Unchanged pressor effect of norepinephrine in normal man following the oral administration of two angiotensin converting enzyme inhibitors, captopril and HOE 498.

The norepinephrine - (50, 100 and 200 ng/kg per min) induced rise in blood pressure (BP) was determined in six health male volunteers following angiotensin converting enzyme (ACE) inhibition by either captopril (100 mg orally) or HOE 498 (10 mg orally). In terms of absolute BP measurements both compounds induced a reduction in basal and norepinephrine stimulated BP, whereas norepinephrine induced increments of BP above individual basal levels were unchanged by either converting enzyme inhibitor. It is concluded that attenuation of the pressor response to norepinephrine does not contribute to the hypotensive action of ACE inhibitors in healthy man.

Blood pressure and endocrine effects of single doses of CS-866, a novel angiotensin II antagonist, in salt-restricted hypertensive patients.

OBJECTIVE: This study was conducted to assess the dose-response relationship of the new angiotensin II (Ang II) antagonist CS-866 on blood pressure and on endocrine parameters in hypertensive patients with an activated renin-angiotensin system. DESIGN: Following a four-way crossover protocol, two groups of eight patients with mild-to-moderate hypertension received a sodium-restricted diet (60 mmol daily) and ingested single doses of 2.5, 10 and 40 mg or 5, 20 and 80 mg of CS-866, respectively, or placebo. Twenty-four hour ambulatory blood pressure measurements, plasma renin activity (PRA), Ang II and concentrations of RNH-6270, the pharmacologically active metabolite of CS-866, were monitored up to 24 h after medication. RESULTS: CS-866 was well tolerated. There was a significant decrease in 24 h diastolic blood pressure (DBP) at all doses of CS-866 above 5 mg. Increasing doses of CS-866 from 2.5 to 10 mg and from 5 to 20 mg lowered the mean 24 h DBP and DBP AUC(0-24h) values considerably more than increasing doses from 10 to 40 mg and from 20 to 80 mg, respectively. The mean 24 h DBP was lowered by 6.9 and 8.4 mmHg after oral doses of 10 and 20 mg CS-866, respectively, compared with placebo and by 8.9 mmHg after 80 mg CS-866. The drug increased PRA and Ang II concentrations in plasma, maximum concentrations of which occurred within 3 h post-dose. The highest RNH-6270 concentrations were also found at the first post-dose measurement 3 h after administration of CS-866. CONCLUSION: The new Ang II receptor antagonist CS-866 is effective and well tolerated. In salt-restricted hypertensive patients, CS-866 lowered blood pressure and increased PRA and Ang II concentrations at low doses. A single oral dose of 10-20 mg CS-866 resulted in almost maximal effects.

Resolution, absolute stereochemistry, and enantioselective activity of nomifensine and hexahydro-1H-indeno[1,2-b]pyridines.

Nomifensine and three selected compounds from the series of H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro-1H-in deno[1,2-b]pyridines have been resolved into their enantiomers. All compounds exhibit pronounced enantioselective activity with respect to their inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity. Nomifensine exhibits the same preference for one enantiomer with respect to dopamine and norepinephrine reuptake, whereas in the indeno[1,2-b]pyridine series in vitro experiments do not discriminate between the optical antipodes. The absolute stereochemistry of the pharmacologically active enantiomers in both series was determined by X-ray analyses and comparative CD spectra. For biological activity the diphenylmethane is an essential structure feature in both series. Its absolute configuration proved to be 4S for nomifensine and 5S for indenopyridines. The similar pharmacological profile of the two chemical entities is therefore reflected in an identical configuration of this pharmacologically important molecular part.

Comparative double-blind study of ramipril and captopril in mild to moderate essential hypertension.

