Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals.

Recent advances in our understanding of disease biology, biomarkers, new therapeutic targets, and innovative modalities have each fueled a dramatic expansion in the development of novel human therapeutics. Many are biotechnology-derived biologics possessing high selectivity and affinity for their intended target; as such they often pose challenges in the development path to approval. One challenge is the selection of the first-in-human (FIH) dose.

Prevalence of smoking assessed biochemically in an urban public hospital: a rationale for routine cotinine screening.

Cotinine, a metabolite of nicotine, has been used to study tobacco smoke exposure in population studies, but the authors are unaware of its use to screen hospitalized patients. The authors measured serum cotinine levels in 948 patients admitted to an urban public hospital in San Francisco, California, between September 2005 and July 2006. On the basis of cotinine levels, they classified patients as active smokers (cotinine > or = 14 ng/mL), recent smokers or significantly exposed to secondhand smoke (SHS) (0.

Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.

What Is Already Known About This Subject: Performance-enhancing dietary supplements have not been clinically tested for safety or efficacy. In clinical trials performed under resting conditions, performance-enhancing supplements raise blood pressure and affect glucose homeostasis. The effect of exercise on the pharmacokinetics and pharmacodynamics of stimulant herbals is unknown.

Incomplete recovery of prescription opioids in urine using enzymatic hydrolysis of glucuronide metabolites.

Confirmation of opioids in urine samples of clinical patients requires liberation of opioids from their glucuronide conjugates. Both acid hydrolysis and enzyme hydrolysis using beta-glucuronidase from various sources have been reported, with the latter approach prevailing in most clinical toxicology laboratories. The goal of this study was to compare the efficiency of acid versus different enzyme hydrolysis methods in recovering morphine and common semisynthetic opioids from glucuronide standards and 78 patient urine samples that were screened positive for opioids as a class.

Gamma-hydroxybutyrate and ethanol effects and interactions in humans.

Background: Gamma-hydroxybutyrate (GHB) is a common drug of abuse that can produce serious toxicity, particularly when used with other sedatives. We examined the individual and combined effects of GHB and ethanol in human volunteers.

Methods: Sixteen healthy adults (7 men) were given 50 mg/kg GHB (Xyrem), 0.

Comparison of an automated and point-of-care immunoassay to GC-MS for urine oxycodone testing in the clinical laboratory.

OxyContin, a controlled-release formulation of oxycodone, is increasingly abused. Monitoring patient compliance by urine drug testing may deter illegal diversion of OxyContin. Two urine immunoassays were evaluated with a 100 ng/mL cutoff for oxycodone.

Hemodynamic effects of ephedra-free weight-loss supplements in humans.

Purpose: Ephedra-free weight loss dietary supplements containing bitter orange (Citrus aurantium), a botanical source of the adrenergic amines synephrine and octopamine, have quickly emerged on consumer markets to replace banned ephedra products. These supplements may have some of the health risks associated with ephedra, but studies in humans are lacking. Our aim was to characterize the pharmacokinetics and cardiovascular effects of C.

Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.

Objective: Serious adverse health events have been reported with the use of dietary supplements containing ephedra and guarana. We sought to determine whether repeated dosing and multi-ingredient formulations contribute to the adverse effects of these supplements.

Methods: In this study, 16 healthy adults (8 women) took 2 doses each of ephedra-guarana alone, Xenadrine RFA, a multicomponent dietary supplement containing 25 mg ephedra alkaloids and 200 mg caffeine, or placebo 5 hours apart in a randomized, double-blind, 3-arm crossover study.

Seizures reported in association with use of dietary supplements.

Background: Seizures in persons using dietary supplements (DS) have been reported through the Food and Drug Administration's (FDA) MedWatch system, but not formally reviewed.

Methods: Sixty-five cases of DS-associated seizures reported to MedWatch from 1993 to 1999 were obtained through the Freedom of Information Act and independently evaluated by three reviewers for probability of causation based on temporal relationship, biological plausibility, and underlying risk factors. Our aims in this review were 1) to assess the probability of causation in each case; 2) to characterize the patterns of use and types of supplements involved in cases of seizures; and 3) to identify trends that may explain potential risks factors for dietary supplement-related seizures.

Determination of ephedra alkaloid and caffeine concentrations in dietary supplements and biological fluids.

Dietary supplements containing botanical forms of caffeine and ephedra alkaloids have been widely promoted and used in the U.S. for weight loss and athletic enhancement despite a lack of adequate research on the pharmacology of these botanical stimulants.

Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements.

Dietary supplements that contain Ma Huang (ephedra alkaloids) and guarana (caffeine) are widely marketed and used in the U.S. for weight loss and athletic performance enhancement, despite a lack of adequate research on the pharmacology of these botanical stimulants.

Enhanced stimulant and metabolic effects of combined ephedrine and caffeine.

Objective: Herbal weight loss and athletic performance-enhancing supplements that contain ephedrine and caffeine have been associated with serious adverse health events. We sought to determine whether ephedrine and caffeine have clinically significant pharmacologic interactions that explain these toxicities.

Methods: Sixteen healthy adults ingested 25 mg ephedrine, 200 mg caffeine, or both drugs in a randomized, double-blind, placebo-controlled crossover study.

An evaluation of selected herbal reference texts and comparison to published reports of adverse herbal events.

Objective: There has been a recent proliferation of medical reference texts intended to guide practitioners whose patients use herbal therapies. We systematically assessed six herbal reference texts to evaluate the information they contain on herbal toxicity.

Methods: We selected six major herbal references published from 1996 to 2000 to evaluate the adequacy of their toxicological information in light of published adverse events.

Pharmacology of ephedra alkaloids and caffeine after single-dose dietary supplement use.

Objective: Serious cardiovascular toxicity has been reported in people taking dietary supplements that contain ma huang (Ephedra) and guarana (caffeine). We assessed the pharmacokinetics and pharmacodynamics of a dietary supplement that contains these herbal stimulants.

Methods: Eight healthy adults received a single oral dose of a thermogenic dietary supplement labeled to contain 20 mg ephedrine alkaloids and 200 mg caffeine after an overnight fast.