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The dose-response curve for benazepril, a new angiotensin-converting enzyme inhibitor, has been established from a systematic series of controlled clinical studies in patients with mild to moderate essential hypertension. The studies included a dose-ranging study, four dose-response studies (placebo-controlled or crossover), and four titration trials. The dose-response studies involved 803 patients and evaluated doses from 2 to 80 mg. Analysis of the data revealed the existence of a dose-response relationship over the dosage range of 10 to 80 mg given once daily. Efficacy of once-daily administration was shown by the persistence of significant blood pressure reduction over the 24-h dosing interval. In addition, the net trough-to-peak ratio (an indicator of net antihypertensive effect at the end of the dosing interval) was generally greater than 50%. The dose-determination studies with benazepril were conducted according to a well-designed strategy in which parameters were carefully defined. Based on these trials, the initial dosage for benazepril appears to be 10 mg once daily. Additional response may be observed at dosages up to 80 mg once daily.

Benazepril, a newer angiotensin-converting enzyme inhibitor, has been evaluated for the treatment of mild to moderate hypertension in patients 55 years of age and older. The results of the clinical trials conducted to date indicate that benazepril provides effective antihypertensive therapy in this population, with efficacy comparable to that demonstrated in younger patients. Benazepril does not produce precipitous decreases in diastolic blood pressure following the initial dose, and is well tolerated by the elderly. It has a safety profile similar to that of placebo and generally better than that of hydrochlorothiazide.

Enalapril is an effective agent in the treatment of mild to severe hypertension. It is equally effective in elderly and young adult patients but appears to be more effective in white than in black hypertensive patients. Following treatment with enalapril, an assessment of maximum exercise performance found a decrease in total peripheral resistance without significant changes in cardiac output, heart rate, or stroke volume compared with pretreatment values. In addition, there have been reports of reversal of left ventricular hypertrophy in enalapril-treated hypertensive patients. Enalapril is also effective and well tolerated in hypertensive patients with renal impairment of varying etiology. The most common adverse experiences reported in controlled clinical trials were headache (5.2%), dizziness (4.3%), and fatigue (3.0%). In high-risk hypertensive patients, no enalapril-treated neutropenia, proteinuria, dysgeusia, or ageusia were reported. It may be concluded that the benefit-to-risk ratio of enalapril is among the best of the antihypertensive therapies currently available.

Background We deal with genetic complexity through population structure to reduce the number of markers, condition case/control study results and combat the confounding influence of genetic heterogeneity and minor locus effects. This abstract describes the screening of patient genomes to construct a DNA based test for measuring Taxol/Carboplatin response proclivities. Methods Pan genome maps of Ancestry Informative Markers to estimate individual biogeographical ancestry admixture for patient samples, integrated with a case/control design were used to screen the genome. Results Taxol/Carboplatin response was associated with Haplotypes in 3 xenobiotic metabolism genes and a few other SNPs. Integrating ancestry and gene-specific features enabled construction of a classification method for predicting Taxol/Carboplatin response proclivities that is capable of relatively sensitive, specific and powerful performance in “blind” sample classification trials. Conclusions When gene haplotype and SNP associations are viewed through the lens of biogeographical ancestry admixture, pattern emerges that enables relatively accurate classification of patient response proclivities to Taxol/Carboplatin in ovarian cancer patients. Clinical Pharmacology & Therapeutics (2005) 77, P61–P61; doi: 10.1016/j.clpt.2004.12.124

A prodrug of methyldopa, the pivaloyloxyethyl (POE) ester, was administered orally to healthy human volunteers at doses equivalent to 500 and 1000 mg of methyldopa and was compared to oral and intravenous doses of methyldopa. The time courses of availability of methyldopa to the general circulation were compared and contrasted with the model-independent estimates of total systemic availability. The POE ester of methyldopa is completely hydrolyzed on the first pass; delivery of methyldopa to the general circulation was faster, more uniform, and more extensive compared to orally administered methyldopa. The systemic availability of methyldopa averaged 64% of the dose with a coefficient of variation (CV) of 15% for the prodrug treatments compared to 27% of the dose with a CV of 63% for methyldopa. First-pass metabolism of drug to the mono-O-sulfate conjugate of methyldopa was lower for the POE ester than for methyldopa.

