the ingested dose should be calculated based on TSF. Dose of TSF ingested by children is similar whether family or children’s toothpaste is used. PMID:24189183

Radioiodine (1-131) Dose for the Treatment of Hyperthyroidism in Rajavithi Hospital.

PubMed

Kuanrakcharoen, Pichit

2016-02-01

The main cause of hyperthyroidism is diffuse toxic goiter (Graves' disease), and the treatment of choice after medical therapy failure is radioiodine (I-131). There are two common methods of determining the optimal I-131 dose: calculated dose or fixed dose. The calculated dose method is based on the following formula: 75-200 microcuri/gram of thyroid gland divided by the percentage of radioiodine uptake at 24 hours (24-hour RAIU). As this is quite complex, some centers use fixed doses, such as 5, 10 or 15 mCi because it is simpler. At Rajavithi Hospital, the applied dose of I-131 is determined based on the thyroid gland weight assessed by palpation and other clinical factors. To study the mean I-131 dose for the initial treatment of hyperthyroidism in Rajavithi Hospital, to find the clinical factors that correlate with I-131 treatment dose, and to devise a formula to predict the optimal I-131 treatment dose. This was a retrospective study of 510 patients with a diagnosis of hyperthyroidism who received initial I-131 treatment at the Department of Nuclear Medicine in Rajavithi Hospital between January 2014 and June 2015. Baseline characteristics including age, sex, age at diagnosis, duration of antithyroid drug (ATD) therapy, gland weight (g), 3-hour RAIU and I-131 treatment dose were reviewed from medical records. The mean age ± SD was 41.93 ± 14.11 years (range 14-81 years), and the male to female ratio was 4.1:1. The mean duration of ATD therapy was 3.54 ± 4.02 years (min-max, 0.8-40.6 years). The mean gland weight was 54.35 ± 32.95 grams, and the mean 3-hour RAIU was 55.5 ± 23.69%. The mean I-131 treatment dose was 14.84 ± 5.71 mCi (min-max, 7-30 mCi). There was no significant correlation between dose and age, age at diagnosis, duration of A TD therapy or 3-hour RAIU. The study showed a significant correlation between I-131 dose and gland size, r = 0.938 (p < 0.001), and the regression relationship equation was: 1-131 dose = 0.235 gland size, r = 0.938. I-131 is the treatment of choice for hyperthyroidism after medical therapy failure, and there are various techniques for determining the optimal dose. At Rajavithi Hospital, the I-131 dose (mean = 14.84 ± 5.71 mCi) is estimated based on the gland weight by palpation and other additional clinical factors. The present study provided a practical formula which is simple and practical for use in determining the I-131 dose for the treatment of hyperthyroidism: Dose of I-131 (mCi) = 0.235 x gland size (g).

Effects of varied doses of psilocybin on time interval reproduction in human subjects.

PubMed

Wackermann, Jirí; Wittmann, Marc; Hasler, Felix; Vollenweider, Franz X

2008-04-11

Action of a hallucinogenic substance, psilocybin, on internal time representation was investigated in two double-blind, placebo-controlled studies: Experiment 1 with 12 subjects and graded doses, and Experiment 2 with 9 subjects and a very low dose. The task consisted in repeated reproductions of time intervals in the range from 1.5 to 5s. The effects were assessed by parameter kappa of the 'dual klepsydra' model of internal time representation, fitted to individual response data and intra-individually normalized with respect to initial values. The estimates kappa were in the same order of magnitude as in earlier studies. In both experiments, kappa was significantly increased by psilocybin at 90 min from the drug intake, indicating a higher loss rate of the internal duration representation. These findings are tentatively linked to qualitative alterations of subjective time in altered states of consciousness.

TU-EF-204-09: A Preliminary Method of Risk-Informed Optimization of Tube Current Modulation for Dose Reduction in CT

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

Gao, Y; Liu, B; Kalra, M

Purpose: X-rays from CT scans can increase cancer risk to patients. Lifetime Attributable Risk of Cancer Incidence for adult patients has been investigated and shown to decrease as patient age. However, a new risk model shows an increasing risk trend for several radiosensitive organs for middle age patients. This study investigates the feasibility of a general method for optimizing tube current modulation (TCM) functions to minimize risk by reducing radiation dose to radiosensitive organs of patients. Methods: Organ-based TCM has been investigated in literature for eye lens dose and breast dose. Adopting the concept in organ-based TCM, this study seeksmore » to find an optimized tube current for minimal total risk to breasts and lungs by reducing dose to these organs. The contributions of each CT view to organ dose are determined through simulations of CT scan view-by-view using a GPU-based fast Monte Carlo code, ARCHER. A Linear Programming problem is established for tube current optimization, with Monte Carlo results as weighting factors at each view. A pre-determined dose is used as upper dose boundary, and tube current of each view is optimized to minimize the total risk. Results: An optimized tube current is found to minimize the total risk of lungs and breasts: compared to fixed current, the risk is reduced by 13%, with breast dose reduced by 38% and lung dose reduced by 7%. The average tube current is maintained during optimization to maintain image quality. In addition, dose to other organs in chest region is slightly affected, with relative change in dose smaller than 10%. Conclusion: Optimized tube current plans can be generated to minimize cancer risk to lungs and breasts while maintaining image quality. In the future, various risk models and greater number of projections per rotation will be simulated on phantoms of different gender and age. National Institutes of Health R01EB015478.« less

Rectal Dose and Source Strength of the High-Dose-Rate Iridium-192 Both Affect Late Rectal Bleeding After Intracavitary Radiation Therapy for Uterine Cervical Carcinoma

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

Isohashi, Fumiaki, E-mail: isohashi@radonc.med.osaka-u.ac.j; Yoshioka, Yasuo; Koizumi, Masahiko

2010-07-01

Purpose: The purpose of this study was to reconfirm our previous findings that the rectal dose and source strength both affect late rectal bleeding after high-dose-rate intracavitary brachytherapy (HDR-ICBT), by using a rectal dose calculated in accordance with the definitions of the International Commission on Radiation Units and Measurements Report 38 (ICRU{sub RP}) or of dose-volume histogram (DVH) parameters by the Groupe Europeen de Curietherapie of the European Society for Therapeutic Radiology and Oncology. Methods and Materials: Sixty-two patients who underwent HDR-ICBT and were followed up for 1 year or more were studied. The rectal dose for ICBT was calculatedmore » by using the ICRP{sub RP} based on orthogonal radiographs or the DVH parameters based on computed tomography (CT). The total dose was calculated as the biologically equivalent dose expressed in 2-Gy fractions (EQD{sub 2}). The relationship between averaged source strength or the EQD{sub 2} and late rectal bleeding was then analyzed. Results: When patients were divided into four groups according to rectal EQD{sub 2} ({>=} or =} or <2.4 cGy.m{sup 2}.h{sup -1}), the group with both a high EQD{sub 2} and a high source strength showed a significantly greater probability of rectal bleeding for ICRU{sub RP}, D{sub 2cc}, and D{sub 1cc}. The patients with a median rectal dose above the threshold level did not show a greater frequency of rectal bleeding unless the source strength exceeded 2.4 cGy.m{sup 2}.h{sup -1}. Conclusions: Our results obtained with data based on ICRU{sub RP} and CT-based DVH parameters indicate that rectal dose and source strength both affect rectal bleeding after HDR-ICBT.« less

A Safety Evaluation of DAS181, a Sialidase Fusion Protein, in Rodents

PubMed Central

Larson, Jeffrey L.; Kang, Seong-Kwi; Choi, Bo In; Hedlund, Maria; Aschenbrenner, Laura M.; Cecil, Beth; Machado, GloriaMay; Nieder, Matthew; Fang, Fang

2011-01-01

DAS181 is a novel inhaled drug candidate blocking influenza virus (IFV) and parainfluenza virus (PIV) infections through removal of sialic acid receptors from epithelial surface of the respiratory tract. To support clinical development, a 28-day Good Laboratory Practices inhalation toxicology study was conducted in Sprague-Dawley rats. In this study, achieved average daily doses based on exposure concentrations were 0.47, 0.90, 1.55, and 3.00 mg/kg/day of DAS181 in a dry powder formulation. DAS181 was well tolerated at all dose levels, and there were no significant toxicological findings. DAS181 administration did not affect animal body weight, food consumption, clinical signs, ophthalmology, respiratory parameters, or organ weight. Gross pathology evaluations were unremarkable. Histological examination of the lungs was devoid of pulmonary tissue damage, and findings were limited to mild and transient changes indicative of exposure and clearance of a foreign protein. DAS181 did not show any cytotoxic effects on human and animal primary cells, including hepatocytes, skeletal muscle cells, osteoblasts, or respiratory epithelial cells. DAS181 did not cause direct or indirect hemolysis. A laboratory abnormality observed in the 28-day toxicology study was mild and transient anemia in male rats at the 3.00 mg/kg dose, which is an expected outcome of enhanced clearance of desialylated red blood cells resulting from systemic exposure with DAS181. Another laboratory observation was a transient dose-dependent elevation in alkaline phosphatase (ALP), which can be attributed to reduced ALP clearance resulting from increased protein desialylation due to DAS181 systemic exposure. These laboratory parameters returned to normal at the end of the recovery period. PMID:21572096

A 12-week DBPC dose-finding study with sublingual monomeric allergoid tablets in house dust mite-allergic patients.

PubMed

Hüser, C; Dieterich, P; Singh, J; Shah-Hosseini, K; Allekotte, S; Lehmacher, W; Compalati, E; Mösges, R

2017-01-01

In sublingual immunotherapy, optimal doses are a key factor for therapeutic outcomes. The aim of this study with tablets containing carbamylated monomeric house dust mite allergoids was to determine the most effective and safe dose. In this double-blind, placebo-controlled dose-finding study, 131 patients with house dust mite-induced allergic rhinoconjunctivitis were randomized to 12-week treatments with 300 UA/day, 1000 UA/day, 2000 UA/day, 3000 UA/day or placebo. Conjunctival provocation tests (CPT) were performed before, during and after treatment. The change in mean allergic severity (primary endpoint), calculated from the severity of the CPT reaction, and the proportion of patients with an improved CPT threshold (secondary endpoint) determined the treatment effect. The mean allergic severity decreased in all groups, including the placebo group. It was lower in all active treatment groups (300 UA/day: 0.14, 1000 UA/day: 0.15, 2000 UA/day: 0.10, 3000 UA/day: 0.15) than in the placebo group (0.30). However, this difference was not statistically significant (P < 0.1). The percentage of patients with an improved CPT threshold was higher in the active treatment groups (300 UA/day: 73.9%; 1000 UA/day: 76.0%; 2000 UA/day: 88.5%; 3000 UA/day: 76.0%) than in the placebo group (64.3%). The difference between placebo and 2000 UA/day was statistically significant (P = 0.04). In 13 (10%) exposed patients, a total of 20 treatment-related adverse events of mild severity were observed. The 12-week daily treatment using 2000 UA/day monomeric allergoid sublingual tablets is well tolerated and reduces the CPT reaction in house dust mite-allergic patients. © 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.

