Kinetics, safety, and efficacy of ramipril after long-term administration in hemodialyzed patients.

We studied the efficacy and safety of ramipril and the kinetics of its active moiety ramiprilat in 12 hypertensive patients receiving regular hemodialysis, after a single dose and after long-term (28 days) administration. Patients received 2.5 mg ramipril after each hemodialysis. On days 1 and 29, ramipril was administered 4 h before the hemodialysis and serial blood samples were obtained for 9 h for determination of pharmacokinetic parameters. Tolerability was good, and all patients completed the study. There was a high degree of angiotensin-converting enzyme (ACE) inhibition throughout the study. Ramipril had a clear-cut antihypertensive effect. Long-term administration of ramipril did not modify the time to peak ramiprilat concentration, but increased the mean maximal concentration significantly: 20.2 +/- 12.7 vs. 10.4 +/- 7.1 ng center dot ml-1. The mean accumulation ratio was 2.2. Ramiprilat hemodialysis clearance was 31.7 ml/min (range 4.2-64.9 ml/min) on day 1 and 21.0 ml/min (range 7.9-56.5 ml/min) on day 29. Ramipril 2.5 mg, administered after hemodialysis, appears to be safe and effective in hypertensive patients receiving periodic hemodialysis. Despite an increase in ramiprilat concentration from day 1 to day 29, the steady state was reached. We describe the role of nonrenal clearance of ramiprilat.

The effects of buserelin microparticles on ovarian function in healthy women.

OBJECTIVE: To investigate the tolerance, pharmacokinetics and pharmacodynamics of the microparticle formulation of buserelin, when it was administered subcutaneously. DESIGN: A single-blind, randomised, parallel-group design was used to investigate the duration of suppression of ovarian function associated with doses of 1.8 3.6 and 7.2 mg buserelin administered subcutaneously as microparticles. SETTING: The study was carried out at the Hoechst Research Centre for Clinical Pharmacology, Department of Pharmacology, University of the Orange Free State, Bloemfontein. PATIENTS: Thirty-two health premenopausal female volunteers aged between 19 and 39 years and weighing between 52 and 85 kg completed the study. OUTCOME MEASURES: Serum progesterone and oestradiol concentrations were measured twice weekly until normal ovarian function resumed, i.e. when serum progesterone concentrations increased to at least 8 nmol/l (a sign of ovulation) and oestradiol concentrations increased to values above 300 pmol/l. Serum and urinary concentrations of buserelin were measured at the same times as those of progesterone and oestradiol. RESULTS: Doses of 1.8 3.6 and 7.2 mg elicited anovulation for mean periods of 52, 77 and 113 days and suppressed ovarian production of oestrogen for 19, 38 and 69 days. Resumption of normal ovarian function occurred when serum buserelin concentrations decreased to between 0.03 and 0.05 microgram/ml. The correlation coefficient between dose and duration of anovulation was 0.75; the correlation coefficient between dose and duration of suppression of oestrogen production was 0.76. CONCLUSION: Apart from minor side-effects such as hot flushes, vaginal spotting and acne, the compound was tolerated well. We conclude that a good relationship exists between dose and duration of suppression of ovarian function. Doses of 3.6 - 7.2 mg buserelin should suppress oestrogen production for approximately 6 - 9 weeks and ovulation for 11 - 16 weeks.

Multiple doses of trandolapril do not affect warfarin pharmacodynamics.

