Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Oct 2003
Clinical TrialCisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny.
Cisapride, a prokinetic agent and substrate for cytochrome P450 (CYP) 3A4, has been used to treat neonates and infants with feeding intolerance and apnea or bradycardia associated with gastroesophageal reflux. At age 1 month, CYP3A4 activity has been reported to be only 30% to 40% of adult activity. This known developmental delay in the expression of CYP3A4 prompted us to conduct a classical open-label pharmacokinetic study of cisapride in neonates and young infants. ⋯ (1) In neonates and infants, cisapride absorption and metabolism to its primary metabolite, norcisapride, were developmentally dependent; (2) approximately 99% of cisapride CL/F in neonates and young infants was nonrenal in nature; (3) CL/F of cisapride in neonates and infants noted in this study was reduced compared with data from older children and adults, likely as a result of developmental reductions in CYP3A4 activity; (4) as reflected by the correlation between postconceptional age and lambda(z), a rapid increase in total CYP3A4 activity occurs in the first 3 months of life.
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Clin. Pharmacol. Ther. · Oct 2003
Clinical and economic consequences of reference pricing for dihydropyridine calcium channel blockers.
Reference pricing is a medication cost-sharing policy that fully covers medications which are less expensive than a standard reference price and requires patients to pay the extra cost of higher-priced drugs in a class of therapeutically substitutable drugs. Little information exists on the clinical and economic consequences. We analyzed changes in drug utilization, physician visits, hospitalizations, long-term care admissions, and expenditures after the introduction of reference pricing for dihydropyridine calcium channel blockers (CCBs) among patients aged 65 years or older in British Columbia, Canada. ⋯ Reference pricing as implemented in British Columbia may be a model for successful pharmaceutical cost-containment without adversely affecting patients or cost-shifting.
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Clin. Pharmacol. Ther. · Sep 2003
Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching.
Our objective was to examine possible changes in the effectiveness of warfarin after a nationwide generic substitution of formulations in 1998. ⋯ Because a general unidirectional change in INR response per unit warfarin dose cannot be explained by biologic mechanisms or confounding, we conclude that slightly reduced bioavailability (within the acceptable bioequivalence range) of the new formulation led to overestimated period 2 doses and reduced apparent warfarin sensitivity in all patient subgroups (by period 1 dose or INR), which was most prominent in those individuals with the lowest maintenance dose requirements.
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Clin. Pharmacol. Ther. · Aug 2003
Randomized Controlled Trial Clinical TrialPeripheral and central antihyperalgesic effects of diclofenac in a model of human inflammatory pain.
Experimental evidence suggests that the antihyperalgesic effect of nonsteroidal anti-inflammatory drugs may include both peripheral (inflammatory site) and central sites of action. The aim of this study was to assess peripheral and central antihyperalgesic effects of diclofenac in a human experimental pain model. ⋯ The higher antihyperalgesic efficacy of oral diclofenac as compared with topical diclofenac at comparable tissue concentrations suggests that not only peripheral but also central mechanisms are involved in the antihyperalgesic effects of systemically administered diclofenac.