Systematic review and meta-analysis of the pharmacokinetics of benznidazole in the treatment of Chagas disease

Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (Cmax), the time to Cmax, the elimination rate constant (kel), the absorption rate constant (Ka), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and Cmax were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. Ka and kel were 1.16 h-1 (95% CrI, 0.59, 1.76 h-1) and 0.052 h-1 (95% CrI, 0.045, 0.059 h-1), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.Fil: Wiens, Matthew O.. University of British Columbia; CanadáFil: Kanters, Steve. Precision Global Health;Fil: Mills, Edward. Mc Master University; CanadáFil: Peregrina Lucano, Alejandro A.. Universidad de Guadalajara; MéxicoFil: Gold, Silvia. Fundación Mundo Sano; ArgentinaFil: Ayers, Dieter. Precision Global Health;Fil: Ferrero, Luis. Fundación Mundo Sano; ArgentinaFil: Krolewiecki, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentin

Dynamics of mechanical feedback-type hydraulic servomotors under inertia loads

An analysis of the dynamics of mechanical feedback-type hydraulic servomotors under inertia loads is developed and experimental verification is presented. The analysis, which is developed in terms of two physical parameters, yields direct expressions for the following dynamic responses: (1) the transient response to a step input and the maximum cylinder pressure during the transient and (2) the variation of amplitude attenuation and phase shift with the frequency of a sinusoidally varying input. The validity of the analysis is demonstrated by means of recorded transient and frequency responses obtained on two servomotors. The calculated responses are in close agreement with the measured responses. The relations presented are readily applicable to the design as well as to the analysis of hydraulic servomotors

An Integrated Model of Legal Transplantation: The Diffusion of Intellectual Property Law in Developing Countries*

Why do some countries adopt exogenous rules into their domestic law when those rules contravene their specific interests? We draw on the policy-diffusion literature to identify four causal mechanisms that we hypothesize explain the adoption of such rules. While existing literature treats these mechanisms as independent, we argue that each works in combination with the others to facilitate legal transplantation. While one mechanism-coercion-tends to initiate the transplantation process, it fades over time and three others largely supplant it: contractualization, socialization, and regulatory competition. These mechanisms act in a mutually supportive manner. We test our claims via a quantitative analysis of legal transplants in the field of intellectual property (IP) that incorporates an original index of IP protection in 121 developing countries over more than 14 years. This article concludes with a plea for theoretical eclecticism, acknowledging multicausality and context-conditionality. Any comprehensive explanation of legal transplantation must include the identification of mutual reinforcement between causal mechanisms, rather than simply rank their relative contributions. " [Laws] should be so specific to the people for whom they are made, that it is a great coincidence if those of one nation can suit another" argued Montesquieu in The Spirit of the Laws (1961:295). Apparently, history is full of coincidence. Laws frequently travel across both time and space. Sections of the Code of Hammurabi, enforced in Babylonia four thousand years ago, were integrated into Persian law, made their way into Greek law, and were subsequently incorporated into Roman law (Watson 1974:22-23). The Roman legacy then inspired the European Civil Codes that include elements of the ancient text. More recently, the European Codes have served as models for legal reform in countries as diverse as Peru, Egypt, and Japan. Legal transplantation proves particularly puzzling in situations of asymmetric interests: Those in which the interests of the adopting state conflict with those of the state in which the rule originated. Why would a country adopt foreign rules that run counter to its own interests? Existing scholarship lacks adequate answers to this question. This article argues that the explanation for legal transplantation lies not in any single causal mechanism but in the succession and reinforcement of multiple mechanisms. In making this claim, we favor analytical eclecticism and answer the call of Sil and Katzenstein for "complex causal stories that forgo parsimony in order to capture the interactions among different types of causal mechanisms normally analyzed in isolation from each other within separate research traditions" (2010:412). The article proceeds in three main sections. The first draws upon legal and political scholarship to build a typology of causal mechanisms for legal transplantation. It introduces an integrated understanding for their interaction under the scope condition of asymmetric interests. While the literature typically presents the mechanisms as being mutually exclusive, this article explores the possibility that they may, in fact, act in concert with one another. In doing so, they facilitate the adoption and maintenance of the legal transplant. The second section presents the case of intellectual property (IP) as an example of the dynamics of legal transplantation under asymmetric interests. It also introduces a new index of IP rules in force in 121 developing countries more than 14 years. The third section of this article examines the integrated understanding in light of quantitative evidence relating to IP. It puts this evidence into context through the use of examples explored in the literature. The results of this examination lead us to conclude that multicausality and context-conditionality constitute critical factors in understanding complex phenomena such as legal transplantation

Unlocking biomarker discovery: Large scale application of aptamer proteomic technology for early detection of lung cancer

Lung cancer is the leading cause of cancer deaths, because ~84% of cases are diagnosed at an advanced stage. Worldwide in 2008, ~1.5 million people were diagnosed and ~1.3 million died – a survival rate unchanged since 1960. However, patients diagnosed at an early stage and have surgery experience an 86% overall 5-year survival. New diagnostics are therefore needed to identify lung cancer at this stage. Here we present the first large scale clinical use of aptamers to discover blood protein biomarkers in disease with our breakthrough proteomic technology. This multi-center case-control study was conducted in archived samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. We measured >800 proteins in 15uL of serum, identified 44 candidate biomarkers, and developed a 12-protein panel that distinguished NSCLC from controls with 91% sensitivity and 84% specificity in a training set and 89% sensitivity and 83% specificity in a blinded, independent verification set. Performance was similar for early and late stage NSCLC. This is a significant advance in proteomics in an area of high clinical need

Healthy Dietary Intake Moderates the Effects of Age on Brain Iron Concentration and Working Memory Performance

Age-related brain iron accumulation is linked with oxidative stress, neurodegeneration and cognitive decline. Certain nutrients can reduce brain iron concentration in animal models, however, this association is not well established in humans. Moreover, it remains unknown if nutrition can moderate the effects of age on brain iron concentration and/or cognition. Here, we explored these issues in a sample of 73 healthy older adults (61-86 years old), while controlling for several factors such as age, gender, years of education, physical fitness and alcohol-intake. Quantitative susceptibility mapping was used for assessment of brain iron concentration and participants performed an N-Back paradigm to evaluate working memory performance. Nutritional-intake was assessed via a validated questionnaire. Nutrients were grouped into nutrition factors based on previous literature and factor analysis. One factor, comprised of vitamin E, lysine, DHA omega-3 and LA omega-6 PUFA, representing food groups such as nuts, healthy oils and fish, moderated the effects of age on both brain iron concentration and working memory performance, suggesting that these nutrients may slow the rate of brain iron accumulation and working memory declines in aging