Clinical pharmacology and therapeutics
-
Clin. Pharmacol. Ther. · Jul 2011
Randomized Controlled Trial Comparative StudyA randomized study of the efficacy and safety of intravenous acetaminophen vs. intravenous placebo for the treatment of fever.
This randomized, double-blind, placebo-controlled study evaluated the antipyretic effect and safety of intravenous (i.v.) acetaminophen using an endotoxin-induced fever model. Subjects exhibiting sufficient fever response following administration of reference standard endotoxin (RSE) were randomly assigned to receive i.v. acetaminophen 1,000 mg (n = 31) or matching placebo (n = 29). The primary efficacy end point was the weighted sum of temperature differences from baseline through 6 h. ⋯ Temperature differences from baseline reached statistical significance at T30 min after endotoxin administration (15 min after completing the study medication infusion). Acetaminophen administered i.v. was well tolerated, and the frequency of adverse events was comparable to that after administration of i.v. placebo. This study shows that i.v. acetaminophen in a single 1,000-mg dose is safe and effective in reducing fever.
-
Clin. Pharmacol. Ther. · Jul 2011
The importance of high-quality evidence of the long-term impact of nonfatal events used in randomized controlled trials: a case study of prasugrel.
Randomized controlled trials (RCTs) are the centerpiece of evidence-based medicine. However, because of the limited follow-up, additional evidence on the long-term consequences of the outcomes used in trials is commonly required for clinical and policy decision making. This article provides insights into the importance and challenges of using such evidence through the case study of nonfatal myocardial infarction (MI) and nonfatal bleeding with prasugrel.
-
Clin. Pharmacol. Ther. · Jul 2011
Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol.
We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. ⋯ This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.
-
Clin. Pharmacol. Ther. · Jul 2011
Alendronate adherence and its impact on hip-fracture risk in patients with established osteoporosis in Taiwan.
A pharmacoepidemiology study was conducted using the health insurance database in Taiwan to assess compliance with osteoporosis drug regimens and the impact of compliance on the risk for secondary fractures. Patients >50 years of age with vertebral/hip fracture who had been started on alendronate therapy for the first time only after the fracture were included. Compliance was measured using the medication possession ratio (MPR) and was included as a time-dependent covariate in the Cox model to compare the difference between compliant (MPR ≥ 80%) and noncompliant patients (MPR <80%) with respect to risk for subsequent hip fractures. ⋯ Over the 4-year follow-up period, the risk of hip fracture among the compliant patients was 70% lower than that among the noncompliant ones (adjusted hazard ratio (HR) 0.30). Among patients with osteoporosis in Taiwan who had experienced a fracture and had started alendronate therapy, compliance with the dosage regimen was suboptimal. It was also found that compliance significantly reduced the risk of secondary hip fracture up to 4 years.