Meta-analysis of observed mortality data from all-controlled, double-blind, multiple-dose studies of losartan in heart failure. Losartan Heart Failure Mortality Meta-analysis Study Group.

Clinical studies of heart failure utilizing losartan, an angiotensin-II receptor antagonist, found that this drug is well tolerated and demonstrates hemodynamic, neurohormonal, and symptomatic improvement. To assess all-cause mortality in heart failure patients treated with losartan, a meta-analysis including 1,896 patients was performed on 6 controlled, double-blind, multiple-dose studies, regardless of sample size or duration of follow-up. A combination of logarithmic (log) odds ratios with a continuity correction was utilized for the meta-analysis. Treatment groups were comparable with regard to demographic characteristics, heart failure characteristics, and concomitant cardiovascular therapies. Concomitant use of open-label angiotensin-converting enzyme (ACE) inhibitors was not allowed in any study. The mean left ventricular ejection fraction obtained in individual studies ranged from 23% to 31%. Seven hundred forty patients were randomized to control therapy and 1,154 patients were randomized to losartan therapy. There were 36 deaths (3.12%) in the losartan groups compared with 47 in the control groups (6.35%) during the double-blind periods. The odds of dying in the losartan groups were 0.51 times (0.31 to 0.81) that of dying in the control groups (p = 0.004). In this analysis, treatment with losartan provided a beneficial effect upon survival. However, because the number of deaths in these studies is relatively small and the follow-up relatively short, a large confirmatory study is needed to assess the mortality benefit of losartan compared with an ACE inhibitor.

[Seasonal changes in donor's sperm motility: CASA parameters]. / Wyniki komputerowej oceny seminologicznej w grupie dawców nasienia--zmiany sezonowe parametrów CASA.

Computer assisted semen analysis was employed to find out whether there are some changes in movement parameters between autumn-winter and spring-summer time. 473 sperm specimens obtained from 12 sperm donors were analyzed. Statistically significant percentage of motile spermatozoa was higher during spring-summer time.

Pharmacokinetics of intravenous and oral losartan in patients with heart failure.

The pharmacokinetics of a selective AT1-subtype, nonpeptide, orally active, angiotensin II receptor antagonist, losartan, were characterized in 11 patients with heart failure (New York Heart Association class II, n = 6; class III, n = 4; class IV, n = 1) after oral and intravenous administration. In these patients, average plasma clearance of losartan was 566 mL/min, volume of distribution at steady-state was 34 L, and terminal plasma half-life was 1.5 hours. Average bioavailability was 36%. No clinically significant accumulation of losartan or its active metabolite, EXP3174, occurred after multiple-dose oral administration for 7 to 8 days. Terminal plasma half-life of EXP3174 after oral administration of losartan was 7.6 hours. The pharmacokinetics of losartan in patients in this study appear to be similar to those in healthy subjects studied previously.

Losartan in heart failure: preclinical experiences and initial clinical outcomes.

Losartan potassium (Cozaar) is an angiotensin II receptor antagonist (AT1 selective) which has undergone extensive clinical trials for the treatment of hypertension. This literature survey will review some of the pre-clinical findings with losartan in models of heart failure, and where appropriate, we will compare the haemodynamic findings in animals with similar studies completed in patients. The major conclusion from these trials is that losartan has clear haemodynamic benefits in patients in heart failure and that the drug appears to be well tolerated, with a low incidence of adverse experiences related to impaired renal function.

First-dose effects of enalapril 2.5 mg and captopril 6.25 mg in patients with heart failure: a double-blind, randomized, multicenter study. The Enalapril-Captopril Investigators.

Significant decreases in blood pressure (BP) may occur when administration of angiotensin-converting enzyme (ACE) inhibitors is initiated for the treatment of heart failure. The purpose of this study was to compare the safety and tolerability of recommended initial doses of the longer-acting ACE inhibitor enalapril (ENAL) with those of the shorter-acting captopril (CAP) in patients with heart failure who were treated concomitantly with digitalis and diuretic agents. We evaluated BP, serum ACE activity, and clinical status when a low, first dose of ENAL (2.5 mg, n = 59) or CAP (6.25 mg, n = 58) was administered in a double-blind, randomized, and parallel fashion to 117 patients with mild to moderate heart failure. BP and serum ACE activity were measured at 30 min and hourly for 8 hours after drug administration. BP decreases were similar for both groups (mean supine BP -6.2/-4.8 mm Hg for ENAL vs -8.3/-6.4 mm Hg for CAP; mean standing BP -9.2/-5.6 mm Hg for ENAL vs -10.0/-4.7 mm Hg for CAP). Although the maximum mean decrease in BP occurred at hours 4 and 5 in the ENAL group and hours 1 and 2 in the CAP group, considerable between-group overlap was observed for individual patients. Decreases in mean serum ACE activity occurred earlier and were of shorter duration in the CAP group. ENAL significantly inhibited serum ACE activity to a greater extent than did CAP at all time points except the 1st hour. Administration of a first dose of ENAL, 2.5 mg or CAP, 6.25 mg to patients with heart failure was well tolerated.

