Expert opinion on drug metabolism & toxicology
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Expert Opin Drug Metab Toxicol · Jun 2011
ReviewThe effects of obesity on drug pharmacokinetics in humans.
The prevalence of obesity and associated co-morbid conditions is increasing globally. Physiological changes accompanying obesity are likely to result in altered drug pharmacokinetics; however, there is paucity of information on how to best dose adjust for the obese. ⋯ There is a nonlinear relationship between total body weight and the physiological variables that determine drug clearance. Metrics that describe pharmacokinetics at the extremes of weight in a semi-mechanistic manner should be used as drug dosing scalars, with clinical trials adequately designed to correctly identify the most appropriate dosing scalar.
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Expert Opin Drug Metab Toxicol · Apr 2011
ReviewEritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies.
Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4. ⋯ Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis are currently under investigation. Even if the ongoing Phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies would be necessary to define its clinical usage.
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Expert Opin Drug Metab Toxicol · Feb 2011
ReviewMethylnaltrexone bromide: research update of pharmacokinetics following parenteral administration.
Opioid-induced constipation is a major side effect of the use of opioid pain medications in a palliative care population. At present, the only approved treatment for opioid-induced constipation is methylnaltrexone bromide subcutaneous injection. Methylnaltrexone is a peripherally restricted opioid antagonist with μ-opioid receptor selectivity that can reduce opioid activity in peripheral organs such as the gastrointestinal tract while sparing the pain relief afforded by the pain medications. ⋯ Studies conducted to date indicate that methylnaltrexone has high bioavailability after subcutaneous administration at therapeutic dose levels, a terminal half-life of ∼ 8 - 9 h, minimal metabolism, elimination involving renal and non-renal routes, and a limited potential for drug-drug interactions. Combined with high efficacy and good tolerability, the predictable pharmacokinetic behavior of methylnaltrexone facilitates its successful utilization in clinical practice for the treatment of opioid-induced constipation in patients with advanced medical illness.
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Although colistin has recently played a key role in the treatment of nosocomial infections due to multidrug resistant Gram-negative pathogens, there is a lack of clinical studies examining colistin pharmacokinetics (PKs) in humans. This refers to all routes of colistin administration in clinical practice. Colistin PK data are also limited in critically ill patients. ⋯ There is a lack of human studies on colistin PK and PD. Significant PD parameters best predicting colistin efficacy and their optimal values such as C(max):MIC ratio, AUC/MIC and T > MIC have not yet been clearly defined. It should be noted that further investigation on colistin PK/PD in vitro and in vivo models is required.
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Systemic toxicity, usually from overdose or intravascular dose, is feared because it mainly affects the heart and brain, and may be acutely life-threatening. ⋯ Of the various models, this reviewer favors a whole-body large animal preparation because of the comprehensive data collection possible. The conscious sheep preparation has contributed more than any other, and may be regarded as the de facto 'standard' experimental model for concurrent study of local anesthetic toxicity ± pharmacokinetics, using experimental designs that can reproduce the toxicity seen in clinical accidents.