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PubMed1995

Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure. Fosinopril Efficacy/Safety Trial (FEST) Study Group.

This study was a 12-week, double-blind, placebo-controlled, multinational trial of fosinopril in 308 patients with mild to moderately severe heart failure (New York Heart Association [NYHA] functional class IIS 17%, IIM 48%, and III 35%; mean ejection fraction [+/-SD] 26.5% [+/-6.9%]; bicycle exercise duration 1 to 11 min). An initial dose of 10 mg once daily was titrated as tolerated to 40 mg once daily. Patients all received diuretic therapy; digoxin was optional. The primary endpoint was maximal bicycle exercise time; a secondary endpoint was occurrence of the following prospectively defined, ordered clinical events indicative of worsening heart failure: death, study discontinuation, hospitalization, emergency room visits, and need for supplemental diuretic. At study endpoint (last value obtained for each patient), bicycle exercise time increased more with fosinopril (38.1 s) than with placebo (23.5 s) (P = 0.101 by ANCOVA and 0.010 by prospectively defined dropout-adjusted endpoint analysis). More patients remained free of clinical events indicative of worsening heart failure when treated with fosinopril (89%) than with placebo (75%), and the worst events of fosinopril-treated patients tended to be less severe than those of placebo patients (P = 0.001). Analysis of the occurrence of individual clinical events showed that the need for supplemental diuretic was markedly reduced with fosinopril (8% vs 20%, of patients, P = 0.002), as were hospitalizations (3% vs 12% of patients, P = 0.002) and study discontinuations (2% vs 12% of patients, P < 0.001) for worsening heart failure; the two groups had similar incidences of death (3% of patients in the fosinopril group vs 2% in the placebo group, P = 0.723). In addition, symptoms of dyspnoea (P = 0.017), fatigue (P = 0.019), and NYHA functional class (P = 0.008) improved with fosinopril relative to placebo. In conclusion, fosinopril, at an initial dose of 10 mg once daily, subsequently titrated as tolerated to 40 mg once daily, increased exercise tolerance and reduced the frequency of clinical events indicative of worsening heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Short- and long-term effects of early fosinopril administration in patients with acute anterior myocardial infarction undergoing intravenous thrombolysis: results from the Fosinopril in Acute Myocardial Infarction Study. FAMIS Working Party.

BACKGROUND: Angiotensin-converting enzyme inhibitors are used in patients who have myocardial infarction with left ventricular (LV) dysfunction. Few data are available in patients whose LV function is within the normal range. METHODS AND RESULTS: The Fosinopril in Acute Myocardial Infarction Study was a 2-year, randomized, double-blind, placebo-controlled, multicenter study of 285 patients with anterior acute myocardial infarction and was designed to investigate the effects of the early (<9 hours) administration of fosinopril and thrombolysis on (1) changes in echocardiographically evaluated LV volumes at 3 months and (2) long-term occurrence of death and congestive heart failure. LV volumes were normal at baseline in more than 70% of patients and were comparable between groups both at baseline and after 3 months of treatment. Fosinopril-treated patients showed a 30% reduction in the 2-year combined prevalence of death or moderate-to-severe congestive heart failure (New York Heart Association class III-IV) despite having a worse clinical profile at baseline. The benefit of fosinopril was confirmed both in patients without congestive heart failure at admission and in those with ejection fraction >40% at baseline. Moreover, the incidence of significant ventricular arrhythmias was lower in the fosinopril group (0.8% vs 6.0%, p < 0.02). CONCLUSIONS: The results of the Fosinopril in Acute Myocardial Infarction Study suggest that early treatment with fosinopril can benefit patients with acute myocardial infarction in addition to a prevention of LV remodeling.

Aged↗
PubMed1999

The hemodynamic effects of long-term ACE inhibition with fosinopril in patients with heart failure. Fosinopril Hemodynamics Study Group.

