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1 Captopril (SQ14,225), an orally active inhibitor of angiotensin- converting enzyme, was administered to nine patients with essential hypertension. Plasma renin activity (PRA) was low in four, 'normal' in three and high in two patients. 2 In the hospital, captopril alone induced a significant drop in BP from 165 +/- 6/106 +/- 2 to 140 +/- 5/90 +/- 1 mmHb (P less than 0.001). PRA increased concomitantly (P less than 0.05), whereas plasma-converting enzyme activity (P less than 0.005) and plasma aldosterone (P less than 0.05) were reduced. 3 Six patients underwent chronic ambulatory therapy with captopril for a mean of 16 +/- 3 weeks. After discharge from the hospital, BP remained normalized but in five out of six patients this required additional diuretic therapy. 4 The results suggest that captopril alone or combined with diuretic therapy provides a new, efficient and well tolerated tool to treat patients with essential hypertension independently of their PRA level. It may turn out to be more effective in lowering BP than beta-adrenoceptor-blocking agents. [ABSTRACT FROM AUTHOR]

1 Nadolol was administered intravenously to five hypertensive patients and three healthy volunteers in balance on a 10 mEq sodium intake. 2 Nadolol (0.3-10.0 micrograms/kg) induced a significant, dose-related increase in renal blood flow, measured with radioxenon, with a maximum increase of 72 +/- 4 ml/100g/min (26%) at 3.0 micrograms/kg. 3 Heart rate and plasma renin activity decreased significantly over the same dose range. 4 The renal vascular response to nadolol contrasts sharply with those found with other beta-adrenoceptor-blocking agents. 5 The magnitude of the increase in renal blood flow, its time-course and the parallel fall in plasma renin activity raise the possibility that the renal vasodilation reflects the reversal of angiotensin's influence on the renal arterial bed. [ABSTRACT FROM AUTHOR]

The S-methyl metabolite of captopril was identified and determined in human plasma by positive chemical ionization selected-ion monitoring gas chromatography-mass spectrometry. After oral administration of 100 mg of captopril to healthy subjects, the maximum plasma level was 60-114 ng/mL. These data for the S-methyl metabolite of captopril were correlated to total and unchanged captopril levels. Captopril--identification and determination of the S-methyl metabolite in human plasma, gas chromatography-selected-ion monitoring mass spectrometry Gas chromatography-selected-ion monitoring mass spectrometry--determination of the S-methyl metabolite of captopril in human plasma after oral administration.

14C-Captopril was given intravenously to four normal subjects in a 4-mg priming dose followed by constant intravenous infusion of 1.7 mg/hr for 3.5 hr with and without concomitant probenecid. Steady-state levels of unchanged captopril were obtained between 1.5 and 3.5 hr. In the presence of probenecid, the average steady-state blood levels of total radioactivity were higher (36%) than on captopril alone. Unchanged captopril levels were slightly higher (14%) in the presence of probenecid. Kinetic evaluations were carried out exclusively on data for unchanged captopril. The average total body clearance (ClT) and renal clearance (ClR) of captopril in the absence of probenecid were 775 and 388 ml/kg/hr. The corresponding values for captopril with probenecid (631 and 217 ml/kg/hr) were lower. The average ratio of ClR to ClT for captopril alone was 0.50 and fell to 0.35 in the presence of probenecid. When captopril alone was given, a minimum of 78% of the renal excretion of captopril during steady-state could be attributed to net tubular secretion, but when captopril was given with probenecid, net tubular secretion was only 56%. The volume of distribution of captopril during steady state was not altered by probenecid. For the first 3.5 hr, cumulative renal excretion of total radioactivity with and without probenecid was 55% and 60%, but cumulative excretion of unchanged captopril was higher after captopril alone (36% of dose) than after the combination (21% of dose).

Captopril is liberated from covalently protein-bound disulfides and other disulfide metabolites in human plasma by reduction with tri-n-butyl-phosphine. The captopril is then treated with N-ethylmaleimide, purified on XAD-2 resin, eluted with ethyl acetate, and methylated prior to its determination by gas chromatography-mass spectrometry with selected-ion monitoring. The limit of detection is 20 ng/mL of plasma.