The angiotensin converting enzyme inhibitors ramipril and captopril were administered in doses of 10 mg once daily and 50 mg twice daily, respectively, to patients with mild to moderate essential hypertension. After a 4-week single-blind placebo washout period, patients were treated for 12 weeks with 1 of the drugs under double-blind conditions. Patients who did not respond after 6 weeks of treatment were given 50 mg hydrochlorothiazide concomitantly. The ramipril group showed greater decreases in blood pressure compared with baseline values: 20.1/14.9 mm Hg (ramipril) compared with 16.5/13.5 mm Hg (captopril). A further 6 weeks of treatment lowered the blood pressure even more: 22.5/20.0 mm Hg (ramipril) compared with 20.5/18.6 mm Hg (captopril). Concomitant hydrochlorothiazide given to nonresponders reduced the blood pressure levels in 24 of 40 patients in the ramipril group and in 20 of 36 patients in the captopril group. At the end of the study the overall response to treatment with ramipril alone and ramipril plus hydrochlorothiazide was 77.1%. The overall response rate in the captopril group was 82.7%. No clinically relevant adverse reaction occurred in any patient. Ramipril given once daily was as effective as captopril given twice daily in lowering blood pressure. Both drugs proved to be safe during treatment for 12 weeks.

Dose-response relation of the angiotensin converting enzyme inhibitor ramipril in mild to moderate essential hypertension.

The effects of various dosage levels of ramipril on blood pressure were examined in a double-blind multicenter clinical trial. Patients with mild to moderate essential hypertension were first entered into a single-blind washout placebo phase of 4 weeks duration. The patients were then randomized to 1 of 3 treatment groups and received either 1.25, 2.5 or 5 mg of ramipril orally once a day for 6 weeks. After 6 weeks of treatment, the diastolic blood pressure had been decreased by 16.0 mm Hg (53 patients), 16.5 mm Hg (54 patients) and 19.9 mm Hg (53 patients) for the 1.25, 2.5 and 5 mg groups, respectively. Systolic blood pressure had decreased by an average of 22.5 mm Hg independent of the dose administered. Diastolic blood pressure was decreased to less than or equal to 90 mm Hg in 64%, 63% and 77% of the patients in the 3 groups, respectively. The differences in these percentages among the groups were not statistically significant. The tolerability of the drug was good; discontinuation of treatment was necessary for 1 patient in the 1.25 mg group and medication was lowered for 2 patients because of adverse reactions. There were no clinically significant changes of any laboratory variables, except for an increase in uric acid serum levels.

A double-blind study to compare the efficacy, tolerance and safety of two doses of the angiotensin converting enzyme inhibitor ramipril with placebo.

In a randomized, double-blind trial, 2 doses of ramipril (2.5 and 5 mg once daily) were compared with placebo in patients with mild to moderate essential hypertension. A 2-week placebo run-in phase was followed by 4 weeks of treatment. Eighty-six patients entered the study and 17 withdrew during the course of the study. Both doses of ramipril appeared to be more effective than placebo in reducing blood pressure, but significant differences between 2.5 mg of ramipril and placebo were not found in any statistical analyses. In the endpoint analyses (taking the last measurement from each patient), the patients receiving 5 mg of ramipril had significantly larger decreases in blood pressure than the patients receiving placebo (t tests: standing systolic, p less than 0.001; supine diastolic, p less than 0.05; standing diastolic, p less than 0.05) and also than the patients receiving 2.5 mg of ramipril (standing systolic, p less than 0.05). It appears from the results of this study that the minimum effective dosage of ramipril is 5 mg once daily. No clinically relevant side effects or clinically relevant changes in laboratory values were observed.

Pharmacokinetics and pharmacodynamics of ramipril in renal failure.