The objective of this study was to evaluate the hemodynamic and clinical effects of fosinopril in patients with heart failure. This was a prospective, multicenter, double-blind, randomized, parallel-group study. Patients 18 to 80 years of age who were receiving diuretics with a systolic blood pressure (SBP) > or = 90 mm Hg, New York Heart Association (NYHA) functional class II-IV, left ventricular ejection fraction < or = 40%, pulmonary capillary wedge pressure (PCWP) > or = 18 mm Hg, and a cardiac index (CI) < or = 2.6 L/min/m(2) were eligible. A total of 179 patients were randomized to a single, double-blind oral dose of placebo or fosinopril at 1, 20, or 40 mg, and hemodynamic monitoring was performed for 24 hours postdose; 155 patients with SBP > or = 90 mm Hg were re-randomized to 10 weeks of double-blind fosinopril at 1, 20, or 40 mg once daily. Hemodynamic monitoring was repeated at the last visit, beginning at 24 hours postdose (trough) and continuing for 12 hours thereafter. Significant decreases in preload (PCWP) and afterload (mean arterial blood pressure [MABP] and systemic vascular resistance [SVR]) were evident 3 to 4 hours after a single dose of fosinopril at 20 and 40 mg and continuing for up to 8 to 12 hours postdose for PCWP and SVR and for up to 24 hours postdose for MABP (P < or = .05 v placebo and baseline). Sustained decreases in PCWP, MABP, SVR, and heart rate and increases in CI and stroke volume index were observed after 10 weeks of treatment with fosinopril at 20 and 40 mg once daily (P < or = .05 v 1 mg group for PCWP and MABP at most time points and P < or = .05 v baseline for other parameters at most time points). Dose-related trends toward reduced supplemental diuretic use (P = .027) and reduced symptoms of dyspnea (P = .008) were observed with the 20-mg and 40-mg fosinopril dose groups. Once daily administration of fosinopril at 20 and 40 mg was safe and well tolerated, provided a sustained beneficial hemodynamic effect, improved left ventricular performance, and reduced symptoms of dyspnea, resulting in a reduced need for supplemental diuretic therapy.

Adult↗
PubMed1998

Differential effects of fosinopril and enalapril in patients with mild to moderate chronic heart failure. Fosinopril in Heart Failure Study Investigators.

OBJECTIVES: To investigate the efficacy and safety of fosinopril in the treatment of chronic heart failure (CHF), patients with mild to moderate CHF and left ventricular ejection fractions <40% were randomly assigned in a double-blind manner to receive fosinopril 5 to 20 mg every day (n = 122) or enalapril 5 to 20 mg every day (n = 132) for 1 year. RESULTS: The event-free survival time was longer (1.6 vs 1.0 months, P= .032) and the total rate of hospitalizations plus deaths was smaller with fosinopril than with enalapril (19.7% vs 25.0%, P= .028). There was consistently better symptom improvement with fosinopril (P< .05). The incidence of orthostatic hypotension was lower in the fosinopril group (1.6% vs 7.6%, P< .05). CONCLUSIONS: Fosinopril 5 to 20 mg every day was more effective in improving symptoms and delaying events related to worsening of CHF and produced less orthostatic hypotension than enalapril 5 to 20 mg every day.

Adult↗
PubMed1995

Effects of fosinopril on exercise tolerance and clinical deterioration in patients with chronic congestive heart failure not taking digitalis. Fosinopril Heart Failure Study Group.

A total of 241 men and women with mild to moderately severe chronic heart failure (New York Heart Association functional class II [90%] or III) and a mean (+/- SD) left ventricular ejection fraction of 25 +/- 7%, entered a 24-week, prospective, double-blind, placebo-controlled trial of 10 or 20 mg/day of fosinopril, a phosphinic acid angiotensin-converting enzyme inhibitor. Patients received concomitant diuretic therapy but not digitalis. Primary end points were mean change in maximal treadmill exercise time and occurrence of prospectively defined clinical events indicative of worsening heart failure (most to least severe): death, withdrawal for worsening heart failure, hospitalization for worsening heart failure, need for supplemental diuretic or emergency room visit for worsening heart failure, and no event. At study end point, treadmill exercise time had improved in the fosinopril versus the placebo group (+28.4 vs -13.5 seconds, p = 0.047). New York Heart Association functional class had improved at end point more frequently (24% vs 13%) and deteriorated less frequently (18% vs 32%) in the fosinopril group (p = 0.003). More patients treated with fosinopril (66% vs 50%) remained free of clinical events indicative of worsening heart failure, and fosinopril-treated patients had less severe clinical events (p = 0.004). Dyspnea, fatigue, and paroxysmal nocturnal dyspnea improved more often and worsened less often in this group (p < or = 0.002), and edema showed a trend toward improvement (p = 0.088). These clinical benefits did not require concomitant digitalis therapy. Fosinopril was associated with an acceptable safety profile.