By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)

We investigated the antihypertensive effect of the angiotensin converting-enzyme inhibitor SQ 14225 in 12 hypertensive patients for periods of three to 24 weeks. Blood pressure decreased in all patients (from 177 +/- 8/110 +/- 2 to 136 +/- 6/88 +/- 2 mm Hg--mean +/- S.E.); oral doses ranged from 400 to 1000 mg daily. Concomitant effects noted were small increases in plasma potassium concentration and pulse rate. One patient experienced a transient febrile reaction. Plasma renin activity rose during treatment, plasma aldosterone decreased, and angiotensin-converting-enzyme activity was virtually eliminated. There was no significant correlation between pretreatment plasma renin activity and degree of blood-pressure fall with SQ 14225. The exact mechanisms contributing to the blood-pressure-lowering effect of this agent remain unclear. SQ 14225 is a promising new antihypertensive agent, effective in patients refractory to traditional medical therapy.

Azthreonam, a monocyclic beta-lactam highly active against aerobic gram-negative bacteria in vitro, was administered to four groups of nine healthy male volunteers in the following four regimens: 500 mg intravenously (i.v.) over 2 min every 8 h, 1,000 mg i.v. over 2 min every 8 h, 500 mg intramuscularly (i.m.) every 8 h, and 1,000 mg i.m. every 8 h for 7 days. Serial samples of serum and urine were assayed by microbiological methods, and urine samples collected during the high-dose i.m. regimen were assayed by a high-pressure liquid chromatographic procedure. Mean peak serum levels were 39 and 99 micrograms/ml after the initial i.v. doses and 18 and 39 micrograms/ml after the initial i.m. doses. There was no evidence of drug accumulation. Mean serum trough levels were 1.0 and 2.5 micrograms/ml during the two i.v. regimens and 1.8 and 3.8 micrograms/ml during the two i.m. regimens. The mean difference among Cmax, area under the curve from 0 to 8 h, and urinary recovery at 0 to 8 h on days 1 and 8 was less than 13% for each regimen. From the i.v. study, the mean steady-state volume of distribution was 0.21 liter/kg, the terminal half-life was 1.6 h, serum clearance was 1.7 ml min-1 kg-1, urinary recovery was 60%, and serum protein binding was 56%. An average of about 6% of a 1,000-mg i.m. dose was excreted in the 8-h urine collection on day 8 as the open beta-lactam ring hydrolysis product of azthreonam. The concentrations of azthreonam in serum were within the range required to inhibit growth of susceptible organisms in vitro.

Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins. The drug also forms mixed disulphides with endogenous thiol-containing compounds (cysteine, glutathione), as well as the disulphide dimer of the parent compound. These components in blood and urine are measured collectively as total captopril. Because of the reversibility of the formation of these inactive disulphides, total captopril may serve as a reservoir of the pharmacologically active moiety, and thus contribute to a duration of action longer than that predicted by blood concentrations of unchanged captopril. To measure free or unchanged captopril concentrations, a chemical stabiliser must be added to the biological samples to prevent the formation of captopril disulphides ex vivo. In healthy subjects given captopril intravenously, the body clearance of captopril and steady-state volume of distribution were about 0.7 L/h/kg and 0.8 L/kg, respectively. The elimination half-life of unchanged captopril was approximately 2 hours. The primary route of elimination of captopril is the kidney. The renal clearance of unchanged captopril exceeds the glomerular filtration rate, due to active tubular secretion of the drug. In healthy subjects, about 70 to 75% of an oral dose is absorbed and the bioavailability of captopril is approximately 65%. Peak blood concentrations are reached about 45 to 60 minutes after oral administration. The bioavailability of captopril is not altered by age or concomitant medications including diuretics, procainamide, allopurinol, cimetidine or digoxin. However, the co-administration of food or antacids, or probenecid with captopril has been shown to diminish the bioavailability of the latter and decrease its clearance, respectively. The decreased bioavailability of captopril when taken with meals does not significantly alter clinical responses to the drug. Over a wide range of oral (10 to 150 mg) and intravenous doses (2.5 to 10 mg) captopril had linear kinetics in healthy volunteers. In healthy subjects with normal renal function and patients with congestive heart failure given captopril 3 times daily, blood concentrations of total captopril accumulated, whereas those of unchanged captopril did not. Severe renal insufficiency was associated with an accumulation of both unchanged and total captopril.(ABSTRACT TRUNCATED AT 400 WORDS)