Risk of Liver Injury Associated with Chinese Herbal Products Containing Radix bupleuri in 639,779 Patients with Hepatitis B Virus Infection

PubMed Central

Lee, Chang-Hsing; Wang, Jung-Der; Chen, Pau-Chung

2011-01-01

Background Chinese herbal products (CHPs) containing Radix bupleuri are often prescribed for chronic hepatitis. There have been no epidemiological studies in populations with hepatitis B virus (HBV) infection. Our study was conducted to determine the association between the use of CHPs containing Radix bupleuri and the risk of hospitalisation related to liver injury among HBV-infected patients in Taiwan. Methods From a total of 639,779 patients with diagnoses related to HBV infection, we included hospitalised adult cases with a primary diagnosis of liver injury in the database of Taiwan's national health insurance during the period 1997–2004. Case-control and case-crossover designs were used to assess the risk of hospitalisation with conditional logistic regression models constructed and adjusted for 270 conventionally hepatotoxic drugs. Cumulative doses of these CHPs and Radix bupleuri were assessed for any dose-response relationship. Findings In total, we collected 1,080 cases fulfilled the inclusion criteria. In the case-control design, the adjusted odds ratio was 1.90 (95% confidence interval [CI]: 1.30 to 2.77). The risks from prescribing the CHPs Xiao-Chai-Hu-Tang and Long-Dan-Xie-Gan-Tang were significantly high, and dose-response relationships were found. The risk of adding each 19 gm dose of Radix bupleuri was 2.19 (95% CI: 1.66 to 2.89). The results using the case-crossover design remained similar. Conclusions Prescribing Xiao-Chai-Hu-Tang, Long-Dan-Xie-Gan-Tang, or CHPs containing more than 19 gram of Radix bupleuri in HBV-infected patients might increase their risks of liver injury. Further studies are indicated to corroborate the above findings. PMID:21264326

Retrospective evaluation of a method to predict fresh-frozen plasma dosage in anticoagulated patients.

PubMed

Frazee, Lawrence A; Bourguet, Claire C; Gutierrez, Wilson; Elder-Arrington, Jacinta; Elackattu, Alphi E P; Haller, Nairmeen Awad

2008-01-01

In the United States, fresh-frozen plasma (FFP) is commonly used for urgent reversal of warfarin; however, dosage recommendations are difficult to find. If validated, a proposed method that uses a nonlinear relationship between international normalized ratio (INR) and clotting factor activity (CFa) would be useful. This study retrospectively evaluated a proposed equation with adult medical inpatients who received FFP for warfarin reversal. For each patient the equation was used to predict the dose of FFP required to achieve the observed change in INR, which was then compared to the actual dose. The equation was considered successful if the predicted dose was within +/-20% of the actual dose. Subgroup analyses included subjects who received concomitant vitamin K; subjects with supratherapeutic INRs (>3); and subjects with significantly elevated INRs (>5). Of the 209 patients screened, 91 met criteria for inclusion in the study. Use of the equation to calculate the predicted dose of FFP was successful in 11 patients (12.1%) with use of actual body weight for prediction and in 23 patients (25.3%) with use of ideal body weight (P = 0.02). The equation performed similarly in all subgroups analyzed. The mean predicted FFP dose was significantly greater than the actual dose in all patients when actual body weight was used (925.2 mL vs. 620.6 mL; P < 0.001). Least-squares regression modeling of repeat INR (converted to CFa) produced a model that accounted for 57% of the variance in repeat INR. The value predicted from the model was closer to the actual CFa than was the value predicted from the published equation in every comparison, but it was statistically different only when actual body weight was used. This study revealed that a published equation for calculation of FFP dose to reverse oral anticoagulation resulted in doses that were significantly higher than the actual dose. Use of ideal body weight improved accuracy but was still not successful for the majority of patients. Until trials are able to prospectively demonstrate the accuracy of a dose-prediction model for FFP, dosing will remain largely empiric.

Medication dosing errors and associated factors in hospitalized pediatric patients from the South Area of the West Bank - Palestine.

PubMed

Al-Ramahi, Rowa'; Hmedat, Bayan; Alnjajrah, Eman; Manasrah, Israa; Radwan, Iqbal; Alkhatib, Maram

2017-09-01

Medication dosing errors are a significant global concern and can cause serious medical consequences for patients. Pediatric patients are at increased risk of dosing errors due to differences in medication pharmacodynamics and pharmacokinetics. The aims of this study were to find the rate of medication dosing errors in hospitalized pediatric patients and possible associated factors. The study was an observational cohort study including pediatric inpatients less than 16 years from three governmental hospitals from the West Bank/Palestine during one month in 2014, and sample size was 400 pediatric inpatients from these three hospitals. Pediatric patients' medical records were reviewed. Patients' weight, age, medical conditions, all prescribed medications, their doses and frequency were documented. Then the doses of medications were evaluated. Among 400 patients, the medications prescribed were 949 medications, 213 of them (22.4%) were out of the recommended range, and 160 patients (40.0%) were prescribed one or more potentially inappropriate doses. The most common cause of hospital admission was sepsis which presented 14.3% of cases, followed by fever (13.5%) and meningitis (10.0%). The most commonly used medications were ampicillin in 194 cases (20.4%), ceftriaxone in 182 cases (19.2%), and cefotaxime in 144 cases (12.0%). No significant association was found between potentially inappropriate doses and gender or hospital (chi-square test p -value > 0.05).The results showed that patients with lower body weight, who had a higher number of medications and stayed in hospital for a longer time, were more likely to have inappropriate doses. Potential medication dosing errors were high among pediatric hospitalized patients in Palestine. Younger patients, patients with lower body weight, who were prescribed higher number of medications and stayed in hospital for a longer time were more likely to have inappropriate doses, so these populations require special care. Many children were hospitalized for infectious causes and antibiotics were widely used. Strategies to reduce pediatric medication dosing errors are recommended.

Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults.

PubMed

Creech, C Buddy; Dekker, Cornelia L; Ho, Dora; Phillips, Shanda; Mackey, Sally; Murray-Krezan, Cristina; Grazia Pau, Maria; Hendriks, Jenny; Brown, Valerie; Dally, Leonard G; Versteege, Isabella; Edwards, Kathryn M

2013-12-01

Malaria results in over 650,000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.

Assessments of Voice Use and Voice Quality among College/University Singing Students Ages 18–24 through Ambulatory Monitoring with a Full Accelerometer Signal

PubMed Central

Schloneger, Matthew; Hunter, Eric

2016-01-01

The multiple social and performance demands placed on college/university singers could put their still developing voices at risk. Previous ambulatory monitoring studies have analyzed the duration, intensity, and frequency (in Hz) of voice use among such students. Nevertheless, no studies to date have incorporated the simultaneous acoustic voice quality measures into the acquisition of these measures to allow for direct comparison during the same voicing period. Such data could provide greater insight into how young singers use their voices, as well as identify potential correlations between vocal dose and acoustic changes in voice quality. The purpose of this study was to assess the voice use and estimated voice quality of college/university singing students (18–24 y/o, N = 19). Ambulatory monitoring was conducted over three full, consecutive weekdays measuring voice from an unprocessed accelerometer signal measured at the neck. From this signal were analyzed traditional vocal dose metrics such as phonation percentage, dose time, cycle dose, and distance dose. Additional acoustic measures included perceived pitch, pitch strength, LTAS slope, alpha ratio, dB SPL 1–3 kHz, and harmonic-to-noise ratio. Major findings from more than 800 hours of recording indicated that among these students (a) higher vocal doses correlated significantly with greater voice intensity, more vocal clarity and less perturbation; and (b) there were significant differences in some acoustic voice quality metrics between non-singing, solo singing and choral singing. PMID:26897545

Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

PubMed Central

Kaplovitch, Eric; Gomes, Tara; Camacho, Ximena; Dhalla, Irfan A.; Mamdani, Muhammad M.; Juurlink, David N.

2015-01-01

Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated. PMID:26291716

Effects of repeated doses of caffeine on performance and alertness: new data and secondary analyses.

PubMed

Hewlett, Paul; Smith, Andrew

2007-08-01

The effects of caffeine on mood and performance are well established. Some authors suggest that caffeine merely reverses effects of caffeine withdrawal rather than having direct behavioural effects. It has also been suggested that withdrawal may be removed by a first dose of caffeine and further doses have little subsequent effect. These issues are examined here. The present study aimed to determine whether caffeine withdrawal influenced mood and performance by comparing regular consumers who had been withdrawn from caffeine overnight with non-consumers. Following this repeated caffeine doses were administered to test the claim that repeated dosing has no extra effect on mood or performance. Secondary analyses of data collected after a day of normal caffeine consumption were also carried out to examine some alternative explanations of their results which showed effects of caffeine after a day of normal caffeine consumption. One hundred and twenty volunteers participated in the study. Regular caffeine consumption was assessed by questionnaire and this showed that 36 of the volunteers did not regularly consume caffeinated beverages. Volunteers were instructed to abstain from caffeine overnight and then completed a baseline session measuring mood and a range of cognitive functions at 08.00 the next day. Following this volunteers were given 0, or 1 mg/kg caffeine in a milkshake, glucose solution or water (at 09:00), followed by a second 0 or 1 mg/kg caffeine dose (at 09:40) and the test battery repeated at 10:00. The baseline data showed no effect of overnight caffeine withdrawal on mood or performance. In contrast, caffeine challenge improved vigilance performance and prevented decreases in alertness induced by completion of the task battery. The magnitude of these effects increased as a function of the number of doses of caffeine given. Secondary analyses of data from Christopher et al. (2003) also confirmed that effects of caffeine did not depend on length of withdrawal. The present findings show no effect of overnight caffeine withdrawal on mood and performance. Caffeine challenge did have the predicted effect on alertness and vigilance, with the size of the effects increasing with caffeine dose. These findings suggest that the effects of caffeine are not due to reversal of effects of withdrawal, a view confirmed by secondary analyses of data collected after a day of normal caffeine consumption. Copyright 2007 John Wiley & Sons, Ltd.

AS03-Adjuvanted, Very-Low-Dose Influenza Vaccines Induce Distinctive Immune Responses Compared to Unadjuvanted High-Dose Vaccines in BALB/c Mice

PubMed Central

Yam, Karen K.; Gupta, Jyotsana; Winter, Kaitlin; Allen, Elizabeth; Brewer, Angela; Beaulieu, Édith; Mallett, Corey P.; Burt, David S.; Ward, Brian J.

2015-01-01

During the 2009–2010 influenza pandemic, an adjuvanted, dose-sparing vaccine was recommended for most Canadians. We hypothesize that differences exist in the responses to AS03-adjuvanted, low antigen (Ag) dose versus unadjuvanted, full-dose vaccines. We investigated the relationship between Ag dose and the oil-in-water emulsion Adjuvant System AS03. BALB/c mice received two IM doses of AS03A or AS03B with exaggerated dilutions of A/Uruguay/716/2007 H3N2 split virion vaccine Ag. Immune responses were assessed 3 weeks after the booster. Unadjuvanted “high” (3 μg) and low-dose (0.03–0.003 μg) vaccines generated similar serum antibody titers and cytokine secretion patterns in restimulated splenocytes. Compared to unadjuvanted “high-dose” vaccination, both AS03A and AS03B-adjuvanted low-dose vaccines tended to elicit higher serum antibody titers, broader induction of cytokine secretion and generated more influenza-specific antibody secreting cells and cytokine-secreting CD4 and CD8 T cells in splenocytes. We show that varying Ag and/or AS03 dose in this influenza vaccination mouse model can strongly influence both the magnitude and pattern of the immune response elicited. These findings are highly relevant given the likelihood of expanded use of adjuvanted, dose-sparing vaccines and raise questions about the use of “standard” doses of vaccines in pre-clinical vaccine studies. PMID:25972874

Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome.