Aged↗
PubMedDate not supplied

Antihypertensive effect of fosinopril, a new angiotensin converting enzyme inhibitor: findings of the Fosinopril Study Group II.

In a double-blind study, after a four- to six-week placebo period, 418 patients with mild to moderate hypertension were randomly assigned to receive 5, 10, 20, or 40 mg of fosinopril or matched placebo orally once daily for four weeks. Seated diastolic blood pressure was determined 24 hours after the most recent dose. For patients with an inadequate blood pressure response after four weeks, doses were doubled during the second four weeks, and hydrochlorothiazide was added during the final four weeks. The patients showed a significant, consistent antihypertensive response in seated and standing systolic and diastolic blood pressures after four weeks of 20 or 40 mg of fosinopril; both dosages produced similar responses. The results indicate that the dose level of fosinopril required to treat uncomplicated mild to moderate hypertension ranges from 5 to 40 mg taken once daily. Treatment was discontinued in 3% of the fosinopril patients and in 1% of the placebo patients because of side effects. No clinically significant abnormal laboratory test results were reported. Fosinoprilat, the active diacid of fosinopril, is eliminated by both the hepatobiliary and renal routes, which suggests that fosinopril may be particularly useful in the treatment of patients with impaired kidney or liver function and of elderly patients.

Adult↗
PubMed1997

Fosinopril national survey: a post-marketing surveillance study of fosinopril (Staril) in general practice in the UK.

This open, non-comparative, PMS study of fosinopril (Staril) involved 12,067 hypertensive patients assessed at baseline and after two and six months of treatment; 10,791 patients provided evaluable data with 5.2 months average treatment totalling 4667 patient-years. Adverse events were reported in 24% of patients, the most common being mild-to-moderate cough (6.05%). Events considered possibly related to fosinopril were reported in 15% of patients, the frequency being lower in younger patients, males and those receiving fosinopril monotherapy. Patient well-being improved during the study. At the end of the study, most patients were taking fosinopril 10 mg once daily. Mean reductions in systolic and diastolic blood pressures were -11.0% and -11.7%, respectively; 71.3% of patients were 'responders'. No important differences were observed between subgroups. This study found fosinopril to be effective, well tolerated in a broad range of hypertensive patients, and with no previously unrecognised adverse events reported.

Adult↗
PubMed1997

Fosinopril. A review of its pharmacology and clinical efficacy in the management of heart failure.

Fosinopril is the prodrug of the active diacid ACE inhibitor fosinoprilat. In patients with heart failure, fosinopril reduces pulmonary capillary wedge pressure, mean arterial blood pressure, mean right atrial pressure and heart rate, and increases stroke volume index and cardiac index. The drug has compensatory dual elimination routes via renal and hepatic systems and accumulates to a lesser extent than enalapril and lisinopril in patients with chronic renal insufficiency with or without heart failure. Comparative studies of 3 or 6 months' duration with fosinopril 10 to 40 mg/day have demonstrated clinical efficacy significantly superior to that of placebo in patients with heart failure [mostly New York Heart Association (NYHA) functional class II or III]. Fosinopril treatment consistently increased exercise duration and improved heart failure symptoms in these patients. Significantly fewer fosinopril than placebo recipients withdrew or were hospitalised because of worsening heart failure. Additionally, significantly more fosinopril than placebo recipients showed improvement, and fewer patients had deteriorated, in terms of NYHA functional class. Fosinopril and enalapril showed similar clinical efficacy over 6 and 12 months' treatment in patients with NYHA functional class II to IV heart failure. As yet, there are no data showing a mortality benefit with fosinopril. Fosinopril was well tolerated in clinical trials in patients with heart failure. Dizziness (11.9 vs 5.4% for placebo), cough (9.7 vs 5.1%) and hypotension (4.4 vs 0.8%) were the most commonly reported adverse events. In 6- or 12-month comparative studies, fosinopril therapy was associated with a lower incidence of dizziness and hypotension, but a higher incidence of vertigo, than enalapril therapy. 0.8% of patients discontinued the drug because of cough, which occurred to a similar extent with fosinopril and enalapril. Thus, based on available clinical evidence, fosinopril is an effective and well tolerated option for the management of patients with heart failure. Although clinical data are limited, fosinopril may be especially useful in patients with renal or hepatic impairment.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Fosinopril versus enalapril in the treatment of hypertension: a double-blind study in 195 patients.

