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Biomedical subjects

K Dickstein

Publications and source records attributed to K Dickstein.

102 records · Page 6Linked to original sources
PubMed1987

The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.

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.

Administration, Oral↗
PubMed1986

Acute hemodynamic and hormonal effects of lisinopril (MK-521) in congestive heart failure.

The acute hemodynamic and hormonal effects of the oral angiotensin-converting enzyme (ACE) inhibitor lisinopril (MK-521) were assessed over a period of 96 hours in 12 patients with heart failure. This compound is the lysine analogue of enalaprilat (MK-422), is biologically active following absorption, and is cleared via the urine without any known metabolic transformation. Single doses of lisinopril, ranging from 1.25 mg to 10 mg, were administered on days 1 and 3, each followed by 48 hours of intensive hemodynamic observation. Across all doses, maximal reductions in mean arterial pressure (17.2%), mean pulmonary capillary wedge pressure (28%), and systemic vascular resistance (25.6%) were observed compared to baseline values. No significant changes in heart rate were recorded. Arterial blood was sampled at frequent intervals for angiotensin II, ACE activity, plasma renin activity, renin substrate, plasma aldosterone, and serum drug levels. Right atrial blood was sampled simultaneously for angiotensin I, thus permitting assessment of the degree of pulmonary conversion to angiotensin II. The results indicate potent inhibition of the renin-angiotensin-aldosterone system along with hemodynamic efficacy over a period exceeding 24 hours. Frequent clinical follow-up on long-term chronic therapy has revealed no adverse experience.

Adult↗
PubMed1986

Pharmacokinetics of enalapril in congestive heart failure.

The pharmacokinetics of the converting enzyme inhibitor enalapril were studied in an open, randomised, balanced crossover design in 12 hospitalised 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 10 mg orally, enalapril 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72-hour period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of both enalapril and enalaprilat. 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, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normal subjects, with differences less than 10%. The rates 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 hours in CHF compared with 4 hours in normal subjects. The maximal hypotensive responses were similar for all three treatments, although the onset of action was rapid following intravenous enalaprilat. It is concluded that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

A double-blind multiple crossover trial evaluating a transdermal nitroglycerin system vs placebo.

Fifty-six patients with angina pectoris on effort participated in a 28-day study comparing a transdermal nitroglycerin system (TNS) against placebo. The protocol was based on a regular double-blind multi-crossover pattern. The variables recorded included daily sublingual nitroglycerin requirement, daily anginal attack frequency, and a subjective patient evaluation of each day on a visual analog scale. TNS dosage ranged from 10 cm2 (5 mg per 24 h) to 60 cm2 (30 mg per 24 h) based on the patient's dosage prior to commencement of the study. All other medication was continued unchanged. The results demonstrate improvement on active therapy in the patient group using greater than or equal to 20 cm2 TNS whereas no significant improvement in patients using 10 cm2 TNS was seen. In the higher dose group, the mean number of daily anginal attacks was 2.5 on placebo and 1.4 on active therapy (P less than 0.0001). Corresponding mean daily sublingual nitroglycerin requirement was 3.6 on placebo and 2.3 on active therapy (P less than 0.0001). Although TNS therapy was associated with significant improvement in the group using the higher dosage, the results suggest the development of tolerance on active therapy. The possibility of rebound effect and the absence of demonstrable efficacy in the low dose group require further investigation.

Administration, Topical↗
PubMed1984

Acute and chronic hemodynamic effects of enalapril (MK-421) in congestive heart failure.

Enalapril, a new long-acting angiotensin-converting enzyme inhibitor, was administered orally to 12 patients with stable congestive cardiac failure, NYHA function class III-IV. Acute and chronic hemodynamic effects were evaluated in addition to clinical response. The results of this open pilot study indicated marked reduction of pulmonary capillary wedge pressure from 21.8 +/- 5.9 mm Hg (mean +/- 1 SD) to 13.3 +/- 4.5 mm Hg (P less than 0.01) and peripheral resistance from 1837 +/- 860 dynes X sec-1 X cm-5 to 1063 +/- 584 dynes X sec-1 X cm-5 at 6 hr (P less than 0.01). Well-tolerated hypotension with mean arterial pressure from 88.0 +/- 11.6 mm Hg to 73.1 +/- 11.7 mm Hg at 6 hr (P less than 0.01) was recorded. No significant increase in cardiac output was observed. Angiotensin-converting enzyme activity was powerfully inhibited at the time of peak hemodynamic effect from 25.3 +/- 9.8 U/ml to 4.9 +/- 3.4 U/ml (P less than 0.01) and sustained, but attenuated reduction at 24 hr (8.7 +/- 4.7 U/ml) was observed. All patients reported subjective improvement and this clinical improvement has been sustained during follow-up from 19 to 21 months although baseline hemodynamic parameters at chronic re-catheterization did not demonstrate significant improvement. The pharmacodynamics and toxicity of enalapril as compared to captopril are discussed. The long half-life, low toxicity and gradual onset of action are seen as representing a clinical advantage with regard to patient therapy.

Aged↗
PubMed1984

Acute and long-term response to enalapril in congestive failure.