To investigate whether dopamine plays a role in the regulation of aldosterone secretion during long-term blockade of the renin-angiotensin system, we studied the effect of metoclopramide, a competitive antagonist of dopamine, in 6 patients with essential hypertension chronically treated with the angiotensin converting enzyme inhibitor enalapril. All but one of these patients received a diuretic in addition to enalapril. Six hours after the daily morning dose of enalapril (10-40 mg p.o.) a 10 mg bolus dose of metoclopramide was injected intravenously. In one patient a hypotensive episode developed following metoclopramide administration. In the 5 other patients plasma aldosterone significantly rose within 30 min after metoclopramide from 51 +/- 8.7 to 128.2 +/- 29.2 pg/ml. This metoclopramide-induced release of aldosterone occurred in the absence of concomitant changes in circulating angiotensin 11, potassium and ACTH levels. Metoclopramide given during chronic blockade of the renin-angiotensin system caused anxiety and agitation in 2 patients. The increase in plasma aldosterone following competitive dopamine blockade in the face of chronic angiotensin converting enzyme inhibition, unchanged plasma potassium and ACTH levels strongly suggests that in hypertensive patients, dopamine exerts a direct inhibitory effect on aldosterone secretion.

A reproducible model of platelet rich thrombi was produced in canine arteries by a previously described technique of intravascular insertion of metal tubing. The effect of platelet suppressants including sulfinpyrazone and ticrynafen, a clofibrate analog, on the rate and nature of thrombus formation was studied. ADP and epinephrine induced platelet aggregation of the animal's platelet rich plasma was monitored during the experiment. Platelet aggregation was impaired after the intravenous administration of either sulfinpyrazone (30 mg/kg body weight) or ticrynafen (100 mg/kg body weight). The rate of thrombus formation was not significantly altered by sulfinpyrazone when compared to the control, but histochemically, the thrombus studied showed a greatly diminished platelet content. In contrast, ticrynafen was able to prevent a complete occlusion of the involved vascular segment and a weak thrombus composed mostly of fibrin was produced instead. This effect of ticrynafen was dose related with minimal changes observed at a dose of 75 mg/kg. The results suggest that this arterial thrombosis model is of value in evaluating antithrombotic agents. They also indicate a potential value of ticrynafen as a therapeutic agent which should be further studied.

Thrombocytopenia complicating heparin therapy is always alarming since the bleeding risk is greatly increased. The observations of Bell et al (Ann Int Med. 85:155, 1976) of a 30% incidence of thrombocytopenia in patients receiving bovine lung heparin was not supported by later reports from Powers et al (JAMA 241:2396, 1979) of only 3.4%. However, the latter study involved the use of heparin prepared from porcine gut mucosal. A prospective randomized study of these two respective heparin preparations was carried out at the VA Lakeside Medical Center on 98 patients to whom heparin therapy was given for the treatment of various forms of thromboembolism. All received a heparin dose that prolonged the activated partial thromboplastin time to l1/2-21/2 times the control level for at least 5 days. 86 patients had heparin for 7 or more days. The observation of platelet counts was carried out for 7 days. 10 patients (10.2%) had a fall in their platelet counts to less than 150×l06/dl during therapy with one of the ten having a platelet count of 95×l06/dl on the 4th day of therapy. All but one of the thrombocytopenias were transient, lasting 1-6 days despite continuation of heparin therapy. Of 49 patients who received porcine heparin, 4 (8.2%) had thrombocytopenia while the incidence was 6 out of 49 (12.2%)in those who received bovine heparin. These results suggest that complications of severe thrombocytopenia are uncommon with heparin derived from both sources.