The new angiotensin-converting enzyme (ACE) inhibitor fosinopril was compared with the ACE inhibitor enalapril in a multicenter (n = 11), multinational (Denmark, Finland, Iceland, Norway, and Sweden), double-blind, randomized, parallel-group 24-week study in 195 patients with mild to moderate essential hypertension [supine diastolic blood pressure, (SDBP) > or = 95 to < or = 110 mm Hg]. After discontinuing all previous antihypertensive medication, patients were entered into a placebo lead-in period of 4-6 weeks, followed by 24 weeks of randomized treatment with the active compounds administered with a double-dummy technique. The dose of fosinopril was 20 mg, which could be increased to 40 mg after 8 weeks (average 25.6 mg); that of enalapril was 10 mg, which could be increased to 20 mg after 8 weeks (average 12.9 mg). Hydrochlorothiazide 12.5 mg could be added after 16 weeks and was administered to 27% of the patients in the fosinopril group and to 30% in the enalapril group. All drugs were administered once daily. Supine systolic BP (SSBP) decreased from 157 to 143 mm Hg in the fosinopril group (p < 0.01), and from 159 to 147 mm Hg in the enalapril group (p < 0.01). SSDP decreased from 100 to 89 mm Hg in the fosinopril group (p < 0.01) and from 100 to 92 mm Hg in the enalapril group (p < 0.01). Throughout the study period, fosinopril reduced SSBP and SDBP numerically more than did enalapril, by 0-3 mm Hg. Adverse events (AE) caused withdrawal of study medication in 8 patients in the fosinopril group and in 14 patients in the enalapril group (NS). The number of reported AE was not statistically different in the two groups. Inhibition of the ACE was assessed in a subgroup of patients (n = 26, 13 in each group). Fosinopril caused a greater inhibition of ACE at the doses used in the present study, which was statistically significant. Both fosinopril and enalapril caused statistically significant reductions in BP of a similar magnitude, and both agents were well tolerated. However, fosinopril was consistently numerically slightly more effective than enalapril in reducing BP. There were fewer withdrawals due to AE (NS) in the fosinopril group, and the overall recorded AE were fewer in the fosinopril group (NS).

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Effects of fosinopril on exercise tolerance, symptoms, and clinical outcomes in patients with decompensated heart failure.

