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Am J Epidemiol ; 188(6): 991-1012, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31155658


The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

J Pharmacol Exp Ther ; 354(3): 484-92, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26177654


The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.

Compostos Azabicíclicos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Cocaína/efeitos adversos , Antagonistas de Dopamina/efeitos adversos , Oxazóis/efeitos adversos , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Compostos Azabicíclicos/farmacologia , Comportamento Aditivo/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cães , Antagonistas de Dopamina/farmacologia , Masculino , Oxazóis/farmacologia
Addiction ; 102 Suppl 1: 96-106, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17493058


BACKGROUND: Methamphetamine abuse has become an increasing problem in both the United States and globally with concomitant increases in adverse medical, social and environmental sequelae. Behavioral therapies have been used with some success to treat methamphetamine abusers and dependent individuals, but are not universally efficacious. Methamphetamine has a rich pharmacology that theoretically provides many opportunities for potential pharmacotherapeutic intervention. Nevertheless, there are no approved medications with an indication for treating methamphetamine abusers or addicts at this time. AIM: To describe briefly how methamphetamine functions and affects function in brain and report how basic researchers and clinicians are attempting to exploit and exploiting this knowledge to discover and develop effective pharmacotherapies. RESULTS: Scientifically based approaches to medications development by evaluating medications that limit brain exposure to methamphetamine; modulate methamphetamine effects at vesicular monoamine transporter-2 (VMAT-2); or affect dopaminergic, serotonergic, GABAergic, and/or glutamatergic brain pathways that participate in methamphetamine's reinforcing effects are presented. CONCLUSION: The evidence supports the rationale that pharmacotherapies to decrease methamphetamine use, or reduce craving during abstinence may be developed from altering the pharmacokinetics and pharmacodynamics of methamphetamine or its effects on appetitive systems in the brain.

Transtornos Relacionados ao Uso de Anfetaminas/terapia , Estimulantes do Sistema Nervoso Central , Imunoterapia/métodos , Metanfetamina , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Animais , Estimulantes do Sistema Nervoso Central/farmacocinética , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Feminino , Previsões , GABAérgicos/farmacologia , Homeostase , Humanos , Masculino , Metanfetamina/farmacocinética , Metanfetamina/farmacologia , Camundongos , Entorpecentes/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Serotoninérgicos/farmacologia