Enalapril in the treatment of congestive heart failure: effects on signs, symptoms and mortality.

This is a review of the effects of E on the symptoms of CHF which affect patients' (pts) quality of life and the signs associated with pts' prognosis. The review is based on clinical studies which were included in the New Drug Application for Vasotec (enalapril maleate, MSD) in the United States. There were 3 open-label (242 pts) and 4 double-blind, placebo (P)-controlled (661 pts) studies of at least 1 month and up to about 2 years duration. One of these, the CONSENSUS Trial evaluated mortality in 253 pts with class IV CHF. Dyspnea and fatigue are considered the most disabling symptoms causing pts' functional impairment and thus reducing the quality of life. Left ventricular gallop, pulmonary rales, cardiomegaly, and ejection fractions are known to adversely effect pts' prognosis. Evaluations of these signs, symptoms, and scores related to these symptoms were included in most, but not all, studies. The pts' NYHA cardiac status was evaluated in all studies. E alleviated the signs and symptoms of CHF and improved various scores in significant number of pts. Pts' quality of life improved as indicated by the number of pts "feeling better" after Rx with E (p less than 0.01 vs P) in a multinational study of 256 pts; reductions of cardiomegaly and increases in ejection fraction were significantly greater in E than in P treated pts; and in severe CHF (CONSENSUS Trial) the mortality was significantly reduced (p less than 0.003 vs P).

Tolerability of long term therapy with enalapril maleate in patients resistant to other therapies and intolerant to captopril.

Patients with severe hypertension and/or congestive heart failure (n = 281) who were unresponsive to other therapies and intolerant to captopril received enalapril treatment (mean dose 19.5 mg/day) under study conditions as part of a Compassionate Use Program. Many of these patients had serious concurrent disorders known to predispose them to a greater risk of adverse experiences and death. The mean duration of enalapril treatment was 29 weeks, with a range of 1 day to approximately 3.5 years. Enalapril was generally well tolerated, and the estimated long term probability of patients terminating enalapril therapy because of adverse effects was low. 20 patients had discontinued captopril treatment because of low white blood cell counts; during subsequent enalapril treatment these reactions resolved in 14 patients, persisted in 2 patients, and could not be evaluated in 4 patients. Captopril-related proteinuria improved or resolved in 9 and persisted in 2 of 15 patients, taste disturbances resolved in 35 and persisted in 2 of 38 patients; and rash resolved in all but 7 of 178 patients during enalapril treatment. 18 patients (6%) discontinued enalapril treatment because of lack of efficacy; 6 of these 18 patients died due to a progression of heart failure, and another 11 patients died for other reasons. The deaths were considered unrelated to therapy with enalapril. Adverse reactions were the reason for discontinuation of enalapril treatment in 53 patients (19%). The most common adverse experiences that resulted in discontinuation of enalapril were: impairment of renal function (5%), hypotension (2%) and rash (2%). No neutropenia, proteinuria, or new taste disturbances were recorded as reasons for discontinuation.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of a once-a-day versus twice-a-day regimen of enalapril for congestive heart failure.

Although an abundance of short-term clinical trials has evaluated the use of enalapril in congestive heart failure (CHF), there has been a paucity of data regarding the long-term effects of this angiotensin-converting enzyme inhibitor. Moreover, a question has arisen as to whether a once- or twice-daily dosing schedule is preferable. To address these issues, a multicenter trial was conducted with the objective of obtaining long-term (48 weeks) experience with enalapril in 142 patients with CHF. A subgroup of patients (n = 88) were randomized to receive enalapril in a dosing schedule of either 20 mg once daily or 10 mg twice daily. Of the overall group, 96 patients completed the 48 weeks of follow-up. Improvement in New York Heart Association functional class, exercise duration and left ventricular ejection fraction was observed. Improvement in clinical status was seen in 68% of all patients, whereas conditions in 5% worsened with enalapril therapy. The most frequent adverse experiences were dizziness and hypotension. There were no obvious differences between the effects of the once- and twice-daily dosing regimens, with doses of 20 mg/day and 2.5 to 15 mg/day being given to about 70 and 30% of patients, respectively. Enalapril appears to provide well-tolerated and effective long-term therapy for CHF.

High-risk patients treated with enalapril maleate: safety considerations.

