Efficacy and acceptability of the new oral phosphate binder Lenziaren(®) in healthy cats fed a renal diet.

The efficacy and acceptability of the new oral phosphate binder Lenziaren(®) (SBR759) were evaluated in healthy cats fed with a commercial diet containing low amounts of phosphate ('renal diet'). Lenziaren(®) at 0.125, 0.25, 0.5 and 1 g/day was compared to a reference product Lantharenol(®) (3.0 g/day) and a placebo in a masked, randomized, parallel-group design study in 36 cats (n = 6 per group). All products were mixed with the ration which was fed once daily for 28 days. Lenziaren(®) produced significant dose-related reductions in serum and urine phosphate concentrations, faecal apparent phosphorus digestibility and fractional urinary phosphate excretion. Cats administered Lenziaren(®) consumed significantly less food than the placebo group, but this had no negative impact on body weight or acceptability assessments. When compared to the positive control, Lantharenol(®) , Lenziaren(®) was significantly more acceptable (0.125, 0.5 and 1.0 g/day doses), was associated with higher food consumption (0.125, 0.5 and 1.0 g/day doses) and had greater efficacy in reducing serum phosphate (0.5 and 1.0 g/day) and urine phosphate concentrations (1.0 g/day). In conclusion, Lenziaren(®) was an effective oral phosphate binder in healthy cats fed with a renal diet. Lenziaren(®) was well accepted and tolerated. Dosages of 0.25-1.0 g/cat per day are recommended for clinical testing.

Efficacy and tolerability of nisoldipine coat-core formulation in the treatment of essential hypertension: The South African Multicenter ANCHOR Study. Ambulatory Nisoldipine Coat-Core Hypertension Outpatient Response (ANCHOR) Investigators.

A double-blind, placebo-controlled, multicenter trial was undertaken to assess the antihypertensive efficacy and tolerability of a controlled-release (Coat-Core [CC] tablet) formulation of the second-generation dihydropyridine calcium channel antagonist, nisoldipine. Of the 208 patients with mild-to-moderate essential hypertension, two were excluded from the main efficacy analysis, and the rest randomized into one of four treatment groups, to receive either placebo, or nisoldipine CC at doses of 10, 20, or 30 mg once daily for 6 weeks, following a 4-week placebo run-in period. Blood pressure measurements (supine, standing, diastolic, and systolic) were taken at trough plasma levels, 24 h after previous dosing at 2-week intervals throughout the study. Adverse events and laboratory parameters (plasma lipid and glucose levels, and thyroid function) were monitored. All three doses of nisoldipine CC lowered blood pressure, as compared with placebo, 24 h after dosing. At endpoint (after 6 weeks) mean changes in supine blood pressure from baseline were (systolic/diastolic) 0.9/-2.3, -8.0/-5.5, -16.9/-9.0, and -15.0/-10.3 mm Hg for the groups assigned to placebo and nisoldipine CC 10, 20, and 30 mg, respectively. The response rates were 35%, 47%, and 63% for nisoldipine CC 10, 20, and 30 mg, respectively. Twenty-four-hour ambulatory blood pressure monitoring showed that nisoldipine CC effectively controlled blood pressure throughout the dosing interval. No change in heart rate was seen for all three doses of nisoldipine CC over the 24-h dosing interval. Nisoldipine CC was at least as effective in black patients as in whites. Generally adverse events were not increased, except for peripheral edema, with rates of 7% in placebo, and 6%, 9%, and 19%, respectively, in those receiving nisoldipine CC 10, 20, or 30 mg daily. There were no clinically significant changes in blood lipids, blood glucose, or thyroid function. In conclusion, once-daily nisoldipine CC at doses of 10 to 30 mg was an effective and well tolerated antihypertensive agent, providing 24-h control of blood pressure without any increase in heart rate.

Bioequivalence of controlled-release calcium antagonists.