Enalapril, a novel long acting angiotensin converting enzyme (ACE) inhibitor, was given orally to 12 patients with chronic heart failure (NYHA functional class III and IV) and cardiomegaly. The optimal dose averaged 17 mg given once-daily. Heart rate, systemic arterial blood pressure, pulmonary arterial pressure, right and left ventricular filling pressures and cardiac index were monitored during dose efficacy titration. Eleven patients were recatheterised 3 months later. After stabilisation of cardiac filling pressures, all patients had left ventricular filling pressures in excess of 20 mmHg. Enalapril increased cardiac index acutely by 34% but at 12 weeks follow-up, cardiac index was not different from control levels. Left ventricular filling pressure was reduced acutely by 36% and by 41% at 3 months. Heart rate, systemic arterial and right atrial pressures and plasma concentrations of aldosterone were reduced during the observation period. ACE activity was inhibited at the time of peak haemodynamic effect from 25.3 +/- 9.8 to 4.9 +/- 3.4 U/ml (P less than 0.01). Renin was markedly elevated. These changes were accompanied by marked and sustained clinical improvement and subjective well-being.

Aged↗
PubMed1984

Acute hemodynamic and hormonal effects of MK-521 in congestive heart failure.

The acute hemodynamic and hormonal effects of the oral angiotensin converting enzyme (ACE) inhibitor MK-521 were assessed over a period of 96 hours in 6 patients with heart failure. This compound is the lysine analogue of enalapril diacid (MK-422) and is biologically active following absorption. Dosages ranging from 1.25 mg to 5.0 mg were administered on days 1 and 3, followed by 48 hours intensive hemodynamic observation. Marked reduction in mean arterial pressure (25.2%), pulmonary capillary wedge pressure (47.3%), and systemic vascular resistance (34.5%) was observed. Arterial blood was sampled at frequent intervals for angiotensin I (AI), angiotensin II (AII), plasma renin activity, renin substrate, plasma aldosterone, urinary aldosterone, ACE activity, and serum drug levels. Right atrial blood was sampled simultaneously for AI and AII thus permitting reliable assessment of the degree of pulmonary conversion to angiotensin II. Prolonged inhibition of the renin-angiotensin-aldosterone system was confirmed and corresponded to drug concentration. The results indicate hemodynamic efficacy and potent ACE inhibition over a period exceeding 24 hours.

Adult↗
PubMed1983

Successful management of severe congestive cardiac failure with enalapril.

The new angiotensin-converting enzyme inhibitor enalapril (MK-421) was administered to a patient with severe congestive cardiac failure. Dramatic and sustained symptomatic and hemodynamic improvement is reported. The possible clinical significance of this agent's favorable profile is briefly discussed.

Dipeptides↗
PubMed1983

Sustained haemodynamic effects of enalapril in left ventricular failure.

Enalapril, a novel angiotensin converting enzyme inhibitor, was given orally to 12 patients with chronic heart failure (NYHA functional class III and VI) and cardiomegaly. Heart rate, systemic arterial blood pressure, pulmonary arterial pressure, right and left ventricular filling pressures and cardiac index were monitored during dose efficacy titration. The optimal dose averaged 17 mg given once-daily. All patients were recatheterized three months later. After stabilization of cardiac filling pressures, all patients had left ventricular filling pressures in excess of 18 mmHg. Enalapril increased cardiac index acutely by 34% but at 12 weeks follow-up, cardiac index was not different from control levels. Left ventricular filling pressure was reduced acutely by 36% and by 41% at three months. Heart rate, systemic arterial and right atrial pressures and plasma concentrations of aldosterone were reduced during the observation period. Renin was markedly elevated. These changes were accompanied by marked and sustained clinical improvement and subjective well-being.

Aged↗
PubMedDate not supplied

Moexipril as add-on therapy to hydrochlorothiazide in moderate to severe hypertension.

This double-blind study was conducted to investigate the efficacy, safety and tolerability of three dose levels of moexipril in comparison to placebo as add-on therapy to hydrochlorothiazide (HCTZ) in patients with moderate to severe hypertension. Two hundred patients who did not respond adequately to a 4-week monotherapy with HCTZ-sitting diastolic blood pressure between 95 and 114 mm Hg- entered the 8-week double-blind period. Patients were randomized to once daily placebo or moexipril 3.75, 7.5 or 15 mg as add-on therapy to open-label HCTZ 25 mg. At biweekly visits, blood pressure and heart rate measurements were obtained and the occurrence of adverse experiences was documented. At the 8-week endpoint, adjusted mean reductions from baseline were significantly (p = 0.003) greater in patients receiving moexipril 3.75, 7.5 and 15 mg compared to placebo (-8.4, -8.8 and -8.9 vs. -4.6 mm Hg). No significant differences between the three dose levels of moexipril could be observed. Moexipril was generally well tolerated. The most frequently reported adverse events for moexipril and placebo were headache, flu syndrome and dizziness (6, 7, 5 vs. 4, 0, 4%). The results indicate that the combination of moexipril and HCTZ is a clinically valuable combination in the treatment of patients with moderate to severe hypertension.

Administration, Oral↗