PubMed

Han, Seunghoon; Kim, Yoo-Jin; Lee, Jongtae; Jeon, Sangil; Hong, Taegon; Park, Gab-Jin; Yoon, Jae-Ho; Yahng, Seung-Ah; Shin, Seung-Hwan; Lee, Sung-Eun; Eom, Ki-Seong; Kim, Hee-Je; Min, Chang-Ki; Lee, Seok; Yim, Dong-Seok

2015-10-23

This report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia. The first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m(2)/day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner. In all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm(3) (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m(2)/day, respectively. The median maintenance dose was 7 mg/m(2)/day. We determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m(2)/day is considered to be the most appropriate starting dose for the regimen studied. Clinicaltrials.gov NCT01277484.

Differential Effects of High Dose Magnetic Seizure Therapy (MST) and Electroconvulsive Shock (ECS) on Cognitive Function

PubMed Central

Spellman, Timothy; McClintock, Shawn M.; Terrace, Herbert; Luber, Bruce; Husain, Mustafa M.; Lisanby, Sarah H.

2008-01-01

Background Magnetic seizure therapy (MST) is under investigation as an alternative form of convulsive therapy that induces more focal seizures and spares cortical regions involved in memory. Using a newly expanded version of the Columbia University Primate Cognitive Profile, we compared the cognitive effects of high-dose MST delivered at 100 Hz (6X seizure threshold) with electroconvulsive shock (ECS) delivered at 2.5X seizure threshold. Methods Daily high-dose MST, ECS, and Sham (anesthesia-only) were administered for 4 weeks each in a within-subject cross-over design. Rhesus macaques (n = 3) were trained on five cognitive tasks assessing automatic memory, anterograde learning and memory, combined anterograde and retrograde simultaneous chaining, and spatial and serial working memory. Acutely following each intervention, monkeys were tested on the cognitive battery twice daily, separated by a 3-hour retention interval. Results Subjects were slower to complete criterion tasks (p’s<0.0001) following ECS, compared to sham and high-dose MST. Moreover, time to task-completion following high-dose MST did not differ from sham. Out of 6 measures of accuracy, treatment effects were found in 4; in all of these, ECS, but not MST, fared worse than Sham. On all accuracy and time to completion measurements, subjects performed as well as following high-dose MST as did subjects from a previous study on moderate-dose MST. Conclusion These findings provide evidence that high-dose MST results in benign acute cognitive side-effect profile relative to ECS, and are in line with our previous studies. PMID:18262171

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia.

PubMed

Azevedo, M C; Velloso, E D R P; Buccheri, V; Chamone, D A F; Dorlhiac-Llacer, P E

2015-02-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia

PubMed Central

Azevedo, M.C.; Velloso, E.D.R.P.; Buccheri, V.; Chamone, D.A.F.; Dorlhiac-Llacer, P.E.

2014-01-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival. PMID:25517921

A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors.

PubMed

Lin, Jianqing; Gilbert, Jill; Rudek, Michelle A; Zwiebel, James A; Gore, Steve; Jiemjit, Anchalee; Zhao, Ming; Baker, Sharyn D; Ambinder, Richard F; Herman, James G; Donehower, Ross C; Carducci, Michael A

2009-10-01

This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit.

Characterization of the aggregation responses of camel platelets.

PubMed

Al Ghumlas, Abeer K; Gader, Abdel Galil M Abdel

2013-09-01

Despite evidence of active hemostasis, camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation. The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists, and to characterize the receptor that mediates the aggregation response to adenosine diphosphate (ADP), the most potent agonist for camel platelets known so far. Aggregation studies were performed with platelet-rich plasma (PRP) in response to multiple doses or combinations of ADP, epinephrine (EPN), collagen, and arachidonic acid (AA). Aggregation responses to ADP were performed before and after the addition of the ADP receptor (P2Y12) antagonist Clopidogrel. Camel platelets responded to ADP at doses higher than the standard dose for human platelets, and to combinations of EPN and other agonists, while no aggregation was elicited with EPN or AA alone. Clopidogrel blocked the ADP-induced aggregation responses in a dose-dependent fashion in vitro. Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP, but not AA or EPN. Irreversible aggregation of camel platelets could also be triggered by a combination of EPN and ADP, and collagen and AA. Inhibition with clopidogrel suggests that camel platelets express the ADP receptor, P2Y12. Understanding platelet function in camels will add to the understanding of platelet function in health and disease. © 2013 American Society for Veterinary Clinical Pathology.

Optimising drug dosing in patients receiving extracorporeal membrane oxygenation.

PubMed

Cheng, Vesa; Abdul-Aziz, Mohd-Hafiz; Roberts, Jason A; Shekar, Kiran

2018-03-01

Optimal pharmacological management during extracorporeal membrane oxygenation (ECMO) involves more than administering drugs to reverse underlying disease. ECMO is a complex therapy that should be administered in a goal-directed manner to achieve therapeutic endpoints that allow reversal of disease and ECMO wean, minimisation of complications (treatment of complications when they do occur), early interruption of sedation and rehabilitation, maximising patient comfort and minimising risks of delirium. ECMO can alter both the pharmacokinetics (PK) and pharmacodynamics (PD) of administered drugs and our understanding of these alterations is still evolving. Based on available data it appears that modern ECMO circuitry probably has a less significant impact on PK when compared with critical illness itself. However, these findings need further confirmation in clinical population PK studies and such studies are underway. The altered PD associated with ECMO is less understood and more research is indicated. Until robust dosing guidelines become available, clinicians will have to rely on the principles of drug dosing in critically ill and known PK alterations induced by ECMO itself. This article summarises the PK alterations and makes preliminary recommendations on possible dosing approaches.

EFFECT OF FOOD TRAINING AND TRAINING DOSE ON NICOTINE SELF-ADMINISTRATION IN RATS

PubMed Central

Garcia, Kristine L.P.; Lê, Anh Dzung; Tyndale, Rachel F.

2014-01-01

Few studies investigate factors that influence acquisition in nicotine self-administration (NSA), such as food training and training dose. Most have utilized peak doses along nicotine’s dose-response curve (15 and 30 μg/kg) that establish NSA in the majority of animals. To investigate the specific and combined effects of training and dose on NSA acquisition, separate and head-to head experiments using food training (FT) or spontaneous acquisition (SP) at multiple doses on the ascending limb of the dose-response curve were tested. First, rats underwent FT or SP under fixed ratio (FR1 and FR2) and progressive ratio (PR) schedules using 7.5–30 μg/kg nicotine. More rats acquired NSA with FT vs. SP at 3.75 μg/kg (56% vs. 38%) and 7.5 μg/kg (88% vs. 40%, p<0.05) and FT rats responded higher under PR. Based on these findings, rats then underwent identical NSA acquisition and PR (with and without nicotine), extinction and reinstatement induced by cue exposure and nicotine in a head-to-head comparison of FT and SP using 7.5 μg/kg. Acquisition differences were replicated: 100% FT and 60% SP rats met criteria (p<0.05). Without nicotine (cue only), no FT rats and 8% SP rats met criteria. FR and PR responding, extinction, and cue and nicotine-induced reinstatement did not differ between FT and SP. FT versus SP enhances acquisition at lower nicotine doses but does not alter subsequent behaviors. Lower doses can reinforce NSA and be used, in the absence of FT, to study influences on acquisition more closely modelling the initial phases of human smoking. PMID:25101539

Effect of food training and training dose on nicotine self-administration in rats.

PubMed

Garcia, Kristine L P; Lê, Anh Dzung; Tyndale, Rachel F

2014-11-01

Few studies investigate factors that influence acquisition in nicotine self-administration (NSA), such as food training and training dose. Most have utilized peak doses along nicotine's dose-response curve (15 and 30μg/kg) that establish NSA in the majority of animals. To investigate the specific and combined effects of training and dose on NSA acquisition, separate and head-to-head experiments using food training (FT) or spontaneous acquisition (SP) at multiple doses on the ascending limb of the dose-response curve were tested. First, rats underwent FT or SP under fixed ratio (FR1 and FR2) and progressive ratio (PR) schedules using 7.5-30μg/kg nicotine. More rats acquired NSA with FT vs. SP at 3.75μg/kg (56% vs. 38%) and 7.5μg/kg (88% vs. 40%, p<0.05) and FT rats responded higher under PR. Based on these findings, rats then underwent identical NSA acquisition and PR (with and without nicotine), extinction and reinstatement induced by cue exposure and nicotine in a head-to-head comparison of FT and SP using 7.5μg/kg. Acquisition differences were replicated: 100% FT and 60% SP rats met criteria (p<0.05). Without nicotine (cue only), no FT rats and 8% SP rats met criteria. FR and PR responding, extinction, and cue and nicotine-induced reinstatement did not differ between FT and SP. FT versus SP enhances acquisition at lower nicotine doses but does not alter subsequent behaviours. Lower doses can reinforce NSA and be used, in the absence of FT, to study influences on acquisition more closely modelling the initial phases of human smoking. Copyright © 2014 Elsevier B.V. All rights reserved.

Mean Absorbed Dose to the Anal-Sphincter Region and Fecal Leakage among Irradiated Prostate Cancer Survivors

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

Alsadius, David, E-mail: david.alsadius@oncology.gu.se; Hedelin, Maria; Division of Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska Institute, Stockholm

2012-10-01

Purpose: To supplement previous findings that the absorbed dose of ionizing radiation to the anal sphincter or lower rectum affects the occurrence of fecal leakage among irradiated prostate-cancer survivors. We also wanted to determine whether anatomically defining the anal-sphincter region as the organ at risk could increase the degree of evidence underlying clinical guidelines for restriction doses to eliminate this excess risk. Methods and Materials: We identified 985 men irradiated for prostate cancer between 1993 and 2006. In 2008, we assessed long-term gastrointestinal symptoms among these men using a study-specific questionnaire. We restrict the analysis to the 414 men whomore » had been treated with external beam radiation therapy only (no brachytherapy) to a total dose of 70 Gy in 2-Gy daily fractions to the prostate or postoperative prostatic region. On reconstructed original radiation therapy dose plans, we delineated the anal-sphincter region as an organ at risk. Results: We found that the prevalence of long-term fecal leakage at least once per month was strongly correlated with the mean dose to the anal-sphincter region. Examining different dose intervals, we found a large increase at 40 Gy; {>=}40 Gy compared with <40 Gy gave a prevalence ratio of 3.8 (95% confidence interval 1.6-8.6). Conclusions: This long-term study shows that mean absorbed dose to the anal-sphincter region is associated with the occurrence of long-term fecal leakage among irradiated prostate-cancer survivors; delineating the anal-sphincter region separately from the rectum and applying a restriction of a mean dose <40 Gy will, according to our data, reduce the risk considerably.« less

Time and dose-response effects of honokiol on UVB-induced skin cancer development.