In this review, several deficiencies of published bioequivalence studies for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studies must be viewed with care. A proper statistical analysis of bioequivalence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test: reference ratio of the means of the pharmacokinetic variables of the test and reference product. The CI must fall completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious methodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and conversely, a conclusion of bioequivalence because of a statistically significant difference, or because of a mere failure to show bioequivalence, are still made. With calcium antagonists in particular, an assessment of the rate of absorption and of the maximum concentration is important, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studies the maximum concentration (Cmax), and the time to the maximum concentration (tmax), and in multiple-dose studies the Cmax, and the peak-trough fluctuation (%PTF) must be considered. Some bioequivalence studies of calcium antagonists are deficient in this respect. To show bioequivalence for controlled-release formulations, multiple-dose studies are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. Some calcium antagonists, such as verpamil, show stereo-selective pharmacokinetics, so that enantiomers may have to be investigated. Unfortunately, few of the published studies of controlled-release calcium antagonists satisfy all requirements. One would expect that data submitted to regulatory authorities for approval of generic formulations are more complete; published data are in many cases not satisfactory.

Efficacy of ramipril versus enalapril in patients with mild to moderate essential hypertension.

This double-blind, randomised, cross-over study investigated the antihypertensive efficacy of ramipril and enalapril was completed by 30 patients with mild-to-moderate essential hypertension. After a four-week placebo run-in phase, the patients received either 2.5mg ramipril or 10mg enalapril once daily for four weeks. The dosages were increased to 5mg ramipril and 20mg enalapril for a further four weeks. After a placebo washout phase of four weeks, the patients were crossed over to the alternative treatment. The decrease in average 24-hour ambulatory diastolic blood pressure from week 0 to week 8 was 1.6mmHg greater with ramipril than enalapril (90% confidence interval 0.6-2.7mmHg). The corresponding reduction in for systolic blood pressure was also greater with ramipril than enalapril by 2.4mmHg (90% confidence interval: 0.5-4.2mmHg). For the difference in the drop of 24-hour ambulatory diastolic blood pressure between ramipril and enalapril the lower level of the 90% confidence interval (CI) is above the clinically relevant difference of -3mmHg. This is an indication that ramipril (2.5 and 5mg dose) is at least as effective as enalapril (10 and 20mg dose) in decreasing blood pressure in patients with mild-to-moderate essential hypertension. The duration of adequate antihypertensive effect was relatively long for both ramipril and enalapril; however, ramipril tended to have a more prolonged antihypertensive effect. Ramipril had a higher diastolic and systolic trough/peak ratio than enalapril, resulting in a more uniform antihypertensive effect over the 24-hour treatment period. Both ramipril and enalapril were well tolerated and the two treatment groups had similar safety profiles.

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.

Relative bioavailability of four clomipramine hydrochloride tablet products.

The relative bioavailability of clomipramine was determined in two single-blind, single-dose, randomized, crossover studies. In the first study, the relative bioavailability of the test product, 2 x 25 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil 2 x 25 mg tablets (clomipramine HCl; Ciba-Geigy (Pty) Ltd.) was determined. In the second study, the relative bioavailability of the test product, 5 x 10 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil 5 x 10 mg tablets (clomipramine HCl; Ciba-Geigy (Pty) Ltd.), was determined. The geometric mean values for the variable Cmax were 31.3 ng mL-1 for the reference and 31.6 ng mL-1 for the test product in study 1. The geometric mean values for the variable AUC were 736 ng h mL-1 and 753 ng h mL-1 for the reference and test, respectively. In study 2, the geometric mean Cmax values were 25.8 ng mL-1 and 23.9 ng mL-1 for the reference and test respectively; the geometric mean AUC values were 569 ng h mL-1 and 547 ng h mL-1. The 90% confidence intervals for the 'test/reference' mean ratios of the plasma clomipramine pharmacokinetic variables Cmax and AUC(0-infinity) (as measures of the rate and extent of absorption of clomipramine, respectively) fall within the conventional bioequivalence range of 80-125% for both studies. The test products (clomipramine HCl) are therefore bioequivalent to the reference products (Anafranil) with respect to the rate and the extent of absorption of clomipramine in both 10 mg and 25 mg strengths.

