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A method for the measurement of the beta-blocker timolol and its 13C3-labeled analog in human plasma is described. A known amount of an internal standard, [2H9]timolol, is added to each plasma sample. The method employs a reversed-phase C18 cartridge for isolation of the drug-containing fraction, capillary column GLC of the trimethylsilyl derivatives, and detection via selected-ion monitoring. The ions monitored for quantification (m/e 86 from timolol and m/e 89 and 95 from the 13C3- and 2H9-labeled analogs, respectively) arise from the side chains of the three compounds [e.g., CH2N+HC(CH3)3 for m/e 86]. Plasma levels of timolol and [13C3]timolol in human subjects given 5 or 10 mg of each compound were followed simultaneously for 12 hr postdosing. A detection level of 0.5 ng/ml of plasma was found. No evidence was found for a metabolic kinetic isotope effect since the ratios of the two species of drug in the plasma samples were the same as the ratios in the administered dose.

Following hemodynamic evaluation using invasive and noninvasive methods, 73 patients were treated in an open, uncontrolled, multicenter study with single oral doses of enalapril maleate 1.25 to 40 mg until the optimal dose for each patient (based upon hemodynamic response) was achieved. Diuretics were withheld and reinstituted only if necessary. Hemodynamic measurements were made at 0 (predrug), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdrug. Patients were discharged on their optimal dose, treated 1 to 4 months and then rehospitalized for repeat hemodynamic measurements. The optimal enalapril single dose was associated with the following mean peak responses: increased cardiac index 42% (SE = 6) and decreased pulmonary capillary wedge pressure 40% (SE = 3), systemic vascular resistance 39% (SE = 2), and mean arterial pressure 23% (SE = 1.5). These changes persisted during chronic therapy. Chronic treatment with enalapril also improved exercise capacity 40% (P less than 0.01), ejection fraction 18% (P less than 0.05) and clinical status (N.Y.H.A. functional class, P less than 0.01). Ten and 20 mg/day, taken as once- or twice-daily regimens, were the most commonly effective doses.

The effects of the new oral converting enzyme inhibitor "MK-421" on blood pressure, plasma renin activity, plasma angiotensin II, aldosterone, and angiotensin converting enzyme were assessed in 16 hypertensive patients. Maximum (maintenance) doses ranged from 2.5 mg-40 mg daily. Blood pressure decreased from 177 +/- 7/111 +/- 4 mm Hg to 145 +/- 6/94 +/- 3 mm Hg supine and from 174 +/- 7/177 +/- 4 mm Hg to 142 +/- 6/101 +/- 3 mm Hg upright (mean +/- SEM, p less than 0.001 for both). Heart rate did not change significantly. Plasma renin activity rose during treatment, whereas plasma angiotensin II, aldosterone, and angiotensin converting enzyme remained suppressed at 24h after the maximum dose. Magnitude of blood pressure reduction after the maximum dose did not correlate with baseline plasma renin activity levels. No side-effects were noted during the 2-10 week observation period. MK-421 is similar to its predecessors in efficacy and clinical and biochemical correlates, the main difference being its higher potency and longer duration of action.