PubMed

Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

2012-06-01

Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

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

NASA Astrophysics Data System (ADS)

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

2014-02-01

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

Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.

PubMed

Pressler, Ronit M; Boylan, Geraldine B; Marlow, Neil; Blennow, Mats; Chiron, Catherine; Cross, J Helen; de Vries, Linda S; Hallberg, Boubou; Hellström-Westas, Lena; Jullien, Vincent; Livingstone, Vicki; Mangum, Barry; Murphy, Brendan; Murray, Deirdre; Pons, Gerard; Rennie, Janet; Swarte, Renate; Toet, Mona C; Vanhatalo, Sampsa; Zohar, Sarah

2015-05-01

Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. European Community's Seventh Framework Programme. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pulmonary nodules: effect of adaptive statistical iterative reconstruction (ASIR) technique on performance of a computer-aided detection (CAD) system-comparison of performance between different-dose CT scans.

PubMed

Yanagawa, Masahiro; Honda, Osamu; Kikuyama, Ayano; Gyobu, Tomoko; Sumikawa, Hiromitsu; Koyama, Mitsuhiro; Tomiyama, Noriyuki

2012-10-01

To evaluate the effects of ASIR on CAD system of pulmonary nodules using clinical routine-dose CT and lower-dose CT. Thirty-five patients (body mass index, 22.17 ± 4.37 kg/m(2)) were scanned by multidetector-row CT with tube currents (clinical routine-dose CT, automatically adjusted mA; lower-dose CT, 10 mA) and X-ray voltage (120 kVp). Each 0.625-mm-thick image was reconstructed at 0%-, 50%-, and 100%-ASIR: 0%-ASIR is reconstructed using only the filtered back-projection algorithm (FBP), while 100%-ASIR is reconstructed using the maximum ASIR and 50%-ASIR implies a blending of 50% FBP and ASIR. CAD output was compared retrospectively with the results of the reference standard which was established using a consensus panel of three radiologists. Data were analyzed using Bonferroni/Dunn's method. Radiation dose was calculated by multiplying dose-length product by conversion coefficient of 0.021. The consensus panel found 265 non-calcified nodules ≤ 30 mm (ground-glass opacity [GGO], 103; part-solid, 34; and solid, 128). CAD sensitivity was significantly higher at 100%-ASIR [clinical routine-dose CT, 71% (overall), 49% (GGO); lower-dose CT, 52% (overall), 67% (solid)] than at 0%-ASIR [clinical routine-dose CT, 54% (overall), 25% (GGO); lower-dose CT, 36% (overall), 50% (solid)] (p<0.001). Mean number of false-positive findings per examination was significantly higher at 100%-ASIR (clinical routine-dose CT, 8.5; lower-dose CT, 6.2) than at 0%-ASIR (clinical routine-dose CT, 4.6; lower-dose CT, 3.5; p<0.001). Effective doses were 10.77 ± 3.41 mSv in clinical routine-dose CT and 2.67 ± 0.17 mSv in lower-dose CT. CAD sensitivity at 100%-ASIR on lower-dose CT is almost equal to that at 0%-ASIR on clinical routine-dose CT. ASIR can increase CAD sensitivity despite increased false-positive findings. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Cumulative effects from repeated exposures to ultraviolet radiation

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

Kaidbey, K.H.; Kligman, A.M.

Repeated exposures to subliminal doses of UVR, given at 24-hr intervals, resulted in a lowering of the erythema threshold dose. At erythemogenically equivalent doses, UV-A was the most effective and UV-C the least. A similar and more pronounced effect was observed following repeated exposures to subthreshold doses of UV-A and topically applied 8-methoxypsoralen. These findings provide quantitative evidence for the cumulative nature of acute UVR damage in human skin.

Association between aspirin and upper gastrointestinal complications: Systematic review of epidemiologic studies

PubMed Central

Rodríguez, Luis A García; Hernández-Díaz, Sonia; de Abajo, Francisco J

2001-01-01

Aims Because of the widespread use of aspirin for prevention of cardiovascular diseases, side-effects associated with thromboprophylactic doses are of interest. This study summarizes the relative risk (RR) for serious upper gastrointestinal complications (UGIC) associated with aspirin exposure in general and with specific aspirin doses and formulations in particular. Methods After a systematic review, 17 original epidemiologic studies published between 1990 and 2001 were selected according to predefined criteria. Heterogeneity of effects was explored. Pooled estimates were calculated according to different study characteristics and patterns of aspirin use. Results The overall relative risk of UGIC associated with aspirin use was 2.2 (95% confidence interval (CI): 2.1, 2.4) for cohort studies and nested case-control studies and 3.1 (95% CI: 2.8, 3.3) for non-nested case-control studies. Original studies found a dose–response relationship between UGIC and aspirin, although the risk was still elevated for doses lower or up to 300 mg day−1. The summary RR was 2.6 (95% CI: 2.3, 2.9) for plain, 5.3 (95% CI: 3.0, 9.2) for buffered, and 2.4 (95% CI: 1.9, 2.9) for enteric-coated aspirin formulations. Conclusions Aspirin was associated with UGIC even when used at low doses or in buffered or enteric-coated formulations. The latter findings may be partially explained by channeling of susceptible patients to these formulations. PMID:11736865

Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers.

PubMed

Krishnan, Suma M; Pennick, Michael; Stark, Jeffrey G

2008-01-01

Attention-deficit/hyperactivity disorder (ADHD) in children often persists into adulthood and is potentially associated with significant social and occupational impairments. It is important to understand the effects of pharmacological treatments of ADHD in adults. This study aimed to assess the absorption, metabolism and elimination of lisdexamfetamine dimesylate in normal, healthy adult subjects following a single oral dose. A secondary objective was to assess the safety and tolerability of treatment. In an open-label, single-centre study, six healthy adult volunteers aged 22-52 years received a single oral 70 mg dose of (14)C-radiolabelled lisdexamfetamine dimesylate in solution following a 10-hour fast. Blood samples drawn pre-dose and at time points up to 120 hours post-dose were used for plasma pharmacokinetic analysis of the active d-amphetamine and the intact parent compound lisdexamfetamine dimesylate. Recovery of radioactivity was determined by liquid scintillation counting of blood samples (whole blood and plasma), urine samples and faecal samples collected pre-dose and at designated time points up to 120 hours post-dose. Urine samples were also analysed for the presence of amphetamine-derived metabolites. Safety was assessed by adverse event reporting, changes in physical findings, vital sign measurements, ECG measurements, and clinical laboratory test results. For intact lisdexamfetamine dimesylate, the median time to reach maximum plasma drug concentration (t(max)) was 1.00 hour, and the mean maximum plasma drug concentration (C(max)) was 58.2 +/- 28.1 ng/mL. Intact lisdexamfetamine dimesylate exhibited modest systemic exposure (area under the drug concentration-time curve from time 0 to infinity [AUC(infinity)] 67.04 +/- 18.94 ng . h/mL), and rapid elimination (mean apparent terminal elimination half-life [t((1/2)beta)] 0.47 hours). For d-amphetamine, the median t(max) was 3.00 hours, and the mean C(max) was 80.3 +/- 11.8 ng/mL. The AUC(infinity) of d-amphetamine was 1342 +/- 216.9 ng . h/mL, and elimination occurred as a first-order process. The t((1/2)beta) of d-amphetamine was 10.39 hours. Peaks consistent with amphetamine and hippuric acid were identified in urine samples by high-performance liquid chromatography radioactive profiling. Relative to dose administered, 41.5% was recovered in urine as d-amphetamine, 24.8% as hippuric acid and 2.2% as intact lisdexamfetamine dimesylate. Less than 0.3% of the administered dose was recovered in the faeces. During the 0- to 48-hour urine samples, no unexpected adverse events or clinically significant laboratory, ECG or physical examination findings related to the study medication were observed. Following a single 70 mg oral dose, lisdexamfetamine dimesylate was quickly absorbed, extensively metabolized to d-amphetamine and its derivatives, and rapidly eliminated. Systemic exposure to d-amphetamine was approximately 20-fold higher than systemic exposure to intact lisdexamfetamine dimesylate in healthy adults. Lisdexamfetamine dimesylate, administered as a single 70 mg dose, was generally well tolerated in this study.

If it is published in the peer-reviewed literature, it must be true?

PubMed

Wagner, Louis K

2014-10-01

Epidemiological research correlating cancer rates in a population of patients with radiation doses from medical X-rays is fraught with confounding factors that obfuscate the likelihood that any positive relationship is causal. This is a review of four studies involving some of those confounding factors. Comparisons of findings with other studies not encumbered by similar confounding factors can enhance assertions of causation between medical X-rays and cancer rates. Even so, such assertions rest significantly on opinions of researchers regarding the degree of consistency between findings among various studies. The question as to what degree any findings truly represent cause and effect will likely still meet with controversy. The importance of these findings to medicine should therefore not lie in any controversy regarding causation, but in what the findings potentially mean with regard to benefit and risk for patients and the professional practice of medicine.

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs

PubMed Central

Paoloni, Melissa C.; Mazcko, Christina; Fox, Elizabeth; Fan, Timothy; Lana, Susan; Kisseberth, William; Vail, David M.; Nuckolls, Kaylee; Osborne, Tanasa; Yalkowsy, Samuel; Gustafson, Daniel; Yu, Yunkai; Cao, Liang; Khanna, Chand

2010-01-01

Background Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients. Methodology/Principal Findings This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy. Conclusions/Significance Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease. PMID:20543980

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

PubMed

Kusawake, Tomohiro; Keirns, James J; Kowalski, Donna; den Adel, Martin; Groenendaal-van de Meent, Dorien; Takada, Akitsugu; Ohtsu, Yoshiaki; Katashima, Masataka

2017-12-01

Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUC inf ) and C max . After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUC inf increased by about 90%. In the bioavailability study, AUC inf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUC inf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated. Astellas Pharma. ClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).

Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior

PubMed Central

Leclercq, Sophie; Mian, Firoz M.; Stanisz, Andrew M.; Bindels, Laure B.; Cambier, Emmanuel; Ben-Amram, Hila; Koren, Omry; Forsythe, Paul; Bienenstock, John

2017-01-01

There is increasing concern about potential long-term effects of antibiotics on children's health. Epidemiological studies have revealed that early-life antibiotic exposure can increase the risk of developing immune and metabolic diseases, and rodent studies have shown that administration of high doses of antibiotics has long-term effects on brain neurochemistry and behaviour. Here we investigate whether low-dose penicillin in late pregnancy and early postnatal life induces long-term effects in the offspring of mice. We find that penicillin has lasting effects in both sexes on gut microbiota, increases cytokine expression in frontal cortex, modifies blood–brain barrier integrity and alters behaviour. The antibiotic-treated mice exhibit impaired anxiety-like and social behaviours, and display aggression. Concurrent supplementation with Lactobacillus rhamnosus JB-1 prevents some of these alterations. These results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria. PMID:28375200

Effects of nicotine and minor tobacco alkaloids on intracranial-self-stimulation in rats.