A comparison between the use of recombinant hirudin and heparin during hemodialysis.

The purpose of this study was to determine the anticoagulant and antithrombotic potential of hirudin during hemodialysis by comparing the efficacy of dialysis with heparin to that of dialysis with recombinant hirudin (r-hirudin). Eleven patients with chronic renal failure and on maintenance hemodialysis were included in this open cross-over study. Conventional doses of heparin were administered during the first dialysis of the study. Two days later r-hirudin, at a dose of 0.15 mg/kg, was given as a bolus at the start of the second dialysis. The mean decreases in plasma levels of urea, uric acid and creatinine were approximately 50% after dialysis with both anticoagulants. Dialysis was therefore equally effective. However, effective dialysis with r-hirudin was achieved with a shorter activated partial thromboplastin time (APTT; range 65 to 103 seconds) compared to that with heparin (> 120 seconds), thereby decreasing the risk of bleeding. Markedly less 111In-labeled platelets accumulated at the inlet of the artificial kidney when r-hirudin was used, suggesting a smaller loss of hollow fiber volume. The results indicate that hirudin may be a suitable alternative anticoagulant for use during hemodialysis and it thus warrants further investigation.

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.

Reference tables for the intrasubject coefficient of variation in bioequivalence studies.

Bioequivalence studies are usually performed as crossover studies and, therefore, information on the intrasubject coefficient of variation is needed for sample size planning. However, this information is usually not accessible in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. It is the purpose of the present communication to provide reference values of the intrasubject coefficient of variation for various previously investigated drugs. The presentation includes pertinent pharmacokinetic characteristics for immediate- and extended-release formulations in single- and multiple-dose crossover studies.

The influence of ipsapirone, a 5-HT1A agonist, on sleep patterns of healthy subjects.

Ipsapirone is a new pyrimidinylpiperazine ligand specific for 5-HT1A receptors, with potential therapeutic use in affective disorders. Because 5-HT is involved in the regulation of sleep, we investigated the effect of ipsapirone hydrochloride on sleep patterns in 18 normal, healthy subjects of both sexes. Compared to placebo, ipsapirone 5 mg administered by mouth three times daily for 14 days decreased rapid eye movement (REM) sleep duration and, by the tenth day of treatment, began to reduce slow wave sleep (SWS) duration. The decrease in REM sleep occurred in the first 3 h of sleep. The latency to REM sleep was increased from the first night following ipsapirone administration, remained increased throughout the 14 days of administration, and fell to equal latency on placebo immediately administration ended. Subjective assessments of sleep revealed no differences between ipsapirone and placebo. Our experiments confirm a role of 5-HT1A receptors in sleep. The effects of ipsapirone on the sleep patterns of patients with affective disorders still need to be determined.

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril.

The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

Pharmacokinetic characteristics for extent of absorption and clearance in drug/drug interaction studies.

Many aspects of drug/drug interaction studies, including aspects of the design, choice of pharmacokinetic characteristics, and statistical analysis can be adapted from bioequivalence studies [Steinijans et al. 1991]. However, an important difference between drug/drug interaction studies and bioequivalence studies is that two formulations in bioequivalence studies generally do not differ with respect to the clearance of the drug under investigation, but in drug/drug interaction studies an effect of one drug on the clearance of another drug is not only possible, but the likely mechanism of interaction for many classes of drugs. Thus, while in bioequivalence studies two formulations are conventionally compared with respect to the rate and extent of absorption of the drug, in drug/drug interaction studies equivalence has to be shown with respect to not only the rate and extent of absorption, but also, and in particular, with respect to the clearance of the drug. Consequently, in drug/drug interaction studies the area under the curve is not a pure characteristic of the extent of absorption, but a composite characteristic of extent of absorption and clearance. This should be taken into account when interpreting the results of drug/drug interaction studies. Apart from standard characteristics such as Cmax and AUC used in bioequivalence studies, for drug/drug interaction studies we suggest the elimination half-life as a characteristic for the clearance, and the ratio of AUC and the elimination half-life as a characteristic for the extent of absorption of a drug.

