Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With captopril, it has been shown that an erroneous measurement of serum angiotensin converting enzyme (ACE) can be induced by the dissociation of the inhibitor-ACE complex during long-term storage. We have studied the possible dissociation of the fosinopril-ACE complex during the storage of serum samples from healthy male volunteers given a single dose of fosinopril. Serum samples were collected from 5 volunteers, 5 min before, then 4 and 24 h after a unique oral dose of 10 mg fosinopril. ACE activity was measured by a colorimetric and a fluorimetric assay during the hour following the sampling (day 0) and after 21 or 61 days of storage at -20 or -196 degrees C. The degree of ACE inhibition measured in vitro in fresh serum samples differed according to the technique used. Fosinopril has a long-lasting effect with 80% inhibition 24 hours after drug administration. Storage at -20 and -196 degrees C induced a significant decrease in the degree of inhibition measured with the colorimetric method. With the fluorimetric method, a decrease in ACE inhibition was only observed after storage at -20 degrees C but not at -196 degrees C.
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PMID:In vitro stability of the inhibition of serum converting enzyme by fosinopril. 131 61

Fosinopril is a phosphinic acid prodrug which, after oral administration, undergoes rapid hydrolysis to its active diacid, the angiotensin converting enzyme (ACE) inhibitor fosinoprilat. Unlike other ACE inhibitors, fosinoprilat has a compensatory dual route of elimination and is cleared by the liver and kidneys. Thus, in patients with diminished renal function increased hepatic clearance of fosinoprilat is noted and, similarly, in patients with diminished hepatic function increased renal clearance seems to occur. Because of this compensatory elimination, fosinopril therapy for all patients can begin with the same recommended dosage. Fosinopril 10 to 40mg administered once daily is an effective antihypertensive regimen that has shown efficacy similar to that of enalapril 5 to 10 mg/day, propranolol 80 to 160 mg/day, hydrochlorothiazide 25 to 50 mg/day and sustained release nifedipine 40 mg/day in preliminary clinical trials. Generally, fosinopril is well tolerated and adverse events associated with the drug are usually mild and similar to those associated with other ACE inhibitors. Thus, fosinopril appears to be a useful alternative to certain 'established' agents used for treating patients with essential hypertension.
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PMID:Fosinopril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in essential hypertension. 137 56

Numerous pharmacologic agents are capable of lowering the blood pressure of hypertensive patients; however, each drug has a characteristic side effect profile and effect on cardiac performance. In this study, the hemodynamic effects of the angiotensin converting enzyme inhibitor fosinopril were assessed at rest and at peak upright bicycle exercise by first-pass radionuclide cineangiography in 12 patients with essential hypertension. Fosinopril reduced blood pressure at rest in the seated position from 152/101 to 131/85 mm Hg (P less than .01) and at peak exercise from 206/103 to 184/91 mm Hg (P less than .01). Fosinopril therapy was associated with an increase in stroke volume and cardiac output and a decrease in systemic vascular resistance at rest and during peak exercise. Both peak ejection rate and peak filling rate increased significantly at rest during fosinopril therapy. The unique cardiotropic response to fosinopril may reflect its effects on the myocardial renin-angiotensin system, and suggests that this agent may offer a therapeutic advantage compared with other angiotensin converting enzyme inhibitors.
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PMID:Effects of fosinopril on cardiac function in patients with hypertension. Radionuclide assessment of left ventricular systolic and diastolic performance. 153 64

Seventeen patients with mild to moderate hypertension, as indicated by a diastolic blood pressure (DPB) of 95-115 mmHg (WHO I), were treated in a randomized, double-blind, parallel study, with either 5 mg of fosinopril, a new phosphinic acid-containing angiotensin converting enzyme (ACE) inhibitor, or 25 mg of hydrochlorothiazide administered orally once daily for 4 weeks after a 4- to 6-week run-in period of placebo. The doses were increased to 10 mg of fosinopril or 50 mg of hydrochlorothiazide if DBP remained above 95 mmHg. The blood pressure (BP) fell from 157 +/- 12/104 +/- 7 mmHg (mean value +/- SD) at the start of the study to 146 +/- 21/97 +/- 8 mmHg (P less than 0.02) after 4 weeks, and to 149 +/- 19/97 +/- 7 mmHg (P less than 0.02) after 8 weeks of fosinopril treatment (n = 8). In the hydrochlorothiazide-treated patients (n = 9), BP fell from 153 +/- 9/105 +/- 5 mmHg at the start of the study to 140 +/- 11/97 +/- 7 mmHg (P less than 0.01) after 4 weeks, and to 131 +/- 11/94 +/- 7 mmHg (P less than 0.01) after 8 weeks. After the first dose, DBP fell from 102 to 99 mmHg (NS) in fosinopril-treated patients, and from 105 to 96 mmHg (P less than 0.02) in hydrochlorothiazide-treated subjects. Serum active fosinoprilate concentration increased to 5.6 ng ml-1, 25.9 ng ml-1, and 43.8 ng ml-1 after 30, 60 and 120 min, respectively, and remained at a level of 6.6-7.7 ng ml-1 after 4 and 8 weeks, respectively. Serum ACE activity decreased from 21.6 +/- 11.0 mumol min-1 l-1 at the start to 9.3 +/- 13.7, 4.4 +/- 4.6, and 2.9 +/- 2.8 mumol min-1 l-1 after 30, 60 and 120 min, respectively. No side-effects and no changes in blood counts, electrolytes or kidney function were attributed to fosinopril during the study. Fosinopril is a safe, long-acting antihypertensive drug with a smooth onset of action. Hydrochlorothiazide treatment caused potassium loss and an increase in the levels of uric acid and triglycerides. Diastolic blood pressure decreased to the same extent as a result of treatment with either drug, while systolic blood pressure was better controlled by hydrochlorothiazide.
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PMID:Comparison of fosinopril and hydrochlorothiazide in patients with mild to moderate hypertension. 183 20