PubMed

Harris, Andrew C; Tally, Laura; Muelken, Peter; Banal, Andrew; Schmidt, Clare E; Cao, Qing; LeSage, Mark G

2015-08-01

While nicotine is the primary addictive compound in tobacco, other tobacco constituents including minor alkaloids (e.g., nornicotine, anabasine) may also contribute to tobacco addiction by mimicking or enhancing the effects of nicotine. Further evaluating the behavioral effects of minor alkaloids is essential for understanding their impact on tobacco addiction and informing development of tobacco product standards by the FDA. This study compared the addiction-related effects of nicotine and the minor alkaloids nornicotine, anabasine, myosmine, anatabine, and cotinine on intracranial self-stimulation (ICSS) thresholds in rats. Acute injection of nicotine produced reinforcement-enhancing (ICSS threshold-decreasing) effects at low to moderate doses, and reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high doses. Nornicotine and anabasine produced similar biphasic effects on ICSS thresholds, although with lower potency compared to nicotine. Myosmine only elevated ICSS thresholds at relatively high doses, while anatabine and cotinine did not influence ICSS thresholds at any dose. None of the alkaloids significantly influenced ICSS response latencies, indicating a lack of nonspecific motoric effects. These findings indicate that some minor tobacco alkaloids can either fully (nornicotine, anabasine) or partially (myosmine) mimic nicotine's addiction-related effects on ICSS, albeit at reduced potency. These findings emphasize the need for further study of the abuse potential of minor alkaloids, including evaluation of their effects when combined with nicotine and other tobacco constituents to better simulate tobacco exposure in humans. Such work is essential for informing FDA regulation of tobacco products and could also lead to the development of novel pharmacotherapies for tobacco addiction. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Stimulation Versus Inhibition—Bioactivity of Parthenin, A Phytochemical From Parthenium hysterophorus L.

PubMed Central

Belz, Regina G.

2008-01-01

Parthenium hysterophorus L. is an invasive weed that biosynthesizes several phytochemi-cals. The sesquiterpene lactone parthenin receives most attention regarding allelopathy of the plant or potential herbicidal properties. Since parthenin exhibits dose-dependent phy-totoxicity with low dose stimulation, this study investigated the occurrence and temporal features of parthenin hormesis in Sinapis arvensis L. sprayed with parthenin under semi-natural conditions. Dose/response studies showed that the occurrence and the magnitude of hormesis depended on climatic conditions and the parameter measured. Within the tested dose range, stimulatory responses were only observed under less-stressful conditions and were most pronounced for leaf area growth [138 % of control; 13 days after treatment (DAT)]. Temporal assessment of leaf area development showed that doses causing a stimulatory response at the end of the experiment (< 0.42 ± 0.04 kg/ha; 13 DAT) were initially inhibitory up to ED50 values (2 DAT). This clearly demonstrated an over-compensatory response. Inhibition of leaf area at 13 DAT reached ED50 values on average at 0.62 ±0.12 kg/ha, and S. arvensis was completely inhibited at doses exceeding 1.81 ±0.56 kg/ha (ED90). Based on these findings, implications of parthenin hormesis are discussed with respect to allelopathy of P. hysterophorus and exploitation of growth stimulatory responses in agriculture. PMID:18648571

Chromosome aberrations in workers occupationally exposed to tritium.

PubMed

Tawn, E Janet; Curwen, Gillian B; Riddell, Anthony E

2018-06-01

This paper reports the findings of an historical chromosome analysis for unstable aberrations, undertaken on 34 nuclear workers with monitored exposure to tritium. The mean recorded β-particle dose from tritium was 9.33 mGy (range 0.25-79.71 mGy) and the mean occupational dose from external, mainly γ-ray, irradiation was 1.94 mGy (range 0.00-7.71 mGy). The dicentric frequency of 1.91 ± 0.53 × 10 -3 per cell was significantly raised, in comparison with that of 0.61 ± 0.30 × 10 -3 per cell for a group of 66 comparable worker controls unexposed to occupational radiation. The frequency of total aberrations was also significantly higher in the tritium workers. Comparisons with in vitro studies indicate that at these dose levels an increase in aberration frequency is not expected. However, the available historical tritium dose records were produced for the purposes of radiological protection and based on a methodology that has since been updated, so tritium doses are subject to considerable uncertainty. It is therefore recommended that, if possible, tritium doses are reassessed using information on historical recording practices in combination with current dosimetry methodology, and that further chromosome studies are undertaken using modern FISH techniques to establish stable aberration frequencies, as these will provide information on a cumulative biological effect.

Contura Multi-Lumen Balloon breast brachytherapy catheter: comparative dosimetric findings of a phase 4 trial.

PubMed

Arthur, Douglas W; Vicini, Frank A; Todor, Dorin A; Julian, Thomas B; Cuttino, Laurie W; Mukhopadhyay, Nitai D

2013-06-01

Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented. Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: ≥ 95% of the prescribed dose (PD) covering ≥ 95% of the target volume (TV); maximum skin dose ≤ 125% of the PD; maximum rib dose ≤ 145% of the PD; and V150 ≤50 cc and V200 ≤ 10 cc. Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P ≤.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%. Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals. Copyright © 2013 Elsevier Inc. All rights reserved.

Contura Multi-Lumen Balloon Breast Brachytherapy Catheter: Comparative Dosimetric Findings of a Phase 4 Trial

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

Arthur, Douglas W., E-mail: darthur@mcvh-vcu.edu; Vicini, Frank A.; Todor, Dorin A.

2013-06-01

Purpose: Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented. Methods and Materials: Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: ≥95% of the prescribed dose (PD) covering ≥95% of the target volume (TV); maximum skin dose ≤125%more » of the PD; maximum rib dose ≤145% of the PD; and V150 ≤50 cc and V200 ≤10 cc. Results: Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P≤.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%. Conclusions: Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals.« less

Different doses of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation

PubMed Central

Estcourt, Lise J; Stanworth, Simon; Doree, Carolyn; Trivella, Marialena; Hopewell, Sally; Blanco, Patricia; Murphy, Michael F

2015-01-01

Background Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people who are thrombocytopenic due to bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 40 years, some areas continue to provoke debate, especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding. This is an update of a Cochrane review first published in 2004, and updated in 2012 that addressed four separate questions: prophylactic versus therapeutic-only platelet transfusion policy; prophylactic platelet transfusion threshold; prophylactic platelet transfusion dose; and platelet transfusions compared to alternative treatments. This review has now been split into four smaller reviews; this review compares different platelet transfusion doses. Objectives To determine whether different doses of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect their efficacy and safety in preventing bleeding in people with haematological disorders undergoing myelosuppressive chemotherapy with or without haematopoietic stem cell transplantation (HSCT). Search methods We searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 23 July 2015. Selection criteria Randomised controlled trials involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people with malignant haematological disorders or undergoing HSCT that compared different platelet component doses (low dose 1.1 × 1011/m2 ± 25%, standard dose 2.2 × 1011/m2 ± 25%, high dose 4.4 × 1011/m2 ± 25%). Data collection and analysis We used the standard methodological procedures expected by The Cochrane Collaboration. Main results We included seven trials (1814 participants) in this review; six were conducted during one course of treatment (chemotherapy or HSCT). Overall the methodological quality of studies was low to moderate across different outcomes according to GRADE methodology. None of the included studies were at low risk of bias in every domain, and all the included studies had some threats to validity. Five studies reported the number of participants with at least one clinically significant bleeding episode within 30 days from the start of the study. There was no difference in the number of participants with a clinically significant bleeding episode between the low-dose and standard-dose groups (four studies; 1170 participants; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.13; moderate-quality evidence); low-dose and high-dose groups (one study; 849 participants; RR 1.02, 95% CI 0.93 to 1.11; moderate-quality evidence); or high-dose and standard-dose groups (two studies; 951 participants; RR 1.02, 95% CI 0.93 to 1.11; moderate-quality evidence). Three studies reported the number of days with a clinically significant bleeding event per participant. There was no difference in the number of days of bleeding per participant between the low-dose and standard-dose groups (two studies; 230 participants; mean difference −0.17, 95% CI −0.51 to 0.17; low quality evidence). One study (855 participants) showed no difference in the number of days of bleeding per participant between high-dose and standard-dose groups, or between low-dose and high-dose groups (849 participants). Three studies reported the number of participants with severe or life-threatening bleeding. There was no difference in the number of participants with severe or life-threatening bleeding between a low-dose and a standard-dose platelet transfusion policy (three studies; 1059 participants; RR 1.33, 95% CI 0.91 to 1.92; low-quality evidence); low-dose and high-dose groups (one study; 849 participants; RR 1.20, 95% CI 0.82 to 1.77; low-quality evidence); or high-dose and standard-dose groups (one study; 855 participants; RR 1.11, 95% CI 0.73 to 1.68; low-quality evidence). Two studies reported the time to first bleeding episodes; we were unable to perform a meta-analysis. Both studies (959 participants) individually found that the time to first bleeding episode was either the same, or longer, in the low-dose group compared to the standard-dose group. One study (855 participants) found that the time to the first bleeding episode was the same in the high-dose group compared to the standard-dose group. Three studies reported all-cause mortality within 30 days from the start of the study. There was no difference in all-cause mortality between treatment arms (low-dose versus standard-dose: three studies; 1070 participants; RR 2.04, 95% CI 0.70 to 5.93; low-quality evidence; low-dose versus high-dose: one study; 849 participants; RR 1.33, 95% CI 0.50 to 3.54; low-quality evidence; and high-dose versus standard-dose: one study; 855 participants; RR 1.71, 95% CI 0.51 to 5.81; low-quality evidence). Six studies reported the number of platelet transfusions; we were unable to perform a meta-analysis. Two studies (959 participants) out of three (1070 participants) found that a low-dose transfusion strategy led to more transfusion episodes than a standard-dose. One study (849 participants) found that a low-dose transfusion strategy led to more transfusion episodes than a high-dose strategy. One study (855 participants) out of three (1007 participants) found no difference in the number of platelet transfusions between the high-dose and standard-dose groups. One study reported on transfusion reactions. This study’s authors suggested that a high-dose platelet transfusion strategy may lead to a higher rate of transfusion-related adverse events. None of the studies reported quality-of-life. Authors’ conclusions In haematology patients who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT, we found no evidence to suggest that a low-dose platelet transfusion policy is associated with an increased bleeding risk compared to a standard-dose or high-dose policy, or that a high-dose platelet transfusion policy is associated with a decreased risk of bleeding when compared to a standard-dose policy. A low-dose platelet transfusion strategy leads to an increased number of transfusion episodes compared to a standard-dose strategy. A high-dose platelet transfusion strategy does not decrease the number of transfusion episodes per participant compared to a standard-dose regimen, and it may increase the number of transfusion-related adverse events. Findings from this review would suggest a change from current practice, with low-dose platelet transfusions used for people receiving in-patient treatment for their haematological disorder and high-dose platelet transfusion strategies not being used routinely. PMID:26505729

Intratracheal fiber glass instillation in rats: IL8 and lymphocytes levels in bronchoalveolar lavage, correlation with the histopathological findings

