Potential interactions of methylphenidate and atomoxetine with dextromethorphan.

Objective: To examine the potential for drug-drug interactions to influence drug metabolism between the attention-deficit/hyperactivity disorder (ADHD) dl-methylphenidate and atomoxetine with dextromethorphan, a probe for interactions involving cytochrome P450 (CYP) 2D6 isoenzyme.

Design: In vitro and ex vivo analysis of changes in metabolism of study drugs.

Setting: Laboratory.

Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect.

The major human metabolite of atomoxetine (4-hydroxyatomoxetine) was tested against a panel of receptors and enzymes, and was found to interact with the mu, delta, and kappa-opioid receptors based upon studies involving both binding and functional assays. 4-hydroxyatomoxetine was determined to be a partial agonist of the kappa-opioid receptor.

Omeprazole disposition in children following single-dose administration.

Unlabelled: Omeprazole is frequently used to treat gastroesophageal reflux in infants and children despite the lack of age-specific pharmacokinetic and dosing information in the approved product labeling. To address this challenge, the authors examined the potential influence of development and cytochrome P450 2C19 (CYP2C19) genotype on omeprazole disposition by conducting two pharmacokinetic (PK) studies in children and adolescents (ages 2-16 years) after a single oral 10- or 20-mg dose of the drug. Plasma omeprazole concentrations were determined by HPLC-MS from seven plasma samples obtained over a 6-hour postdose period.

Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant.

Kappa-opioid receptor-mediated thermonociceptive mechanisms in streptozotocin diabetes.

The effects of the benzomorphan kappa-opiate antagonist MR 2266 and its dextro enantiomer MR 2267 were assessed on thermonociception in male Swiss Webster mice. Experimental diabetes was induced by injecting streptozotocin (200 mg/kg IP, 7-8 days before). Animals with dextrose treatment (5 g/kg, IP, at the time of opiate injection) were used as acute hyperglycemic controls.