A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

Pharmacokinetics of rizatriptan in healthy elderly subjects.

OBJECTIVE: Rizatriptan is a serotonin 5-HT1B/1D receptor agonist for acute treatment of migraine. Its pharmacokinetics were assessed in healthy elderly males and females receiving a single 10 mg tablet oral dose. The pharmacokinetic data (AUC(0-infinity) and Cmax) for the elderly in this study were compared with historical data from previous studies for healthy young adults (n = 65). METHODS: In a double-blind, parallel, placebo-controlled study, healthy elderly female and male subjects aged 65 or older (n = 8 each) received a single oral dose of 10 mg rizatriptan. Plasma and urine concentrations of drug were determined by HPLC with tandem mass spectrometry detection at several collection time points or intervals starting at predose and postdose over 24 h. RESULTS: In elderly subjects, the geometric mean values for AUC(0-infinity) and Cmax were 77.7 ng/h/ml and 21.9 ng/ml; the average values for tmax, half-life (t 1/2), renal clearance (Clr), and percent urinary excretion of dose (Ue) were 1.2 h, 1.8 h, 197 ml/min and 9.3%, respectively. The AUC(0-infinity) and Cmax of rizatriptan were similar in elderly and young subjects. The geometric mean AUC ratio of elderly to young was 0.96 with 90% confidence interval (0.83, 1.11), p > 0.25. The geometric mean Cmax ratio was 0.89 with 90% confidence interval (0.72, 109), p > 0.25. No significant pharmacokinetic differences were observed between elderly males and females. CONCLUSIONS: The plasma pharmacokinetics of rizatriptan appear to be similar in the elderly and young. In the elderly, the pharmacokinetics of rizatriptan do not appear to differ between male and female to a clinically significant extent.

MK-927, a topical carbonic anhydrase inhibitor. Dose response and reproducibility.

We investigated the dose-response and reproducibility of the intraocular pressure-lowering effect of MK-927 in ocular hypertensive patients. Patients were enrolled until at least 8 "marked responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye greater than or equal to 6 mm Hg) and 7 "mild responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye less than or equal to 3 mm Hg) were identified. In part A, 27 patients received one drop of 2% MK-927 in one eye (baseline mean +/- SEM intraocular pressure, 28.0 +/- 1.0 mm Hg) and placebo in the contralateral eye. Intraocular pressure was measured at baseline and 1, 2, 3, 4, and 6 hours. Maximum reduction in intraocular pressure was 4.0 +/- 0.8 mm Hg at 3 hours, with a duration of 4 hours. Ten patients were identified as marked responders and 7 as mild responders. In part B, 8 of the marked responders entered a four-period crossover study and received 2%, 0.5%, and 0.125% MK-927 and placebo in the same treated eye as in part A, and placebo in the contralateral eye. The 7 mild responders in part C received 2% MK-927 in a similar fashion as in part A. MK-927 in concentrations of 0.125% and 0.5% had little or no effect on intraocular pressure in patients with a marked response to 2% MK-927. Within-patient variability in peak response to single doses of 2% MK-927 was substantial (coefficient of variation of 0.3 and 0.5 for marked responder and mild responder groups, respectively.

MK-927: a topical carbonic anhydrase inhibitor. Dose response and duration of action.

The dose response to a single topical administration of the carbonic anhydrase inhibitor MK-927 was investigated in 24 patients with primary open angle glaucoma or ocular hypertension. Three concentrations of MK-927 (2%, 1%, and 0.5%) and placebo were administered in a two-center, double-masked, randomized, placebo-controlled, four-period crossover study. MK-927 at the 0.5% concentration appeared to be minimally effective in reducing intraocular pressure. A single topical dose of 1% MK-927 resulted in a significantly greater percent reduction in intraocular pressure for up to 6 hours when compared with treatment with placebo. Similarly, a single dose of 2% MK-927 significantly lowered intraocular pressure for 8 hours compared with treatment with placebo. The pressure reduction from baseline measured 23.7% and 11.3% at 8 hours after instillation of a single drop of 2% MK-927. The medication was well tolerated and appeared to lower intraocular pressure in a dose-dependent fashion.

MK-927: a topically effective carbonic anhydrase inhibitor in patients.

The effects on intraocular pressure of the novel topical carbonic anhydrase inhibitor MK-927 were investigated for the first time in patients. Three drops of 2% MK-927 was administered in a two-center, double-masked, randomized, placebo-controlled, two-period crossover study in 25 patients with bilateral primary open angle glaucoma or ocular hypertension. At 4.5 hours after the dose, MK-927-treated eyes demonstrated a peak mean change of -7.7 mm Hg from a mean intraocular pressure of 27.8 mm Hg immediately before the dose; this compares with a change of -3.9 mm Hg from a mean intraocular pressure of 28.2 mm Hg when the same eyes were treated with placebo. The peak mean percent change in intraocular pressure in eyes treated with MK-927 was -26.7% at 6 hours after the dose compared with a change of -13.7% after treatment with placebo. No contralateral effect on intraocular pressure due to MK-927 was observed.