PubMed Central

HANCU, BIANCA DOMOKOS; POP, MONICA

2013-01-01

Introduction Fiberglass (FG) is the largest category of man –made mineral fibers. Many types of FG are manufactured for specific uses building insulation, air handling, and sound absorption. Because of increasing use and potential for widespread human exposure, a chronic toxicity instillation study was conducted in Wistar rats, which were found to be sensitive to the induction of mesotheliomas with another MMVF. Aim The present study is focused on the effect of fiber glass on lung through intratracheal exposure, the analysis of bronchoalveolar lavage and measurement of IL 8 levels, lymphocytes number and histopathological finding after the exposure period. Material and method Four groups of 8 female Wistar rats were included in the study. The animals were divided into three groups of 8 each, exposed to different doses of FG and one control group. The first group (1–8) was exposed to 6 mg dose/0.2 ml saline 5 days/week for 10 weeks, the second (9–16) group was exposed to 10 mg/0.2 ml saline 5 days/week 10 weeks, the third group (17–24) was exposed to 12 mg FG/0.2 ml saline solution 5 days/week 10 weeks and the control group (25–32) was exposed to the same volume of saline. The fibers had been size selected to be rat respirable. At the end of the exposure period of 10 weeks the rats were killed one week after the last exposure. Following preparation of the lungs, they were lavaged with 2x5 ml saline without massage. The lavage fluid was collected in calibrated tubes and harvested volume was recorded. Supernatant was obtained after centrifugation at 1,500 r.p.m for 5 minutes and IL8 levels and lymphocytes number were measured. Results The IL8 levels were found to be dose related; the first group had values ranging from 10 to 19.8 pg/ml and the total lymphocytes number in the bronchoalveolar lavage fluid ranging from 1,500–1,900 and minimal/slight inflammatory lesions. The second group had the IL8 levels ranging between 60.4–80.4 pg/ml, lymphocytes number between 680–881 and moderate to marked inflammatory lesions. For the third group the IL8 values ranged between 88.3–113.2, the lymphocytes number ranged between 241–342 and the histopathological findings were marked and severe including emphysema, lung and pleural fibrosis. The control group had IL8 values between 10–19.4, there were no lymphocytes in the bronchoalveolar lavage and no histopathological findings. Conclusion These findings indicate that IL8 levels were dose related and IL8 levels have an inverse correlation with lymphocytes count in BAL, also correlated with the histopathological findings for the studied groups. PMID:26527915

Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine.

PubMed

Cellini, Miriam; Santaguida, Maria Giulia; Gatto, Ilenia; Virili, Camilla; Del Duca, Susanna Carlotta; Brusca, Nunzia; Capriello, Silvia; Gargano, Lucilla; Centanni, Marco

2014-08-01

An increased need for T4 has been described in patients with different gastrointestinal disorders. However, there is a lack of systematic studies assessing the need for T4 in hypothyroid patients with lactose intolerance, a widespread and often occult disorder. The objective of the study was to assess the replacement T4 dose required in hypothyroid patients with lactose intolerance. This was a cohort study. The study was conducted at an outpatient endocrinology unit in a University Hospital. The replacement T4 dose has been analyzed, from 2009 to 2012, in 34 hypothyroid patients due to Hashimoto's thyroiditis and lactose intolerance and being noncompliant with a lactose-free diet. An individually tailored T4 dose was measured. In all patients with isolated Hashimoto's thyroiditis, target TSH (median TSH 1.02 mU/L) was obtained at a median T4 dose of 1.31 μg/kg/d. In patients with lactose intolerance, only five of 34 patients reached the desired TSH (median TSH 0.83 mU/L) with a similar T4 dose (1.29 μg/kg/d). In the remaining 29 patients, the T4 dose was progressively increased and the target TSH (median TSH 1.21 mU/L) was attained at a median T4 dose of 1.81 μg/kg/d (+38%, P < .0001). In six of these patients, other gastrointestinal disorders were diagnosed, and their median T4 requirement was higher (2.04 μg/kg/d; +55%; P = .0032). In the remaining 23 patients with isolated lactose intolerance, a median T4 dose of 1.72 μg/kg/d (+31% P < .0001) has been required to attain pharmacological thyroid homeostasis. These findings show that lactose intolerance significantly increased the need for oral T4 in hypothyroid patients.

Cardiac damage induced by 2-amino-3-methyl-imidazo[4,5-f]quinoline in nonhuman primates.

PubMed Central

Thorgeirsson, U P; Farb, A; Virmani, R; Adamson, R H

1994-01-01

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus and rhesus monkeys. The finding of high cardiac IQ-DNA adduct levels prompted a histopathological study of perfusion-fixed hearts from 10 tumor-bearing monkeys chronically dosed with IQ at 10 mg/kg or 20 mg/kg 5 days per week for 48-80 months. Two monkeys dosed only with the vehicle for IQ, hydroxypropylcellulose, served as controls. All the monkeys had normal heart weights, and no abnormalities were observed upon gross inspection of the hearts. Microscopically, focal myocardial lesions were observed in 8 of 10 monkeys dosed with IQ. Light microscopic abnormalities included myocyte necrosis with or without chronic inflammatory infiltrates, interstitial fibrosis with myocyte hypertrophy or atrophy, and vasculitis. Electron microscopic findings included disruption of the mitochondrial architecture (i.e., mitochondrial swelling and clearing of matrix densities), myofibrillar loss, disorganization of the normal alignment of sarcomeres, and occasional myocytes showing nuclear hypertrophy or peripheral clumping of the nuclear chromatin. There was some correlation between the cumulative dose of IQ and the extent of the myocardial abnormalities. These findings suggest that chronic exposure to IQ can lead to myocardial damage in monkeys. Although focal and not associated with clinical evidence of heart failure, these abnormalities may represent the initial stages of IQ-induced toxic cardiomyopathy. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 2. A Figure 2. B Figure 3. A Figure 3. B Figure 3. C Figure 3. D Figure 4. A Figure 4. B Figure 5. A Figure 5. B PMID:8033851

Range of therapeutic prothipendyl and prothipendyl sulfoxide concentrations in clinical blood samples.

PubMed

Krämer, Michael; Heese, Peter; Banger, Markus; Madea, Burkhard; Hess, Cornelius

2018-06-01

Due to a lack of reference blood concentrations in the literature, the forensic evaluation of prothipendyl findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested prothipendyl amounts were often vague. To describe a concentration range in clinical samples, prothipendyl and prothipendyl sulfoxide concentrations were determined in serum samples of 50 psychiatric patients receiving 40 mg, 80 mg, or 160 mg doses of prothipendyl. The analyses of prothipendyl and prothipendyl sulfoxide were carried out using validated methods of high performance liquid chromatography coupled to triple quadrupole mass spectrometry (LC-QQQ-MS), respectively. 40 mg doses caused average prothipendyl serum concentrations of 18.0 ng/mL (1 hour after intake) and 7.9 ng/mL (10.5 hours after intake), while 80 mg doses caused averages of 42.6 ng/mL and 15.2 ng/mL at the mentioned times of sampling. Irrespective of the given dose, prothipendyl concentrations below 30 ng/mL were observed in 80% of the patient samples taken 1 hour after ingestion as well as in 90% of the samples collected 10.5 hours after administration. Serum concentrations of the Phase I metabolite prothipendyl sulfoxide averaged 4.3 ng/mL (1 hour after intake) and 3.6 ng/mL (10.5 hours after intake). Possible drug-drug interactions regarding absorption and metabolism of prothipendyl are discussed. Results of the herein presented study are useful for the interpretation of analytical prothipendyl findings in forensic toxicology. The utility of the described concentration range is demonstrated by discussing two death cases involving prothipendyl findings. Copyright © 2017 John Wiley & Sons, Ltd.

Caffeine Increases the Linearity of the Visual BOLD Response

PubMed Central

Liu, Thomas T.; Liau, Joy

2009-01-01

Although the blood oxygenation level dependent (BOLD) signal used in most functional magnetic resonance imaging (fMRI) studies has been shown to exhibit nonlinear characteristics, most analyses assume that the BOLD signal responds in a linear fashion to stimulus. This assumption of linearity can lead to errors in the estimation of the BOLD response, especially for rapid event-related fMRI studies. In this study, we used a rapid event-related design and Volterra kernel analysis to assess the effect of a 200 mg oral dose of caffeine on the linearity of the visual BOLD response. The caffeine dose significantly (p < 0.02) increased the linearity of the BOLD response in a sample of 11 healthy volunteers studied on a 3 Tesla MRI system. In addition, the agreement between nonlinear and linear estimates of the hemodynamic response function was significantly increased (p= 0.013) with the caffeine dose. These findings indicate that differences in caffeine usage should be considered as a potential source of bias in the analysis of rapid event-related fMRI studies. PMID:19854278

Comparison of particulate matter dose and acute heart rate variability response in cyclists, pedestrians, bus and train passengers.

PubMed

Nyhan, Marguerite; McNabola, Aonghus; Misstear, Bruce

2014-01-15

Exposure to airborne particulate matter (PM) has been linked to cardiovascular morbidity and mortality. Heart rate variability (HRV) is a measure of the change in cardiac autonomic function, and consistent links between PM exposure and decreased HRV have been documented in studies. This study quantitatively assesses the acute relative variation of HRV with predicted PM dose in the lungs of commuters. Personal PM exposure, HR and HRV were monitored in 32 young healthy cyclists, pedestrians, bus and train passengers. Inhaled and lung deposited PM doses were determined using a numerical model of the human respiratory tract which accounted for varying ventilation rates between subjects and during commutes. Linear mixed models were used to examine air pollution dose and HRV response relationships in 122 commutes sampled. Elevated PM2.5 and PM10 inhaled and lung deposited doses were significantly (p<0.05) associated with decreased HRV indices. Percent declines in SDNN (standard deviation of normal RR intervals) relative to resting, due to an inter-quartile range increase in PM10 lung deposited dose were stronger in cyclists (-6.4%, 95% CI: -11.7, -1.3) and pedestrians (-5.8%, 95% CI: -11.3, -0.5), in comparison to bus (-3.2%, 95% CI: -6.4, -0.1) and train (-1.8%, -7.5, 3.8) passengers. A similar trend was observed in the case of PM2.5 lung deposited dose and results for rMSSD (the square root of the squared differences of successive normal RR intervals) followed similar trends to SDNN. Inhaled and lung deposited doses accounting for varying ventilation rates between modes, individuals and during commutes have been neglected in other studies relating PM to HRV. The findings here indicate that exercise whilst commuting has an influence on inhaled PM and PM lung deposited dose, and these were significantly associated with acute declines in HRV, especially in pedestrians and cyclists. © 2013.

The "doses" of initial, untreated hallucinations and delusions: a proof-of-concept study of enhanced predictors of first-episode symptomatology and functioning relative to duration of untreated psychosis.