Captopril inhibits angiotensin II formation and bradykinin degradation in vivo. Eleven patients with essential hypertension (EH) and four patients with renovascular hypertension (RVH) were treated with captopril for periods ranging from 3 days to 12 months. All patients had a diastolic blood pressure (DBP) over 95 mm Hg after receiving a placebo for 3 days. Captopril given in ascending doses (10-1000 mg/day) caused normalization of blood pressure in all but three patients, one with severe RVH whose pressure fell 11%, one patient with severe EH, whose pressure fell 27%, and one with EH whose blood pressure fell 8.5%. The average control DBP in patients with EH was 113.7 +/- 5.5 (SE) mm Hg and fell to 89.9 +/- 3.6 mm Hg (p less than 0.001), while DBP in patients with RVH fell from 110.7 +/- 7.6 mm Hg to 94.5 +/- 8.2 (p less than 0.005). All patients were studied in balance on a 100 mEq sodium (Na) diet. Plasma renin activity (PRA) versus 24-hour urinary Na excretion increased sevenfold during therapy while converting enzyme activity fell by about one half. The magnitude of the blood pressure response was not related to control PRA. Cardiac output was estimated by echocardiography during placebo administration and during maintenance therapy with captopril. A significant change was not observed. Total peripheral resistance fell an average of 18.9% (p less than 0.05) in 11 of the 13 patients in whom the measurement could be made. It is concluded that captopril effectively lowers blood pressure in patients with EH or RHV by reducing total peripheral resistance.

The disposition of captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100-mg tablet of 35S-labeled drug. Average absorption parameters for unchanged captopril in blood were Tmax 0.93 +/- 0.08 hr and Cmax 800 +/- 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 +/- 0.08 hr and Cmax 1,580 +/- 90 ng/ml (as captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of captopril:time, elimination half-life (t1/2) of unchanged drug could not be determined. At 1 hr unchanged captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24-hr urine sample (66% of the dose) was 58% captopril (38% of dose), 2% captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

Captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was given by mouth and intravenously in 10-mg doses to five healthy subjects. After intravenous dosing, semilogarithmic plots of captopril blood levels : time showed a triexponential decay. Data were analyzed using an open three-compartment model. The average volume of distribution (Vd) was 0.2 l/kg for the central compartment and 2 l/kg for the elimination (beta) phase. The Vd at steady-state was 0.7 l/kg. The total body clearance of captopril averaged 0.8 l/kg/hr and the mean blood half-life during the beta phase was 1.9 hr. In the 0- to 96-hr urine, after intravenous and oral drug, excretion of radioactivity accounted for 87% and 61% of dose. In the 0- to 24-hr urine, averages of 38% (intravenous) and 24% (oral) of the doses were excreted as unchanged captopril. Absolute absorption of the radioactive oral dose was 71% and the absolute oral bioavailability of captopril was 62%.

Plasma levels of nadolol and propranolol following a single 80 mg dose of each beta blocker in the presence and absence of cimetidine were determined in 12 healthy male subjects. Cimetidine increased (p less than 0.01) the area under the plasma concentration-time curve and peak plasma levels of propranolol by 46% and 35%, respectively. Nadolol kinetics were not altered significantly by cimetidine, except for a reduction in time to reach peak concentrations. The higher blood levels of propranolol during administration of cimetidine were not associated with any changes in resting blood pressure or heart rate compared with propranolol alone. Cimetidine had no effect on elimination half-lives or apparent mean residence times for either beta blocker.

1. Captopril or SQ 14 225, administered orally twice a day, reduced the blood pressure of hypertensive patients whatever their clinical diagnosis and even when their plasma renin activity was 'normal' or low. 2. Long-term administration of captopril, either alone or together with diuretics, provides a powerful new tool with which to treat ambulatory hypertensive patients. 3. The renin system may play an important role in maintaining blood pressure in a majority of hypertensive patients.