The purpose of this prospective, multicenter, randomized, double blind, placebo controlled study was to determine the clinical effects of fosinopril in patients with decompensated or worsening heart failure (HF). Patients >/=18 years with New York Heart Association (NYHA) functional class II-IV HF who had been hospitalized or seen in the ER or outpatient clinic for treatment of worsening or decompensated HF were eligible. Patients had to be on diuretic therapy and have a left ventricular ejection fraction (LVEF) </=35% and a treadmill exercise tolerance test (ETT) duration of </=8 minutes. Randomized patients began 12 weeks of fosinopril 10 mg (or placebo) qAM and were titrated within 4 weeks to fosinopril 20 mg and then to 40 mg (or placebo) qAM (if seated, systolic blood pressure (SBP) >/=90 mm Hg). ETTs (modified Naughton protocol) were performed at weeks 1, 3, 6, and 12. A total of 206 patients (mean age 62 years) were randomized to fosinopril (n=102) or placebo (n=104). Most patients were NYHA functional class III (58%) or IV (30%) at presentation; 145 patients completed 12 weeks of treatment (fosinopril, n=85; placebo, n=60). After adjustment for baseline imbalances and investigator effects, fosinopril-treated patients had a 513 second mean exercise duration at endpoint vs. a 489 second duration in placebo-treated patients (p=0.353). When the analysis was adjusted for the impact of dropouts on ETT time, fosinopril-treated patients had a greater exercise duration than those treated with placebo (p=0.043). Fewer patients in the fosinopril group were discontinued from study medication (p=0.008) or hospitalized (p=0.005) for worsening HF. At endpoint, more patients improved their NYHA Functional Class and fewer had worsened with fosinopril vs. placebo (p=0.018); fosinopril-treated patients showed improvements in dyspnea (p=0.054), fatigue (p=0.052), edema (p=0.012), and paroxysmal nocturnal dyspnea (p=0.003) vs. the placebo group. Once-daily fosinopril had a favorable effect on dropout-adjusted exercise tolerance, reduced the frequency of discontinuations or hospitalizations for worsening HF, improved HF signs and symptoms, and was safe and well tolerated. (c)1999 by CHF, Inc.

Journal Article↗
PubMed1989

Fosinopril, a phosphinic acid inhibitor of angiotensin I converting enzyme: in vitro and preclinical in vivo pharmacology.

Fosinopril is the first member of a new chemical class of angiotensin I (AI) converting enzyme (ACE) inhibitors, the phosphinic acids. In vitro, SQ 27,519, the active moiety of the prodrug fosinopril, was a more potent inhibitor of purified rabbit lung ACE- (IC50 = 11 vs. 23 nM) and bradykinin-induced contractions of guinea pig ileum than captopril. In vivo, SQ 27,519 was equipotent to captopril as an inhibitor of an AI pressor response after intravenous (i.v.) administration to conscious rats and monkeys but appeared to be less potent in conscious dogs. After oral administration, fosinopril again was equipotent to captopril as an inhibitor of an AI pressor response in rats and monkeys and slightly less potent in dogs. However, both SQ 27,519 (i.v. studies) and fosinopril (oral studies) had a longer effect than captopril in all three species. When fosinopril was administered orally for 5 days, its effects on an AI pressor response were the same on days 1 and 5, suggesting lack of tolerance to the compound. The ACE inhibitory effect of captopril, but not fosinopril, was prolonged in conscious rats with glycerol-induced acute renal failure, suggesting that fosinopril is excreted by an extrarenal route. Finally, fosinopril had no effect on the pressor or chronotropic effects of norepinephrine (NE) or 1,1-dimethyl-4-phenylpiperinium (DMPP) or electrical stimulation of the sympathetic ganglia of pithed rats. Fosinopril attenuated the pressor, but not the chronotropic effects of tyramine. We conclude that fosinopril is a potent and long-lasting inhibitor of ACE in conscious animal models that does not impair adrenergic function or reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed2002

Apoptosis, myocardial fibrosis and angiotensin II in the left ventricle of hypertensive rats treated with fosinopril or losartan.