PubMed

Compton, Michael T; Gordon, Tynessa L; Weiss, Paul S; Walker, Elaine F

2011-11-01

A prominent limitation of literature on duration of untreated psychosis (DUP) is that researchers have studied only unidimensional duration as an early-course predictor, neglecting potential effects of frequency/severity of initial, untreated psychosis. This study demonstrates utility of the concept of "doses" of initial, untreated hallucinations and delusions-representing more complete measures of "exposure"-as enhanced predictors of symptomatology/functioning relative to DUP alone. 109 first-episode patients with a psychotic disorder based on Structured Clinical Interview for DSM-IV Axis I Disorders criteria were assessed at 3 public-sector psychiatric units serving an urban, socially disadvantaged, predominantly African American community between July 2004 and June 2008. Dependent variables included negative symptoms, general psychopathology, insight, and global functioning at initial hospitalization. When added to a baseline model (age, gender, and premorbid academic and social functioning), DUP predicted current negative symptoms (P = .02, model R(2) = 0.20), though dose of hallucinations and dose of delusions did not. However, regarding general psychopathology symptoms, DUP was not predictive, though dose of delusions was, when controlling for the other 5 variables (P = .02, model R(2) = 0.15). DUP was not a significant predictor of insight, though dose of hallucinations was, such that a greater dose of initial, untreated hallucinations was associated with better insight at initial hospitalization (P < .01, model R(2) = 0.20). DUP was associated with global functioning (P = .05), and dose of delusions added significantly to this prediction (P = .04; model R(2) = 0.13). Doses of initial, untreated hallucinations and delusions add substantively, though differentially, to the prediction of early-course symptomatology and functioning. Findings suggest a need for focused research on frequency/severity of pretreatment psychotic symptoms beyond duration measures. © Copyright 2011 Physicians Postgraduate Press, Inc.

The Impact of Low-Dose Disease-modifying Anti-rheumatics Drugs (DMARDs) on Bone Mineral Density of Premenopausal Women in Early Rheumatoid Arthritis.

PubMed

Rexhepi, Sylejman; Rexhepi, Mjellma; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan; Boshnjaku, Shkumbin

2016-04-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarthritis and multisystemic involvement. The aim of this study was to assess the impact of low dose of methotrexate on bone mineral density (BMD) in patients with early rheumatoid arthritis (RA). This paper follows a retrospective study, which involves 60 female patients with early onset RA diagnosed according to the American Rheumatism Association Criteria (ACR/EULAR 2010). The patients were divided into two groups group I was composed of thirty patients treated with dose of 7.5 mg/weekly methotrexate (MTX), while group II included thirty patients treated with dose of 2 g/daily sulfasalazine (SSZ). The Disease Activity was measured by a combination of Erythrocyte Sedimentation Rate (ESR) and Disease Activity Score (DAS-28). Bone mineral density of the lumbar spine (L2-4), and femoral neck, was measured by dual energy X-ray absorptiometry (DEXA) (Stratos 800). Laboratory findings included: In this study, we found no negative effect on BMD in RA patients treated with low dose MTX in comparison to patients treated with SSZ. There was not observed significant difference in BMD of the lumbar spine, femur neck or trochanter, of MTX and SSZ patients in the pretreatment phase, nor after 12 months of treatment. No significant change in the biochemical parameters of the both groups. Based on the results of our study, low dose of methotrexate has no negative effect on BMD in premenopausal RA patients. We believe that these results might provide new insights and that further longitudinal studies with larger groups of premenopausal RA patients are required.

The Impact of Low-Dose Disease-modifying Anti-rheumatics Drugs (DMARDs) on Bone Mineral Density of Premenopausal Women in Early Rheumatoid Arthritis

PubMed Central

Rexhepi, Sylejman; Rexhepi, Mjellma; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan; Boshnjaku, Shkumbin

2016-01-01

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarthritis and multisystemic involvement. Objective: The aim of this study was to assess the impact of low dose of methotrexate on bone mineral density (BMD) in patients with early rheumatoid arthritis (RA). Materials and methods: This paper follows a retrospective study, which involves 60 female patients with early onset RA diagnosed according to the American Rheumatism Association Criteria (ACR/EULAR 2010). The patients were divided into two groups group I was composed of thirty patients treated with dose of 7.5 mg/weekly methotrexate (MTX), while group II included thirty patients treated with dose of 2 g/daily sulfasalazine (SSZ). The Disease Activity was measured by a combination of Erythrocyte Sedimentation Rate (ESR) and Disease Activity Score (DAS-28). Bone mineral density of the lumbar spine (L2–4), and femoral neck, was measured by dual energy X-ray absorptiometry (DEXA) (Stratos 800). Laboratory findings included: In this study, we found no negative effect on BMD in RA patients treated with low dose MTX in comparison to patients treated with SSZ. There was not observed significant difference in BMD of the lumbar spine, femur neck or trochanter, of MTX and SSZ patients in the pretreatment phase, nor after 12 months of treatment. No significant change in the biochemical parameters of the both groups. Conclusion: Based on the results of our study, low dose of methotrexate has no negative effect on BMD in premenopausal RA patients. We believe that these results might provide new insights and that further longitudinal studies with larger groups of premenopausal RA patients are required. PMID:27147781

[Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate].

PubMed

Mücke, M; Conrad, R; Marinova, M; Cuhls, H; Elsner, F; Rolke, R; Radbruch, L

2016-12-01

To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

Occupational radiation exposure and its health effects on interventional medical workers: study protocol for a prospective cohort study.

PubMed

Ko, Seulki; Chung, Hwan Hoon; Cho, Sung Bum; Jin, Young Woo; Kim, Kwang Pyo; Ha, Mina; Bang, Ye Jin; Ha, Yae Won; Lee, Won Jin

2017-12-15

Although fluoroscopically guided procedures involve a considerably high dose of radiation, few studies have investigated the effects of radiation on medical workers involved in interventional fluoroscopy procedures. Previous research remains in the early stages and has not reached a level comparable with other occupational studies thus far. Furthermore, the study of radiation workers provides an opportunity to estimate health risks at low doses and dose rates of ionising radiation. Therefore, the objectives of this study are (1) to initiate a prospective cohort study by conducting a baseline survey among medical radiation workers who involve interventional fluoroscopy procedures and (2) to assess the effect of occupational radiation exposure and on the overall health status through an in-depth cross-sectional study. Intervention medical workers in Korea will be enrolled by using a self-administered questionnaire survey, and the survey data will be linked with radiation dosimetry data, National Health Insurance claims data, cancer registry and mortality data. After merging these data, the radiation organ dose, lifetime attributable risk due to cancer and the risk per unit dose will be estimated. For the cross-sectional study, approximately 100 intervention radiology department workers will be investigated for blood tests, clinical examinations such as ultrasonography (thyroid and carotid artery scan) and lens opacity, the validation of badge dose and biodosimetry. This study was reviewed and approved by the institutional review board of Korea University (KU-IRB-12-12-A-1). All participants will provide written informed consent prior to enrolment. The findings of the study will be disseminated through peer-reviewed scientific journals, conference presentations, and a report will be submitted to the relevant public health authorities in the Korea Centers for Disease Control and Prevention to help with the development of appropriate research and management policies. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Occupational radiation exposure and its health effects on interventional medical workers: study protocol for a prospective cohort study

PubMed Central

Ko, Seulki; Chung, Hwan Hoon; Cho, Sung Bum; Jin, Young Woo; Kim, Kwang Pyo; Ha, Mina; Bang, Ye Jin; Ha, Yae Won; Lee, Won Jin

2017-01-01

Introduction Although fluoroscopically guided procedures involve a considerably high dose of radiation, few studies have investigated the effects of radiation on medical workers involved in interventional fluoroscopy procedures. Previous research remains in the early stages and has not reached a level comparable with other occupational studies thus far. Furthermore, the study of radiation workers provides an opportunity to estimate health risks at low doses and dose rates of ionising radiation. Therefore, the objectives of this study are (1) to initiate a prospective cohort study by conducting a baseline survey among medical radiation workers who involve interventional fluoroscopy procedures and (2) to assess the effect of occupational radiation exposure and on the overall health status through an in-depth cross-sectional study. Methods and analysis Intervention medical workers in Korea will be enrolled by using a self-administered questionnaire survey, and the survey data will be linked with radiation dosimetry data, National Health Insurance claims data, cancer registry and mortality data. After merging these data, the radiation organ dose, lifetime attributable risk due to cancer and the risk per unit dose will be estimated. For the cross-sectional study, approximately 100 intervention radiology department workers will be investigated for blood tests, clinical examinations such as ultrasonography (thyroid and carotid artery scan) and lens opacity, the validation of badge dose and biodosimetry. Ethics and dissemination This study was reviewed and approved by the institutional review board of Korea University (KU-IRB-12-12-A-1). All participants will provide written informed consent prior to enrolment. The findings of the study will be disseminated through peer-reviewed scientific journals, conference presentations, and a report will be submitted to the relevant public health authorities in the Korea Centers for Disease Control and Prevention to help with the development of appropriate research and management policies. PMID:29248885

Safety assessment of Hibiscus sabdariffa after maternal exposure on male reproductive parameters in rats.

PubMed

de Arruda, Aline; Cardoso, Claudia Andrea L; Vieira, Maria do Carmo; Arena, Arielle Cristina

2016-01-01

Hibiscus sabdariffa L. (Malvaceae) is a species widely used in folk medicine for the treatment of some disorders. This study evaluated the effects of H. sabdariffa (HS) on the development of the male reproductive tract in rats following in utero exposure. Pregnant rats received 250 or 500 mg/kg of HS extract or vehicle from gestational day 12 until day 21 of lactation. Both doses of HS increased the body weight of male offspring at weaning, without compromising the puberty onset parameters. At puberty, there was a significant increase in the vas deferens absolute weight and a significant reduction in the relative weight of kidney at higher dose. These animals also presented a significant reduction in the sperm number in the caput/corpus of epididymis after exposure to both doses and a reduction in the sperm number in the cauda epididymis for the lower dose. At adulthood, the highest dose significantly reduced the sperm production in relation to controls and both doses provoked a reduction in the relative sperm number in the epididymis without affecting the sperm morphology. These findings demonstrated that maternal exposure to H. sabdariffa can adversely influence the male reproductive system in rats.

An Approach in Radiation Therapy Treatment Planning: A Fast, GPU-Based Monte Carlo Method.

PubMed

Karbalaee, Mojtaba; Shahbazi-Gahrouei, Daryoush; Tavakoli, Mohammad B

2017-01-01

An accurate and fast radiation dose calculation is essential for successful radiation radiotherapy. The aim of this study was to implement a new graphic processing unit (GPU) based radiation therapy treatment planning for accurate and fast dose calculation in radiotherapy centers. A program was written for parallel running based on GPU. The code validation was performed by EGSnrc/DOSXYZnrc. Moreover, a semi-automatic, rotary, asymmetric phantom was designed and produced using a bone, the lung, and the soft tissue equivalent materials. All measurements were performed using a Mapcheck dosimeter. The accuracy of the code was validated using the experimental data, which was obtained from the anthropomorphic phantom as the gold standard. The findings showed that, compared with those of DOSXYZnrc in the virtual phantom and for most of the voxels (>95%), <3% dose-difference or 3 mm distance-to-agreement (DTA) was found. Moreover, considering the anthropomorphic phantom, compared to the Mapcheck dose measurements, <5% dose-difference or 5 mm DTA was observed. Fast calculation speed and high accuracy of GPU-based Monte Carlo method in dose calculation may be useful in routine radiation therapy centers as the core and main component of a treatment planning verification system.

The question of nonlinearity in the dose-response relation between particulate matter air pollution and mortality: can Akaike's Information Criterion be trusted to take the right turn?