The pharmacokinetics of captopril were studied in 12 healthy male volunteers aged 65 to 76 years, who each received a single 100-mg oral dose. Blood and urine samples were collected over a 24-hour period, and assayed for unchanged captopril (CAP), S-methylcaptopril (Me-CAP, plasma concentrations from 2 subjects only), and total captopril levels (TOT, a mixture of CAP and its dimer and mixed disulfides with endogenous thiol-containing compounds such as glutathione and cysteine). Mean values for the maximum concentration (Cmax) were 803 and 66.3 ng/mL for CAP and Me-CAP, respectively. Mean time to maximum concentration (tmax) was determined as 1.0, 1.4, and 1.0 for CAP, TOT, and Me-CAP, respectively. Mean areas under the plasma concentration-time curve (AUC) were 1,394 hr-ng/mL (CAP, 0-8 hr) and 17,316 hr-ng/mL (TOT, 0-24 hr). The mean estimated half-life (t 1/2) for CAP was 1.4 hr, and its renal clearance was 187 mL/hr/kg. Mean urinary excretion over 24 hr was 20.8 and 53.1 for CAP and TOT, respectively. Cmax, and AUC for CAP were 9% less and 13% greater, respectively, than in a historical control group of 18-35-year-old men, treated in the same clinic, by the same personnel, using the same analytic procedures, whereas the 24-hour urinary excretion was 25% lower and eight-hour renal clearance 36% lower in the older population. Since the values for Cmax, AUC, and t 1/2 were similar in the two populations, it does not appear that the pharmacokinetics of CAP are altered markedly with age alone.

The antihypertensive effect of the orally active angiotensin-converting enzyme inhibitor captopril (SQ 14225) was assessed in 22 hypertensive patients of whom 17 were followed for periods ranging from 1 to 7 months. Of these, eight had essential hypertension, eight had renovascular hypertension, and six had hypertension associated with chronic renal failure. Blood pressure decreased markedly in all patients, including those with low renin levels. Nevertheless, the magnitude of blood pressure reduction correlated with the base-line plasma renin activity (r = 0.58, P less than 0.01). Increasing the dose of captopril from 25 to 200 mg did not enhance the amplitude of the antihypertensive effect but did increase its duration. Patients' blood pressure remained well controlled and free of side-effects with a maximal daily dose of up to 200 mg by mouth twice daily. Despite the blood pressure reduction, sodium excretion tended to increase, probably because of reduced aldosterone secretion. There was no evidence of orthostatic hypotension, and no escape from the antihypertensive effect was observed. These results indicate that chronic inhibition of the angiotensin-converting enzyme with an orally active compound offers a new, efficient, and well-tolerated approach to the treatment of hypertension.

14C-Captopril was administered as 100-mg tablets to 12 subjects in a two-way crossover study in which subjects were either fasted or were given a standard meal immediately prior to dosing. Based on blood level and urinary excretion data, both the absorption of total radioactivity and the bioavailability of captopril were decreased approximately 35 to 40 per cent after a meal. Whether this moderate decrease in the absorption and the bioavailability of captopril caused by food is of clinical significance has not yet been determined.

The pharmacokinetic characteristics of iodamide, a contrast agent for excretion urography, were studied in seven normal subjects and in 15 patients with various degrees of renal impairment. Two different formulations were administered, namely, a 65% solution (iodamide 300) by slow intravenous injection and a 24% solution by slow intravenous (drip) infusion. Both preparations of iodamide exhibited characteristics of an open two-compartment model. In both normal subjects and patients, the contrast agent was excreted almost exlusively in urine. In normal subjects, the pharmacokinetic parameters of both formulations were similar, with a distribution half-life (1/2alpha) of about 3 minutes and a disposition half-life (t1/2beta) of about 69 minutes. An average of 84 per cent of the dose was excreted in urine within 4 hours after administration of iodamide with net renal tubular secretion of about 38 per cent. The binding of iodamide to plasma proteins was negligible, and the extent of biotransformation of iodamide was minimal. In patients with renal impairment, the disposition half-life (t1/2beta) of iodamide ranged from 4.1 to 16.4 hours. Other changes in pharmacokinetic parameters were also seen in patients with renal impairment.

An orally active inhibitor of the angiotensin-converting enzyme, SQ 14,225 (D-2-methyl-3-mercaptopropanoly-L-proline), was administered to fourteen normal male volunteers to evaluate its safety and efficacy in inhibiting pressor responses to exogenous angiotensin I. SQ 14,225 produced significant blockade within 15 min of oral administration. The magnitude and duration of inhibition were dose-related. After a dose of 20 mg, complete blockade was observed for more than 2 h and partial inhibition for over 4 h. There was no effect on pressor responses to angiotensin II. SQ 14,225 promises to provide a new approach to the diagnosis and treatment of disorders involving over-activity of the renin-angiotensin system.