OBJECTIVE: To investigate the different effects of an angiotensin II type 1 (AT(1)) receptor antagonist, losartan, and an angiotensin converting enzyme (ACE) inhibitor, fosinopril, on cardiomyocyte apoptosis, myocardial fibrosis, and angiotensin II (Ang II) in the left ventricle of spontaneously hypertensive rats (SHRs). METHODS: SHRs of 16-week-old were randomly divided into 3 groups: SHR-L (treated with losartan, 30 mg.kg(-1) x d(-1)), SHR-F (treated with fosinopril, 10 mg x kg(-1) x d(-1)), and SHR-C (treated with placebo). Each group consisted of 10 rats. Five rats, randomly selected from each group, were killed at the 8th and 16th week after treatment. Cardiomyocyte apoptosis, collagen volume fraction (CVF), perivascular collagen area (PVCA) and Ang II concentrations of plasma and myocardium were examined. RESULTS: Compared with the controls at the 8th and 16th week, systolic blood pressures were similarly decreased in both treatment groups. Left ventricular weight and left ventricular mass indexes were significantly lower in both treatment groups. However, the latter parameter at the 16th week was reduced to a less extent in the fosinopril group than that in the losartan group. Compared with the controls, cardiomycyte apoptotic index was significantly reduced at the 8th week only in the fosinopril group, and at the 16th week in both treatment groups. The index of the fosinopril group was lower than that of the losartan group at the latter endpoint examined. Compared with the controls, the left ventricular collagen volume fraction and perivascular collagen area at the 8th and 16th weeks were significantly reduced in the SHRs treated with either fosinopril or losartan. However, the collagen volume fraction at the latter endpoint in the fosinopril group was lower than that in the losartan group. Compared with the controls at endpoints, plasma and myocardium Ang II levels were significantly increased in the losartan group. However, plasma Ang II concentrations were not altered, and myocardium Ang II concentrations at the 8th and 16th weeks were significantly reduced in the fosinopril group. CONCLUSIONS: Both losartan and fosinopril could effectively inhibit cardiomyocyte apoptosis and myocardial fibrosis and reverse heart hypertrophy. Fosinopril may be more effective in these cardioprotective effects, suggesting that the effects of both drugs are related to the inhibition of myocardium renin-angiotension-aldsterone system.

Angiotensin II↗
PubMed1993

Fosinopril monotherapy: relationship between blood pressure reduction and time of administration.

The time to peak antihypertensive effect and the trough-to-peak ratio were determined in 64 Caucasian patients (19 men, 45 women) with mild to moderate hypertension [supine diastolic blood pressure (DBP) 95 to 115 mmHg]. They received placebo or fosinopril 10, 20, or 40 mg once daily for 4 weeks. The study consisted of a 4-week placebo lead-in, 4 weeks' double-blind treatment, and a 1-week placebo washout period. Vital signs were determined biweekly before dosing, and blood pressures were measured every 1 to 2 h during two 27-h periods at the beginning and end of treatment. After the first and last doses of all three regimens, the peak effect on blood pressure occurred 5 to 7 h after all three dosages. Neither peak nor trough blood pressure changes showed a clear dose-response relationship. Trough to peak ratios for the first dose, corrected for placebo effects, were 79% for fosinopril 10 mg, 48% for fosinopril 20 mg, and 74% for fosinopril 40 mg, and the trough-to-peak ratios for the last dose were 41% for fosinopril 10 mg, 32% for fosinopril 20 mg, and 44% for fosinopril 40 mg. In the 38 responders among the 48 patients receiving fosinopril (supine DBP decrease of at least 5 mmHg at 24 h postdose), trough-to-peak ratios ranged from 50 to 81%, and the range indicates that fosinopril is efficacious when administered once daily. Adverse effects were mild to moderate, and no patient discontinued treatment. Changes in the laboratory test results, electrocardiograms, or the results of physical examinations were unremarkable.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Metabolic effects of converting enzyme inhibitors: focus on the reduction of cholesterol and lipoprotein(a) by fosinopril.

It is generally believed that the use of angiotensin-converting enzyme (ACE) inhibitors has no effect on the lipid profile. Our recent data show that in patients with proteinuric renal disease, serum levels of total cholesterol and lipoprotein(a) [Lp(a)] may be lowered during treatment with an ACE inhibitor, fosinopril sodium. During a 12-week randomized, placebo-controlled, double-blind study involving 26 patients with mild-to-moderate renal impairment, fosinopril administration was associated with significant decreases in both urinary protein excretion and serum total cholesterol levels, whereas placebo was not. During a 6-week washout phase, both parameters returned to baseline in fosinopril-treated patients and remained unchanged in placebo recipients. In addition, fosinopril-treated patients had a decrease in plasma levels of Lp(a), whereas this was not seen in placebo-treated patients. When data from a subset of 13 patients with proteinuric renal disease and hypertension were examined, a significant decrease in serum total cholesterol levels was observed; this decrease reversed after discontinuation of fosinopril. Analysis of the effect of fosinopril on plasma Lp(a) levels in a subset of patients who had type II diabetes mellitus and overt proteinuria revealed a significant decrease in plasma Lp(a) after administration of fosinopril. Moreover, fosinopril lowered plasma Lp(a) levels in blacks, whose pretreatment levels were higher than those of whites with comparable degrees of proteinuria and levels of serum total cholesterol. Thus, the reduction in serum Lp(a) levels may be related not only to amelioration of proteinuria, but also to another direct action of fosinopril on the metabolism of Lp(a).