Absolute bioavailability of a new high dose methylprednisolone tablet formulation.

This was a single-blind, single-dose, randomized crossover study to determine the absolute bioavailability of Medrol, a new high dose (100 mg) methylprednisolone tablet product, by comparing it with 100 mg methylprednisolone from an intravenous formulation, Solu-Medrol. Fourteen healthy, non-smoking, Caucasian male volunteers took part. On treatment days volunteers remained recumbent for 4 hours after drug administration, with food and fluid intake standardized over this period. Serial blood samples were drawn over a 14-hour period after drug administration. Plasma methylprednisolone concentrations were determined by high performance liquid chromatography. The geometric means of AUCi.v. and AUCtablet were 4,049 and 3,334 ng.h/ml, respectively. The absolute bioavailability of the tablet product was 82%, which is in agreement with published data for other oral dosage forms of methylprednisolone. Volunteers displayed the expected rise in peripheral blood neutrophil count, but no other clinically relevant changes in hematology or clinical chemistry were observed. No adverse drug reactions were recorded. It is concluded that the tablet product can be used as a substitute for parenteral methylprednisolone in situations requiring high-dose therapy.

Choice of characteristics and their bioequivalence ranges for the comparison of absorption rates of immediate-release drug formulations.

For immediate release drug formulations the maximum concentration (Cmax), the time to the maximum concentration (tmax), and the ratio Cmax/AUC have been suggested as absorption rate characteristics. Although tmax is easier to interpret as absorption rate characteristic than Cmax and Cmax/AUC, the latter are generally preferred in practice because these characteristics can be observed with higher precision, and are easier to handle statistically than tmax. In this paper we propose a strategy for setting appropriate bioequivalence ranges for tmax and Cmax/AUC, and for choosing the best characteristic for the comparison of absorption rates when planning a bioequivalence study. This involves motivating the bioequivalence range on that scale which is most convenient for that purpose, namely in terms of differences in tmax. Exploiting the pharmacokinetic relationship between tmax and Cmax/AUC this bioequivalence range is then translated into the corresponding bioequivalence range for Cmax/AUC. The characteristic that gives the greatest power to show bioequivalence can then be specified as the primary absorption rate characteristic. For drugs with short elimination half-lives, or short fastest disposition half-lives if the drug concentrations follow a higher compartmental model, Cmax/AUC is the best characteristic, but for drugs with long elimination or fastest disposition half-lives tmax can be superior to Cmax/AUC.

Presentation of the intrasubject coefficient of variation for sample size planning in bioequivalence studies.

Bioequivalence studies are generally performed as crossover studies and, therefore, information on the intrasubject coefficient of variation is needed for sample size planning. Unfortunately, this information is usually not presented in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. Thus, the essential information for sample size planning of future studies is not made available to other researchers. In order to overcome such shortcomings, the presentation of results from bioequivalence studies should routinely include the intrasubject coefficient of variation. For the relevant coefficients of variation, theoretical background together with modes of calculation and presentation are given in this communication with particular emphasis on the multiplicative model.

Prolonged endurance exercise and sleep disruption.

To determine whether exercise duration effects the recovery sleep following exercise, eight fit male endurance athletes, ages 23-42 yr, had their sleep electrophysiologically studied. This was done on four separate occasions: after a day on which no specific exercise was performed; after a day of a 15-km run; after a 42.2-km run day; after a day in which the athletes participated in a strenuous ultra-triathlon. Sleep patterns following the no exercise day and the 15-km and the 42.2-km run days were similar. The sleep pattern of the ultra-triathlon day when compared with the other three days showed significantly increased wakefulness and delayed and decreased rapid eye movement (REM) sleep. The duration of slow wave sleep (SWS) in the first 6 h after lights out, however, was no different. The increased wakefulness and decreased REM clearly indicate increased stress after the ultra-triathlon. REM sleep appears to be a more sensitive index of exercise induced stress than SWS.

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.

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.

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.