The pharmacokinetics and pharmacodynamics of the novel angiotensin converting enzyme (ACE) inhibitor ramipril were studied in 6 patients with a glomerular filtration rate of less than 20 ml/min/1.73 m2 of body surface area. A single oral dose of 5 mg was given and serum concentrations of the compound and its diacid, the active metabolite (ramiprilat), as well as ACE activity, blood pressure and pulse rate were monitored for 28 days. The original compound reached peak serum concentrations of 42.8 +/- 26.5 ng/ml about 1 hour after dosing and was completely eliminated from the serum after 24 hours. Ramiprilat reached peak values of 14.4 +/- 11.6 ng/ml after about 6 hours. In contrast with the parent compound, low concentrations of ramiprilat were still detected in the serum after 28 days. ACE activity decreased to approximately 5% of baseline values, remained low for the next 48 hours, then increased slowly thereafter but reached only 84.5% of initial values after 28 days. Blood pressure decreased significantly and remained low for 24 hours after dosing. The drug was well tolerated in all patients. It is concluded that a single 5 mg dose of ramipril was effective in inhibiting plasma ACE activity and lowering blood pressure in patients with renal failure. There was a slower decline in ramiprilat concentrations compared with subjects with normal renal function.

The pharmacokinetic profile of RS-8359.

RS-8359 is very rapidly absorbed, metabolized and distributed following oral dosing, with significant concentrations of both parent drug and its principal metabolite appearing in plasma within 15 min. Plasma levels were linearly related to doses of up to 300 mg, beyond which absorption was diminished, perhaps due to a saturation effect. Clearance of RS-8359 is mainly through the renal system as the metabolite, and is virtually complete within 24 h. The kinetic profile of the drug best fits a two-compartment model, and mean residence time and half-life (beta) of the drug support a twice a day regimen for extended use. During multiple dosing twice a day for up to 6 weeks, steady state plasma drug levels were achieved within 48 h and there was no evidence of significant accumulation.

[Protective effect of forskolin in acetylcholine provocation in healthy probands. Comparison of 2 doses with fenoterol and placebo]. / Protektiver Effekt von Forskolin gegenüber Acetylcholinprovokation bei gesunden Probanden. Vergleich von 2 Dosen mit Fenoterol und Placebo.

Forskolin, a potent adenylate cyclase activating diterpene-derivative, isolated from the Indian plant Coleus forskohlii, was tested double-blind and cross-over in 12 healthy volunteers (nonsmokers) by whole body plethysmography. All drugs were administered by metered dose inhalers. The bronchodilating effect (after 5 minutes) was as good as following fenoterol. At the beginning (after 3 and 5 minutes) the protective effect against inhaled acetylcholine was as good as following fenoterol while later on (after 15 and 30 minutes) fenoterol resulted in a stronger action.

Effects of the new oral angiotensin converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) in essential hypertension.

In a dose titration study patients with mild to moderate essential hypertension were treated with increasing doses of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) (up to 8 mg daily) for 3 weeks. Hoe 498 was tolerated well. 9 out of 20 patients responded to 1 mg b.i.d., the blood pressure in a further 5 patients normalized with 2 mg b.i.d. Six patients did not respond to Hoe 498 treatment (4 mg b.i.d. in the last week) according to the criterion: recumbent diastolic blood pressure less than or equal to 90 mm Hg. But all 6 patients showed a clear decrease in blood pressure during treatment.

Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects.

The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme inhibitor HOE 498 were investigated in 10 healthy normotensive male subjects. Serum levels of the active metabolite M 1 (dicarboxylic acid) of HOE 498 were measured by HPLC up to 14 days after a single oral dose of 10 mg HOE 498. Peak serum concentration of M 1 between 5-50 ng/ml was observed 1.5-3.0 h after administration. The serum concentration-time curve of M 1 was polyphasic and exhibited a prolonged terminal phase with a half-life of approximately 110 h. Despite the long terminal half-life M 1 could not be detected in urine later than 72 h after administration. The activity of the angiotensin converting enzyme in plasma was completely suppressed for up to 12 h, and 72 h after dosing 50% inhibition of the enzyme was still observed.

Pharmacokinetics of pheniramine (Avil) and metabolites in healthy subjects after oral and intravenous administration.

