Effects of methylphenidate hydrochloride on the cardiovascular system in vivo and in vitro: a safety pharmacology study.

INTRODUCTION: : We examined the effects of methylphenidate hydrochloride (MPH) on the cardiovascular system using in vivo and in vitro study methods in accordance with the ICH-S7B guideline. METHODS: MPH was orally administered at doses of 3, 10 and 30 mg/kg to unrestrained conscious dogs implanted with a telemetry transmitter and attached with body surface electrodes, and electrocardiogram (ECG) leads. The QTcF interval was determined while heart rate (HR), and blood pressure (BP) were measured. Action potentials in isolated guinea-pig papillary muscle and the rapid component of the delayed rectifier potassium current (I(Kr)) in HEK-293 cells stably transfected with hERG were also investigated at concentrations of 0.1, 0.3 and 1 microg/mL (0.37, 1.1 and 3.7 micromol/L) of MPH. RESULTS: No ECG changes were observed except for a shortening of the QT interval due to a shortening of the RR interval at the maximum dose tested, 30 mg/kg. The only observed change was an elevation of BP in dogs at the dose of 30 mg/kg, which is approximately 10 times higher than the maximum therapeutic dose for use in children with attention deficit hyperactivity disorder (ADHD). Neither APD prolongation nor I(Kr) inhibition was observed by MPH in the in vitro studies up to the maximum concentration tested, 1 microg/mL (3.7 micromol/L), which is approximately 34 times higher than the clinically attainable unbound plasma MPH concentrations in children with ADHD. DISCUSSION: These results suggest that it is unlikely that MPH affects ventricular repolarization processes at the therapeutically recommended dose levels in patients with ADHD.

[Pharmacological and clinical profile of exemestane (Aromasin), a novel irreversible aromatase inhibitor].

Aromatase is the rate-limiting enzyme playing a role at the final step of estrogen biosynthesis, which is attracting attention as the target enzyme of hormone therapy of postmenopausal breast cancer. Exemestane (Aromasin) is a novel steroidal irreversible aromatase inhibitor that was approved in Japan as a therapeutic drug for postmenopausal breast cancer. Exemestane selectively inhibits aromatase activity in vitro, in a time-dependent and irreversible manner, suggesting the mechanism of action that exemestane covalently binds to aromatase as a pseudo-substrate and inactivates the enzyme. In vivo studies show the inhibitory effect of exemestane on the ovarian aromatase activity and plasma estradiol level of PMSG-primed rats. In studies using DMBA-induced rat mammary tumor models, exemestane shows antitumor activity in both conventional (premenopausal) and ovariectomized, testosterone-treated postmenopausal models. Despite its steroidal structure, exemestane does not have hormonal or anti-hormonal activity, except for a slight androgenic activity. In the early and late phase II clinical trials conducted in Japan on postmenopausal breast cancer patients who received 25 mg/day of exemestane, the response rates were 31.4% and 24.2%, respectively. Blood estrogen levels were also markedly reduced. These results confirmed the clinical relevance of non-clinical study results, as well as the possibility of extrapolation to foreign trial data.