The safety of 738 high-risk patients treated with enalapril under various clinical programs was evaluated. High risk was defined as the presence of a collagen vascular disease; a renal disease, including renovascular hypertension; or either hypertension or refractory cardiac failure with serum creatinine greater than or equal to 1.7 mg/dl at baseline. Essential hypertension was the primary diagnosis in most of these patients. Treatment with enalapril in these patients usually continued without interruption for the length of the particular protocol. The incidence of adverse reactions resulting in discontinuation of treatment was comparable to that observed with other standard antihypertensive therapies in patients with milder forms of disease. No enalapril-related neutropenia, proteinuria, dysgeusia or ageusia were reported in these high-risk patients. The incidence of discontinuation due to rash was less than 0.5%. Resolution and/or improvement of captopril-related adverse effects was observed in many patients crossed over to treatment with enalapril. In patients with collagen vascular diseases and those with severe impairment of renal function (serum creatinine greater than or equal to 3.0 mg/dl), the incidence of discontinuation due to adverse experiences or death as well as the profile of reported adverse experiences was similar to those for the total group of high-risk patients. The data suggest that enalapril is efficacious and well tolerated by the high-risk patients.

Effect of intravenous enalaprilat in moderate and severe systemic hypertension.

The antihypertensive effect and tolerability of enalaprilat, an intravenously administered angiotensin converting enzyme inhibitor, was studied in 65 patients with moderate or severe hypertension. In this randomized, double-blind study, enalaprilat was compared with placebo in 42 (22 enalaprilat, 20 placebo) moderate hypertensive (diastolic blood pressure [BP] 100 to 114 mm Hg) patients. It was compared with furosemide in 23 (12 enalaprilat, 11 furosemide) severe hypertensive (diastolic BP 115 to 130 mm Hg) patients. Enalaprilat (1.25 or 5.0 mg), placebo (5% dextrose) or furosemide (40 or 80 mg) was given every 6 hours intravenously up to 48 hours. In the moderate hypertension stratum, the mean supine diastolic BP was significantly (p less than or equal to 0.01) reduced from baseline at all timepoints in the enalaprilat group. These diastolic BP reductions were significantly (p less than or equal to 0.01) greater in the enalaprilat group than the placebo at 1 to 24 hours (-12 vs -4 mm Hg), with 59% of the patients responding to enalaprilat compared with 30% of the patients responding to placebo. An even greater reduction (p less than or equal to 0.01) was seen at 25 to 48 hours (-14 vs -7 mm Hg, with 73% enalaprilat vs 58% placebo responders). Significant (p less than or equal to 0.01) reductions in mean, supine systolic BP were also seen at 1 to 24 hours (-22 vs -2 mm Hg) and 25 to 48 hours (-24 vs -8 mm Hg) during the 48 hours of the double-blind treatment phase in the enalaprilat group compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP+ and paraquat in Rana pipiens.

We demonstrate that injections of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP), 1-methyl-4-phenyl-pyridinium ion (MPP+) and Paraquat (PQ+) produce in Rana Pipiens different behavioral, biochemical and skin pigmentation changes. MPTP causes in frogs the main symptoms of Parkinsonism (rigidity, akinesia and tremor) and it darkens the skin of animals. It also decreases brain and, less so, adrenal medulla dopamine. These effects are blocked by Pargyline. MPP+ causes the same symptoms but more rapidly. In contrast, skin pigmentation is clearly lightened. Brain and particularly adrenal dopamine reserves are nearly abolished. Pargyline increases these effects. Paraquat, in a cumulative fashion, eventually causes the same behavioral changes and a slight increase in pigmentation. It initially produces an increase in brain and adrenal dopamine concentrations, but later a significant dopamine concentration decrease. Pargyline potentiates these long term effects, blocks the dopamine increase, but reverses the PQ+ effect upon melanin, producing the same depigmentation as MPP+ alone.

Long-term enalapril--a new converting enzyme inhibitor--in the treatment of mild to moderate essential hypertension, results of a worldwide multiclinic study. Comparing two ways of analyzing data.

The antihypertensive effect of enalapril maleate, a new converting enzyme inhibitor, was evaluated in a multiclinic, double-blind, randomized study in patients with mild to moderate essential hypertension. The analyses were done in two ways, with patients who violated the entry criteria of the protocol excluded, and according to the intention to treat principle. Enalapril in dosages of 10 to 40 mg daily administered alone or concomitantly with hydrochlorothiazide was compared to propranolol (80 to 240 mg daily) alone or concomitantly with the diuretic. The study showed that enalapril significantly lowered both systolic and diastolic blood pressure. At each timepoint measured in the course of 26 weeks of therapy, the patients in the enalapril group consistently had greater decreases in blood pressure than patients in the propranolol group although not always significantly. The enalapril treatment group had a decrease in the mean arterial blood pressure of 22.2 mmHg compared to the propranolol group of 17.9 mmHg at the end of the study. These results were similarly independent of the way the data were analyzed. Fewer patients in the enalapril group required the addition of hydrochlorothiazide to maintain optimal control of blood pressure. Enalapril was found to be safe and well tolerated over the long-term of 48 weeks. Side effects such as leukopenia and taste perversions believed to be sulfhydryl-related were not encountered. The occurrence of rash and proteinuria was rare. Thiazide-induced hypokalemia, hyperuricemia and hyperglycemia appeared to be attenuated by enalapril. The favorable efficacy and side-effect profile provide the basis for enalapril to be a drug of choice when initiating antihypertensive therapy.