The pharmacokinetics of pheniramine and its two metabolites (N-desmethyl pheniramine and N-didesmethyl pheniramine) were determined in six healthy male subjects after intravenous (n = 3) or oral (n = 3) administration (30.5 mg of pheniramine - free base). Serum and urine levels were measured by HPLC. After i.v. administration, serum concentrations of pheniramine between 231 and 894 ng/ml were reached and after oral administration peak serum concentrations between 173 and 274 ng/ml were reached after 1-2.5 h. AUC values up to 72 h were 3035-4662 (i.v.) and 3507-5768 (ng/ml X h) (oral). The terminal half-lives were estimated to range between 8 and 17 h (i.v.) and 16 and 19 h (oral). Serum levels of the N-desmethyl derivative remained very low (up to 21 ng/ml), but were still detectable after 72 h. Serum levels of the N-didesmethyl derivative were below the detection limit. The amount of pheniramine excreted in the urine for up to 120 h varied between 5.7 and 11.6 mg and 10.2 and 13.2 mg after i.v. and oral administration respectively. Unlike the serum, considerable fractions of the drug occurred as metabolites in urine. Values were 8.1-16.4 mg (i.v.) and 7.4-13.3 mg (oral) for N-desmethyl pheniramine, 0.4-2.9 mg (i.v.) and 0.2-0.8 mg (oral) for N-didesmethyl pheniramine.

Bioavailability and pharmacodynamics of a sustained-release glibenclamide product (Deroctyl) in comparison to a standard tablet formulation (Euglucon, Daonil).

Pharmacodynamics and tolerance, as well as the bioavailability of two oral dosage forms of 5 mg glibenclamide were determined in eight healthy male volunteers in a double-blind crossover study. These preparations were Euglucon (regular tablets) and Deroctyl (sustained-release capsules). Blood glucose levels were determined by the hexokinase method and serum glibenclamide, insulin, and C-peptide levels by radioimmunoassay. Following Deroctyl both the rate and extent of absorption of glibenclamide and therefore its serum levels were much lower than that observed after the same dose of Euglucon. The differences between Cmax, AUC0-4, AUC0-8, and AUC0-24 were statistically significant. For glucose, only Cmin values were found to be significantly lower following Euglucon. For insulin AUC0-8 and AUC4-8 values and for C-peptide AUC0-4 and AUC0-8 values were found to be significantly greater following Euglucon. A single oral dose of either preparation was well tolerated and no side effects occurred. It is concluded that Derocytl is not bioequivalent to Euglucon: its relative bioavailability is only 62.5% (AUC0-24).

Single-dose pharmacokinetics of temocapril and temocapril diacid in subjects with varying degrees of renal impairment.

OBJECTIVE: The aim of this study was to determine the influence of renal impairment on the single-dose pharmacokinetics of temocapril and its pharmacologically active metabolite, temocapril diacid. METHODS: A single oral dose of 20 mg temocapril hydrochloride was given after an overnight fast to eight healthy (control) subjects (group A, n = 8) with a mean baseline creatinine clearance (CLCR) of 115.2 ml.min-1 and to three groups of patients with decreased renal function (mean CLCR 56.9 ml in group B, n = 8, 30.0 ml.min-1 in group C, n = 8 and 15.4 ml.min-1 in group D, n = 5). RESULTS: The mean peak concentration and median time to peak concentration for both temocapril and its diacid metabolite as well as the man area under the curve (AUC0-infinity) for temocapril did not differ significantly between groups. The mean AUC0-infinity for temocapril diacid increased only two- to threefold from group A to D. The mean terminal elimination half-life (t1/2) for temocapril diacid was prolonged in subjects with impaired renal function. However, prolongation of mean t1/2 and increase in AUC0-infinity did not parallel the decrease of mean renal clearance for temocapril diacid. CONCLUSION: The results suggest the existence of an alternative pathway in addition to the renal excretion of temocapril, e.g. via the bile. This pathway substantially contributes to the elimination of the active metabolite, temocapril diacid, in patients with decreased renal function. Nonetheless, to avoid any risks, the dose of temocapril hydrochloride in patients with moderate to severe renal impairment should be reduced.

Effects of the new angiotensin-converting enzyme inhibitor, ramipril, in patients with essential hypertension.

