Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Sep 2011
ReviewChemotherapy-induced peripheral neuropathy: prevention and treatment.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of many chemotherapeutic agents. Although many therapies have been investigated for the prevention and/or treatment of CIPN, there is no well-accepted proven therapy. In addition, there is no universally accepted, well-validated measure for the assessment of CIPN. ⋯ Other promising therapies are also reviewed in this paper. Cutaneous electrostimulation is a nonpharmacological therapy that appears, from an early pilot trial, to be potentially effective in the treatment of CIPN. Finally, there is a lack of evidence of effective treatments for the paclitaxel acute pain syndrome (P-APS), which appears to be caused by neurologic injury.
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Clin. Pharmacol. Ther. · Sep 2011
The population pharmacokinetics of fentanyl in patients undergoing living-donor liver transplantation.
Fentanyl, an opioid analgesic with a high hepatic extraction ratio, is frequently used to supplement general anesthesia during liver transplantation and is also continuously infused to provide postoperative analgesia. However, because fentanyl is metabolized mainly in the liver, the pharmacokinetics of fentanyl may vary widely during the different phases of the surgery, potentially leading to adverse events. Using nonlinear mixed-effects modeling, we characterized the pharmacokinetics of fentanyl in 15 patients (American Society of Anesthesiologists Physical Status Classification 2 or 3) undergoing living-donor liver transplantation (LDLT). ⋯ Estimates were made of the pharmacokinetic parameters during the preanhepatic, anhepatic, and neohepatic phases: central volume of distribution (V(1)) (l): 59.0 + hourly volume infused by rapid infusion system (RIS) × 42.5, 113.0, and 189.0, respectively, × (body weight/69)(1.3); peripheral volume of distribution (V(2)) (l): 94.3, 412.0, and 427.0, respectively; intercompartmental clearance (Q) (l/h): 96.4 × (cardiac output (CO)/6.7)(2.5), 22.6, and 28.2, respectively; metabolic clearance (Cl) (l/h): 21.7 during the preanhepatic and neohepatic phases, and 0 during the anhepatic phase. The preanhepatic central volume of distribution was found to be markedly influenced by the massive infusion of fluids and blood products. The more hyperdynamic the circulation was during the preanhepatic phase, the higher the distributional clearance.
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Clin. Pharmacol. Ther. · Aug 2011
Randomized Controlled TrialGenetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects.
A double-blind crossover study was conducted in four CYP2C19 genotype-defined metabolizer groups to assess whether increase in clopidogrel dosing can overcome reduced pharmacodynamic response in CYP2C19 poor metabolizers (PMs). Ten healthy subjects in each of four metabolizer groups were randomized to a clopidogrel regimen of a 300-mg loading dose (LD) and a 75-mg/day maintenance dose (MD) for 4 days followed by 600-mg LD and 150 mg/day MD, or vice versa. The exposure levels of clopidogrel's active metabolite H4 (clopi-H4) in PMs were 71% lower on the 75-mg/day regimen and 64% lower on the 150-mg/day regimen than the corresponding exposure levels in extensive metabolizers (EMs). ⋯ PMs who were on the clopidogrel regimen of 600-mg LD/150 mg/day MD showed clopi-H4 exposure and MPA levels similar to those in EMs who were on the regimen of 300-mg LD/75 mg/day MD. In a pooled analysis evaluating CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms (N = 396 healthy subjects), only CYP2C19 had a significant impact on antiplatelet response. In healthy CYP2C19 PMs, a clopidogrel regimen of 600-mg LD/150 mg/day MD largely overcomes diminished clopi-H4 exposure and antiplatelet response, as assessed by MPA levels.
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Clin. Pharmacol. Ther. · Aug 2011
Randomized Controlled TrialThe norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA ("ecstasy") in humans.
This study assessed the pharmacodynamic and pharmacokinetic effects of the interaction between the selective norepinephrine (NE) transporter inhibitor reboxetine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in 16 healthy subjects. The study used a double-blind, placebo-controlled crossover design. ⋯ These effects were evident despite an increase in the concentrations of MDMA and its active metabolite 3,4-methylenedioxyamphetamine (MDA) in plasma. The results demonstrate that transporter-mediated NE release has a critical role in the cardiovascular and stimulant-like effects of MDMA in humans.