Enalapril is administered as the ethyl ester of the potent angiotensin converting enzyme (ACE) inhibitor enalaprilat. As such, it is 60% absorbed and 40% bioavailable as the active species. Absorption is not affected by food. Serum concentrations are proportional to dose, less a small drug residue apparently bound to the enzyme. The half-life for accumulation is approximately 11 h. The drug is eliminated by the kidney without further metabolism. Maximum inhibition of plasma ACE occurs 2-4 h after administration and persists for more than 24 h with clinical doses. ACE inhibition is associated with increases in plasma renin and angiotensin I levels, decreases in angiotensin II and aldosterone concentrations and reduction in blood pressure. All of these events are closely correlated when analysed statistically. The clinical and haemodynamic effects of these actions are addressed in other papers.

In a crossover study, the pivaloyloxyethyl ester (POE) of methyldopa, labeled either with 3H in the methyldopa moiety or 14C in the pivalic acid moiety, was administered orally to four volunteers in 1000-mg single doses (equivalent to 500 mg of methyldopa). The majority (93%) of either the 3H- or 14C-labeled dose was excreted in the urine. Methyldopa, which was assayed by a fluorometric technique, peaked (approximately 6 micrograms/ml) at 1 hr in the plasma. Forty-five per cent of the dose was excreted as methyldopa as opposed to 18% normally seen after oral methyldopa dosages. Intact POE was absent in the urine of three volunteers and present in only trace amounts in urine from a fourth volunteer. Thus, the oral dose of POE was well absorbed and rapidly hydrolyzed to methyldopa. After oral administration of methyldopa, methyldopa sulfate is the principal urinary metabolite in man. However, after administration of POE, a relatively small fraction (13%) of the dose was excreted as methyldopa sulfate. The major urinary metabolite of POE, other than methyldopa, was 3-OCH3 methyldopa. Methyldopamine was a minor metabolite. It was concluded that a shift from sulfation to methylation occurred in the metabolic profile of methyldopa when it was administered as POE and that the metabolites of POE (including conjugated pivalic acid) were rapidly eliminated from the body.

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.

The kinetics of atrial natriuretic peptides (ANP) and the kinetic profile of their effect on blood pressure and renal hemodynamic and electrolyte excretion were investigated in 20 salt-loaded healthy volunteers during and after constant rate infusion. At steady state, mean plasma concentrations of ANP were measured at 210, 430, and 2990 pg/ml and mean systemic clearance was 2.6, 2.5, and 1.7 L/min for ANP infusion rates of 0.5, 1, and 5 μg/min, respectively, which corresponds to the clearance rate of other vasoactive peptide hormones. The apparent volume of distribution averaged 17 L and the mean half-life was 4.5 minutes. ANP induced dose-related effects on systemic and renal hemodynamic, as well as urinary electrolyte excretion, albeit with a time lag between onset and full effect. Clinical Pharmacology and Therapeutics (1987) 41, 671–677; doi:10.1038/clpt.1987.94

This study was undertaken to evaluate whether, after long-term enalapril administration tachyphylaxis to the blockade of angiotensin II (Ang II) generation occurs. After a mean follow-up of 24 months, six patients taking enalapril once daily with or without an associated diuretic were studied for 7 h in hospital. Blood pressure, heart rate, plasma converting enzyme activity, angiotension I (Ang I), Ang II and aldosterone were measured before and 2, 4 and 6 h after the morning dose of enalapril. While blood pressure remained unchanged after drug administration, Ang II and aldosterone levels fell following enalapril to very low levels, similar to those observed during the initial study, at the time of peak effect of enalapril. After enalapril administration, there was no correlation between plasma Ang I and Ang II suggesting that blockade of Ang II generation was complete, excluding the possibility of Ang I related interference with the Ang II measurements. These results indicate that virtually complete angiotension converting enzyme inhibition can still be achieved after prolonged use of enalapril.