Black People↗
PubMed1999

The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice.

OBJECTIVE: To investigate the possible mechanisms of the antiatherosclerotic effects of the angiotensin-converting enzyme (ACE) inhibitor, fosinopril, in apolipoprotein (apo) E deficient mice. METHODS: Apo E deficient (E0) mice at the age of 8 weeks received either placebo or a high dose (25 mg/kg/d) of fosinopril supplemented in their drinking water. RESULTS: After 12 weeks of treatment, fosinopril reduced the aortic lesion size by 70%, compared with the placebo group. At this dosage, fosinopril significantly reduced blood pressure from 93 +/- 2 mmHg before treatment to 70 +/- 2 mmHg at the end of the treatment period (P < 0.005). Fosinopril also increased the resistance of the mice plasma low density lipoprotein (LDL) to CuSO4-induced oxidation, as shown by a 90% reduction in the LDL content of malondialdehyde (MDA) and also by a prolongation of the lag time required for the initiation of LDL oxidation (from 100 min in the placebo-treated mice to more than 240 min in the fosinopril-treated mice; P < 0.001). In addition, fosinopril inhibited CuSO4-induced oxidation of LDL that was obtained from the aortas of the treated mice, as shown by an 18% and 37% reduction in the LDL content of lipid peroxides and hydroperoxy-cholesterol linoleate, respectively, compared with the placebo-treated mice (P < 0.01). A low dosage of fosinopril (5 mg/kg/d) that was still adequate to reduce their plasma ACE activity and LDL propensity to lipid peroxidation was insufficient to lower their blood pressure. This dosage also reduced the aortic lesion size in the apo E deficient mice by 40% (P < 0.01). CONCLUSIONS: The antiatherogenic effects of fosinopril in apo E deficient mice are due not only to blood pressure reduction but also to the direct inhibition of angiotensin II-dependent effects, which are probably also associated with the inhibition of LDL oxidation.

Angiotensin Receptor Antagonists↗
PubMed1992

Fosinopril: a new generation of angiotensin-converting enzyme inhibitors.

Fosinopril, the first agent in a new chemical class of phosphorus-containing angiotensin-converting enzyme (ACE) inhibitors, has unique pharmacologic properties. Fosinopril administration leads to complete inhibition of plasma ACE activity for 12-24 h. In patients with normal renal function, approximately equal amounts of the drug are eliminated via the hepatic and renal routes. With worsening renal function, increasing amounts of fosinopril are eliminated hepatically. This dual elimination allows for the administration of fosinopril using the same starting dosage to any patient, regardless of renal function. Fosinopril may provide end-organ protection against the effects of hypertension and antihypertensive therapy; this drug potentially protects the kidney by increasing renal functional reserve, while maintaining cardiac left ventricular performance. Moreover, despite marked blood reductions, cerebral blood flow is maintained. Controlled trials show that fosinopril in single daily doses of 10-40 mg is efficacious and safe for the long-term treatment of hypertension. At these doses, favorable responses were seen in up to 80% of patients. Fosinopril is equally effective in elderly as well as younger patients and works in black as well as in nonblack patients. The incidence of adverse events does not differ significantly between fosinopril- and placebo-treated patients. Fosinopril represents a clinically useful agent for the treatment of hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Fosinopril and hydrochlorothiazide combination versus individual components: lack of a pharmacokinetic interaction.