PubMed

Roberts, Steven; Martin, Michael A

2006-12-15

The shape of the dose-response relation between particulate matter air pollution and mortality is crucial for public health assessment, and departures of this relation from linearity could have important regulatory consequences. A number of investigators have studied the shape of the particulate matter-mortality dose-response relation and concluded that the relation could be adequately described by a linear model. Some of these researchers examined the hypothesis of linearity by comparing Akaike's Information Criterion (AIC) values obtained under linear, piecewise linear, and spline alternative models. However, at the current time, the efficacy of the AIC in this context has not been assessed. The authors investigated AIC as a means of comparing competing dose-response models, using data from Cook County, Illinois, for the period 1987-2000. They found that if nonlinearities exist, the AIC is not always successful in detecting them. In a number of the scenarios considered, AIC was equivocal, picking the correct simulated dose-response model about half of the time. These findings suggest that further research into the shape of the dose-response relation using alternative model selection criteria may be warranted.

Sorption Studies and Characterization of As (III) Adsorption over Developed Iron-Biochar Composites from Water.

NASA Astrophysics Data System (ADS)

Singh, P.; Mohan, D.

2016-12-01

Problem related to arsenic occurrence in groundwater has caused severe threat to human health in worldwide. Thus there is an increasing demand to find the chemistry and plausible mechanism of arsenic adsorption while remediating it from water. In present study iron-biochar composites are synthesised using agricultural waste materials. The rice husk iron-biochar composite (RIBC) and wheat husk iron-biochar composite (WIBC) were characterised and utilised for As (III) remediation from aqueous solution. The rice husk (RIBC) and wheat husk (WIBC) iron biochar composites were characterised. XPS, FT-IR, and XRD, were studied to analyse their elemental composition and functional group identification. While SEM, TEM, SEM-EDX were conducted to study their surface chemistry, mineralogy, porosity and crystallinity etc. Batch sorption studies were conducted for both rice husk (RIBC) and wheat husk (WIBC) iron-biochar composites to find sorption efficiency. Maximum As (III) adsorption was achieved in pH range 6-8 for both iron-biochar composites. Kinetic studies were conducted to establish the mechanism of As (III) adsorption at different dose and time. Optimum dose of 2g/L and 1g/L were reported for rice husk (RIBC) and wheat husk (WIBC) iron-biochar composites respectively. Electrostatic forces developed between arsenites and iron hydroxyl surface developed over the surface may have caused the removal of As (III). Significant amount of oxygen containing groups have been revealed through studies. Higher As (III) adsorption capacities were obtained for both iron-biochar composites to measure the amount of surface sites. Furthermore, various adsorption models are used to find the monolayer adsorption capacity. These findings suggest that developed iron-biochar composites may be used to remediate As (III) from contaminated water.

No Association between Radiation Dose from Pediatric CT Scans and Risk of Subsequent Hodgkin Lymphoma.

PubMed

Berrington de Gonzalez, Amy; Journy, Neige; Lee, Choonsik; Morton, Lindsay M; Harbron, Richard W; Stewart, Douglas R; Parker, Louise; Craft, Alan W; McHugh, Kieran; Little, Mark P; Pearce, Mark S

2017-05-01

Background: We examined the relationship between estimated radiation dose from CT scans and subsequent Hodgkin lymphoma in the UK pediatric CT scans cohort. Methods: A retrospective, record linkage cohort included patients ages 0 to 21 years who underwent CT scans between 1980 and 2002 and were followed up for cancer or death until 2008. Poisson regression analysis was used to evaluate the relationship between estimated radiation dose (lagged by 2 years) and incident Hodgkin lymphoma diagnosed at least 2 years after the first CT scan. Results: There were 65 incident cases of Hodgkin lymphoma in the cohort of 178,601 patients. Neither estimated red bone marrow dose nor mean lymphocyte dose from CT scans was clearly associated with an increased risk of Hodgkin lymphoma (RR for 20+ mGy vs. <5 mGy = 0.92 (0.38-2.22) P trend > 0.5 and 1.44 (0.60-3.48) P trend > 0.5), respectively. Conclusions: Radiation exposure from pediatric CT scans 2 or more years before diagnosis was not associated with Hodgkin lymphoma in this large UK cohort. Impact: These findings are consistent with the majority of previous studies, which do not support a link between ionizing radiation and Hodgkin lymphoma. The results contrast our previous positive findings in this cohort for brain tumors and leukemia, both of which are known to be strongly linked to radiation exposure during childhood. Cancer Epidemiol Biomarkers Prev; 26(5); 804-6. ©2017 AACR . ©2017 American Association for Cancer Research.

Cost-effectiveness analysis of pharmacogenetic-guided warfarin dosing in Thailand.

PubMed

Chong, Huey Yi; Saokaew, Surasak; Dumrongprat, Kuntika; Permsuwan, Unchalee; Wu, David Bin-Chia; Sritara, Piyamitr; Chaiyakunapruk, Nathorn

2014-12-01

Pharmacogenetic (PGx) test is a useful tool for guiding physician on an initiation of an optimal warfarin dose. To implement of such strategy, the evidence on the economic value is needed. This study aimed to determine the cost-effectiveness of PGx-guided warfarin dosing compared with usual care (UC). A decision analytic model was used to compare projected lifetime costs and quality-adjusted life years (QALYs) accrued to warfarin users through PGx or UC for a hypothetical cohort of 1,000 patients. The model was populated with relevant information from systematic review, and electronic hospital-database. Incremental cost-effectiveness ratios (ICERs) were calculated based on healthcare system and societal perspectives. All costs were presented at year 2013. A series of sensitivity analyses were performed to determine the robustness of the findings. From healthcare system perspective, PGx increases QALY by 0.002 and cost by 2,959 THB (99 USD) compared with UC. Thus, the ICER is 1,477,042 THB (49,234 USD) per QALY gained. From societal perspective, PGx results in 0.002 QALY gained, and increases costs by 2,953 THB (98 USD) compared with UC (ICER 1,473,852 THB [49,128 USD] per QALY gained). Results are sensitive to the risk ratio (RR) of major bleeding in VKORC1 variant, the efficacy of PGx-guided dosing, and the cost of PGx test. Our finding suggests that PGx-guided warfarin dosing is unlikely to be a cost-effective intervention in Thailand. This evidence assists policy makers and clinicians in efficiently allocating scarce resources. Copyright © 2014 Elsevier Ltd. All rights reserved.

Optimal dose selection of N-methyl-N-nitrosourea for the rat comet assay to evaluate DNA damage in organs with different susceptibility to cytotoxicity.

PubMed

Kitamoto, Sachiko; Matsuyama, Ryoko; Uematsu, Yasuaki; Ogata, Keiko; Ota, Mika; Yamada, Toru; Miyata, Kaori; Funabashi, Hitoshi; Saito, Koichi

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is a promising technique to evaluate DNA damage in vivo. However, there is no agreement on a method to evaluate DNA damage in organs where cytotoxicity is observed. As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the comet assay, we examined DNA damage in the liver, stomach, and bone marrow of rats given three oral doses of N-methyl-N-nitrosourea (MNU) up to the maximum tolerated dose based on systemic toxicity. MNU significantly increased the % tail DNA in all the organs. Histopathological analysis showed no cytotoxic effect on the liver, indicating clearly that MNU has a genotoxic potential in the liver. In the stomach, however, the cytotoxic effects were very severe at systemically non-toxic doses. Low-dose MNU significantly increased the % tail DNA even at a non-cytotoxic dose, indicating that MNU has a genotoxic potential also in the stomach. Part of the DNA damage at cytotoxic doses was considered to be a secondary effect of severe cell damage. In the bone marrow, both the % tail DNA and incidence of micronucleated polychromatic erythrocytes significantly increased at non-hematotoxic doses, which were different from the non-cytotoxic doses for liver and stomach. These findings indicate that an optimal dose for detecting DNA damage may vary among organs and that careful attention is required to select an optimum dose for the comet assay based on systemic toxicity such as mortality and clinical observations. The present study shows that when serious cytotoxicity is suggested by increased % hedgehogs in the comet assay, histopathological examination should be included for the evaluation of a positive response. Copyright © 2015 Elsevier B.V. All rights reserved.

Risk Assessment Study of Fluoride Salts: Probability-Impact Matrix of Renal and Hepatic Toxicity Markers.

PubMed

Usuda, Kan; Ueno, Takaaki; Ito, Yuichi; Dote, Tomotaro; Yokoyama, Hirotaka; Kono, Koichi; Tamaki, Junko

2016-09-01

The present risk assessment study of fluoride salts was conducted by oral administration of three different doses of sodium and potassium fluorides (NaF, KF) and zinc fluoride tetrahydrate (ZnF2 •4H2O) to male Wistar rats. The rats were divided into control and nine experimental groups, to which oral injections of 0.5 mL distilled water and 0.5 mL of fluoride solutions, respectively, were given. The dosage of fluoride compounds was adjusted to contain 2.1 mg (low-dose group, LG), 4.3 mg (mid-dose group, MG), and 5.4 mg fluoride per 200 g rat body weight (high-dose group, HG) corresponding to 5, 10, and 12.5 % of LD50 values for NaF. The 24-h urine volume, N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (Ccr) were measured as markers of possible acute renal impact. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined in serum samples as markers of acute hepatic impact. The levels of serum and urinary fluoride were determined to evaluate fluoride bioavailability. The results reveal that higher doses of NaF, KF, and ZnF2 induced renal damage as indicated by higher urinary NAG (p < 0.05 with ≥90th percentile of control). High doses of ZnF2 also induced a significant Ccr decrease (p < 0.05 with ≤10th percentile of control). Low doses of NaF and mid-doses of ZnF2 induced polyuria (p < 0.05 with ≥90th percentile of control) while medium doses of NaF and low doses of KF also induced liver damage, as indicated by a high level of AST (p < 0.05 with ≥90th percentile of control). These findings suggest that oral administration of fluoride is a potential, dose-dependent risk factor of renal tubular damage.

The injury and cumulative effects on human skin by UV exposure from artificial fluorescence emission.

PubMed

Tian, Yan; Liu, Wei; Niu, TianHui; Dai, CaiHong; Li, Xiaoxin; Cui, Caijuan; Zhao, Xinyan; E, Yaping; Lu, Hui

2014-01-01

The injury and cumulative effects of UV emission from fluorescence lamp were studied. UV intensity from fluorescence lamp was measured, and human skin samples (hips, 10 volunteers) were exposed to low-dose UV irradiation (three times per week for 13 consecutive weeks). Three groups were examined: control group without UV radiation; low-dose group with a cumulative dose of 50 J cm(-2) which was equivalent to irradiation of the face during indoor work for 1.5 years; and high-dose group with 1000 J cm(-2) cumulative dose equivalent to irradiation of the face during outdoor activities for 1 year. Specific indicators were measured before and after UVA irradiation. The findings showed that extending the low-dose UVA exposure decreased the skin moisture content and increased the transepidermal water loss as well as induced skin color changes (decreased L* value, increased M index). Furthermore, irradiated skin showed an increased thickness of cuticle and epidermis, skin edema, light color and unclear staining collagen fibers in the dermis, and elastic fiber fragmentation. In addition, MMP-1, p53 and SIRT1 expression was also increased. Long-term exposure of low-dose UVA radiation enhanced skin photoaging. The safety of the fluorescent lamp needs our attention. © 2014 The American Society of Photobiology.

Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?

PubMed Central

Day, Troy; Read, Andrew F.

2016-01-01

High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients. PMID:26820986