The antihypertensive and hormonal effects of the new angiotensin-converting enzyme (ACE) inhibitor, ramipril, were assessed by means of a single-blind trial in ten unselected patients with mild-to-moderate essential hypertension. After a 2-week period on placebo, 5 mg ramipril was administered once daily for 2 weeks. Blood pressure returned to normal in five patients and decreased in the remaining patients, without significant changes in heart rate or orthostatic hypotension. A fall in blood pressure was apparent within 1-2 h of the first dose; the maximum decrease was reached at 4-6 h and a fall in pressure was still detectable after 24 h. At 24 h post dose angiotensin-converting enzyme activity was suppressed to 40% of the baseline. Blood pressures for the 10 h interval post dosing showed smooth through-the-day control with minimal peak/trough difference in lowering effect. The magnitude of the blood pressure decrement achieved with the inhibitor did not correlate with baseline renin levels or the rise in renin following treatment. No side-effects were noted during the 2-week observation period. The study demonstrates that ramipril, given in a once-daily regimen over a period of 2 weeks, is well tolerated and provides smooth and effective blood pressure control throughout the 24-h interval between doses.

Comparison of temocapril and atenolol in the long-term treatment of mild to moderate essential hypertension.

This 1-year, dose-titration, General Practitioner (GP) study compared efficacy, tolerability and safety of oral temocapril (10-40 mg once daily) with atenolol (25-100 mg once daily) in mild to moderate adult hypertensives (diastolic blood pressure (DBP) 95-114 mmHg). A 12-week dose-titration period, randomized 3:1 temocapril: atenolol, preceded 40 weeks long-term treatment. An intent-to-treat population of 472 patients was analysed for efficacy after 12 weeks dose-titration. Sitting DBP fell significantly (p < 0.001) in both groups, by mean +/- standard deviation (SD) 15.9 +/- 5.7 mmHg on temocapril and by 16.6 +/- 5.9 mmHg on atenolol. Therapeutic equivalence was demonstrated using the two one-sided t-tests procedure according to Schuirmann (equivalence interval [theta 1 - theta 2] < or = 5 mmHg). Responders (DBP < or = 90 mmHg) represented 89.9% of temocapril and 94.0% of atenolol patients. The lower doses were effective in 70.9% of temocapril patients (10 or 20 mg) and in 63.7% of atenolol patients (25 or 50 mg), these doses being continued after the dose titration period. No clinically relevant changes in haematological, biochemical and urinalysis variables occurred. Adverse events were few, largely unrelated to treatment and comparable between groups. In conclusion, temocapril and atenolol proved to be therapeutically equivalent antihypertensives.

Tolerance and pharmacodynamics of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) in healthy volunteers.

In healthy volunteers a single oral dose of 5 mg 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) was well tolerated. Following 5 mg Hoe 498 plasma angiotensin converting enzyme (ACE) activity was inhibited by almost 100% up to 8 h. A marked effect on plasma ACE was observed for more than 8 days. Plasma renin activity increased whereas aldosterone plasma levels decreased only slightly. Sodium and potassium excretion was not influenced by the compound. Systolic and diastolic blood pressure was slightly lowered by Hoe 498, whereas no relevant changes in pulse rate were observed.

Pharmacokinetic aspects of the interaction between clobazam and cimetidine.

The pharmacokinetic interaction between clobazam and cimetidine was studied in 9 healthy male volunteers in an open-labelled study. After a single oral dose of clobazam 30 mg, a wash-out period of 14 days was followed by daily doses of cimetidine 1 g for one week. Thereafter a single oral dose of clobazam 30 mg was again given. The plasma concentrations of clobazam and its main metabolite N-desmethyl-clobazam were measured by gas-chromatography. The area under the curve (AUC0-infinity) of plasma clobazam level was significantly larger after pretreatment with cimetidine and the elimination half life of clobazam was significantly longer. There were no statistically significant differences in Cmax and tmax for plasma clobazam. The plasma levels of N-desmethyl-clobazam did not show any significant change after the intake of cimetidine.