OBJECTIVE: The effects of multiple doses of trandolapril (a new angiotensin-converting enzyme inhibitor) on the pharmacodynamics of a single 25 mg dose of warfarin were investigated in 19 men. DESIGN: A double-blind, placebo-controlled cross-over design was used. The study consisted of two periods of 13 days each, during which subjects received either trandolapril 2 mg or placebo once daily according to a randomisation plan. Warfarin was given on day 8 of each of these periods. SETTING: The study was carried out at the Hoechst Research Centre for Clinical Pharmacology, Department of Pharmacology, University of the Orange Free State, Bloemfontein. PATIENTS: Nineteen healthy white men aged between 18 and 28 years and weighing between 65 and 98 kg volunteered for the study. OUTCOME MEASURES: Prothrombin time (PT) and coagulation factors II, VII, IX and X were measured before and sequentially up to 6 days after warfarin administration. Areas under the PT and coagulation factor time curves for warfarin + trandolapril were compared with the corresponding areas for warfarin + placebo. The two treatment combinations were also compared at each measuring time. RESULTS: The point estimate for the ratio of the treatment means of warfarin + trandolapril relative to warfarin + placebo for PT was 97% (90% confidence interval: 90%-103%). The corresponding value for factor VII was 97% (90% confidence interval: 91%-102%). CONCLUSION: The concomitant administration of trandolapril did not affect the pharmacodynamic effects of warfarin.

Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination.

The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0-4 h) and ramiprilat (0-24 h) (from 15.8 to 19.8 ng.ml-1.h, and from 63.4 to 74.6 ng.ml-1.h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73% of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.

Lack of interaction between ramipril and simvastatin.

Twenty two healthy males participated in a randomised, placebo-controlled, double blind, cross-over study to investigate the influence of simvastatin on the pharmacokinetics of ramipril and its active metabolite (ramiprilat), and on the ACE-inhibiting effect of ramiprilat. During two study periods, each of 7 days, subjects received daily either simvastatin 20 mg at 19.00 h or placebo; ramipril (5 mg) was given on Day 5 of each of the periods. Plasma concentrations of ramipril and ramiprilat and ACE-activity were measured in sequential blood specimens, and ramipril and ramiprilat concentrations were measured in urine. Blood and urine collections for pharmacokinetic and pharmacodynamic assessment were made up to 72 h after the dose of ramipril. The mean AUC of ramipril for ramipril+placebo (R+P) and ramipril+simvastatin (R+S) was 22.2 and 21.3 ng.h.ml-1, respectively; for ramiprilat the corresponding figures were 61.3 and 57.6 ng.h.ml-1. The urinary excretion of ramipril+metabolites for (R+P) and (R+S) was 25.2 and 24.1% of dose. The maximum percentage inhibition of ACE-activity for (R+P) was 94.6%, and for (R+S) it was 94.1%. It is concluded that concomitant administration of simvastatin and ramipril has no clinically relevant effect on the pharmacokinetics or ACE-inhibition of the latter drug and its metabolites.

Assessing the risk of ovulation in interaction studies of drugs and oral contraceptives.

When certain drugs are taken concomitantly with an oral contraceptive, the efficacy of the contraceptive may be obtunded, and pregnancy may ensue. Since the function of oral contraceptives is to suppress ovulation, the risk of ovulation is an important parameter in clinical studies investigating interactions between drugs and oral contraceptives. The purpose of this paper is to compare a crossover design, and a new study design used for assessing a possible interaction between a drug and an oral contraceptive, and to discuss the statistical issues involved in the planning and evaluation of the results of such studies.

The effects of felodipine on the pharmacokinetics of diazepam.

Twelve consenting, caucasian male volunteers participated in a double-blind, randomized, crossover study of the effects of felodipine, a calcium antagonist, on the pharmacokinetics of diazepam. There were two trial periods of 12 days each with a wash-out period of 9 days between them (total duration: 12 + 12 + 9 = 33 days). During the 12-day periods they received either felodipine or placebo each morning under fasting conditions. On day 6 of each of the two 12-day periods, diazepam, 10 mg was injected i.v. 30 minutes after the felodipine/placebo. Diazepam and desmethyldiazepam concentrations were measured in plasma up to 168 hours after the injection. Diazepam plasma concentrations and pharmacokinetic parameters were not affected by the concomitant medication with felodipine. However, the co-administration of felodipine increased desmethyldiazepam plasma concentrations relative to placebo: mean area under the plasma concentration-time curve of 4,910 vs 5,581 ng.h/ml and mean peak concentrations of 40 vs 47 ng/ml. Felodipine might cause a retarded elimination of desmethyldiazepam, possibly by obtruding the formation of oxazepam. The clinical relevance of these findings remains to be elucidated.