OBJECTIVE: To evaluate the pharmacokinetic interaction and bioequivalence of a combination formulation of the angiotensin-converting enzyme inhibitor fosinopril and the diuretic hydrochlorothiazide (HCTZ). METHODS: In an open-label, balanced, randomized incomplete block, three-way crossover fashion, healthy men received single doses of three of four regimens in one of two independent studies. Regimens for study A (36 subjects): (1) fosinopril 10-mg tablet, (2) HCTZ 12.5-mg tablet, (3) a combination tablet of fosinopril 10 mg plus HCTZ 12.5 mg, or (4) coadministered tablets of fosinopril 10 mg and HCTZ 12.5 mg. Study B (40 subjects) received: (1) fosinopril 20-mg tablet, (2) HCTZ 12.5-mg tablet, (3) a combination tablet of fosinopril 20 mg plus HCTZ 12.5 mg, or (4) coadministered tablets of fosinopril 20 mg and HCTZ 12.5 mg. RESULTS: There was no evidence of any significant effect of HCTZ on the pharmacokinetics of fosinoprilat, based on maximum concentration value, AUC, or cumulative urinary recovery over 24 hours. Fosinoprilat had no clinically important effect on the pharmacokinetics of HCTZ only slightly decreasing its AUC by 14% in study A. Coadministration was well tolerated; no new adverse events were reported with the combination tablet. CONCLUSIONS: Fosinopril and HCTZ in a combination tablet display pharmacokinetic profiles similar to those achieved when either drug is administered alone or when coadministered in separate tablets. When used with HCTZ, the favorable pharmacokinetic feature of fosinopril, dual and compensatory pathways of renal and hepatic elimination, is preserved.

Adolescent↗
PubMedDate not supplied

[Head-to-head comparison of clinical, biochemical and functional effects of fosinopril and enalapril in patients with systolic heart failure].

INTRODUCTION: The aim of this study was to evaluate short-term clinical, biochemical and functional effects of fosinopril versus enalapril in patients with heart failure. MATERIAL AND METHODS: 59 consecutive patients (mean age 57 +/- 8 years, EF 18.9 +/- 6.3%, NYHA III or IV class 19/59) were randomized to receive fosinopril or enalapril for three months. All patients underwent echocardiography, metabolic testing, and a 6-minute walk test and completed the Minnesota questionnaire on inclusion and three months later. Additionally, serum creatinine, BUN, total cholesterol and triglycerides were measured. Kaplan-Meier curve was created to assess event-free survival for cardiac death and hospitalization for heart failure. RESULTS: There was no statistically significant difference in event-free survival between patients on fosinopril and enalapril (86.7% vs. 82.8%, log rank 4.21 p=0.43). However, time to the event was longer in patients on fosinopril (77.0 +/- 25.35 vs. 40.2 +/- 6.8 days, p=0.04). At the end of the study, no difference between fosinopril and enalapril group existed with respect to maximal oxygen consumption (20.90 +/- 4.47 vs. 20.89 +/- 6.86 ml/kg/min), ejection fraction (20.5 +/- 7.4 vs. 21.4 +/- 7.8%), distance during the 6-minute test walk (313 +/- 74 vs. 352 +/- 129 meters) and quality of life (23.8 +/- 15.8 vs. 25.6 +/- 20.3 points), but patients on enalapril had higher creatinine (99 +/- 13 vs. 113 +/- 17 micromol/L, p=0.002) and BUN (7.28 +/- 1.7 vs. 8.89 +/- 2.39 mmol/L, p=0.01) levels. Increase in fosinopril dose during the study was higher than increase in enalapril dose (24.1% +/- 23.8% vs. 9.5 +/- 24.5%, p=0.04). CONCLUSIONS: Fosinopril and enalapril have similar short-term effects on event-free survival, ejection fraction, functional capacity and quality of life in patients with heart failure. Patients on fosinopril presented with longer survival without event and had lower creatinine and BUN at the end-of the follow-up. Additionally, fosinopril can be easily titrated to the maximum therapeutic dose.

Angiotensin-Converting Enzyme Inhibitors↗