Available information indicates that about 78 new molecules belonging to the class of angiotensin converting enzyme (ACE) inhibitors are under investigation, and that at least 11 or 12 of the newer ACE inhibitors will be available for clinical use. The newer ACE inhibitors can be classified, according to the zinc ion ligand of ACE, into 3 main chemical classes: sulfhydryl-, carboxyl- and phosphoryl-containing ACE inhibitors. All the newer sulfhydryl-containing ACE inhibitors differ from captopril since they are prodrugs, and among them alacepril and probably moveltipril (altiopril, MC 838) are converted in vivo to captopril. When compared with captopril, they show a slower onset and a longer duration of action, and obviously the same route of elimination. Zofenopril, a prodrug that is converted in vivo to the active diacid, shows a greater potency, a similar peak time and a longer duration of action than captopril and, unlike captopril, partial elimination through the liver. The newer carboxyl-containing ACE inhibitors are prodrugs which are converted in vivo to active diacids. Like enalaprilat, they are excreted via the kidney; the exception is spirapril, which is totally eliminated by the liver. Compared to enalapril, benazepril shows an earlier peak time and a slightly shorter terminal half-life, cilazapril and ramipril have an earlier peak time and even longer terminal half-life, perindopril shows similar peak time and terminal half-life, while delapril, quinapril and spirapril show an earlier peak time and a shorter half-life. The phosphoryl-containing ACE inhibitors belong to a new chemical class. Fosinopril is a prodrug which is converted to the active diacid in vivo, shows a relatively late peak time, a long terminal half-life, and is eliminated partially by the liver. SQ 29852, the only newly developed ACE inhibitor which is not a prodrug, seems to be more effective than captopril, with a much longer lasting effect and elimination through the kidney. When the differences in potency between these drugs are compensated by dosage adjustment, all the newer ACE inhibitors are expected to exert a similar amount of inhibition of circulating ACE, and therefore to inhibit to a similar extent the generation of circulating angiotensin II and the breakdown of bradykinin. Obviously they may differ in timing and the duration of circulating ACE inhibition according to their pharmacokinetic properties. With regard to the possibility that they may stimulate prostaglandin synthesis, it is suggested that this action, which does not seem to be specific to this drug class, plays only a minor role in their antihypertensive action; the hypothesis that the sulfhydryl group exerts an additional stimulating action remains to be proved.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Newer ACE inhibitors. A look at the future. 207 97

Fosinopril (SQ 28,555) is a member of a new chemical class of angiotensin converting enzyme inhibitors being developed by The Squibb Institute for Medical Research. During or following absorption, fosinopril, a prodrug, is hydrolyzed pharmacologically to the active diacid, SQ 27,519. A specific radioimmunoassay (RIA) for the measurement of SQ 27,519 in human serum has been developed. The assay utilizes a specific SQ 27,519 antibody, 125I-iodohistamine-SQ 27,519 radiolabel, and human serum standards. Satisfactory zero binding and assay sensitivity are achieved after a 2-h incubation at room temperature. Separation of the antibody-bound and free radiolabeled antigens is achieved by using polyethylene glycol-goat anti-rabbit gamma globulin separant. Recovery efficiencies ranged from 97.2 to 109.4%. The assay exhibited little or no cross-reactivity with captopril. Cross-reactivities for prodrug (SQ 28,555) and phenolic SQ 27,519 were 5 and 9%, respectively. Intra-assay variability (3.3-5.6%) and interassay variability (7.1-6.6%) were observed. Linear regression analysis indicates that RIA and [14C] thin-layer radiochromatography (TLRC) methods gave a highly significant correlation (RIA = 1.0 [14C]TLRC + 0.17, r = 0.991). Pharmacokinetic profiles of patient sera containing SQ 27,519 obtained by RIA and [14C]TLRC are identical. The RIA has been used routinely in support of the bioavailability and pharmacokinetic studies of fosinopril in humans.
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PMID:A radioimmunoassay for SQ 27,519, the active phosphinic acid-carboxylic diacid of the prodrug fosinopril in human serum. 214 79

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)
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PMID:Fosinopril, a phosphinic acid inhibitor of angiotensin I converting enzyme: in vitro and preclinical in vivo pharmacology. 248 Nov 87

Fosinopril is distinguished from other ACE inhibitors by a pharmacokinetic pecularity in the sense that is can be metabolized either by liver or kidney. This was the rationale of the present research the aim of which was to verify if administered to patients with liver cirrhosis the drug was liable to alter global liver function and ability to metabolize drugs. Eight cirrhotic males, mean age 56 years, also suffering from high blood pressure, were studied. In these patients, liver and kidney function tests (BUN, creatinine blood level, serum and urinary electrolytes, creatinine clearance, calcium and phosphor blood level, transaminases, alkaline phosphatase prothrombin time, cholinesterase, gamma-glutamyl-transpeptidase) were carried out at baseline and after 30 days' fosinopril treatment (1 capsule every morning in the fasting state); in addition total functioning liver mass was assessed by the galactose test, and drug-metabolizing capacity by the antipyrine test. Treatment resulted in a significant improvement of pressure values in all patients (p < 0.01) and did not alter liver and kidney function parameters. Besides, no side effects were registered, especially no case of orthostatic hypotension. The antipyrine test was not influenced by fosinopril treatment. Therefore, short-term treatment with this ACE-inhibitor can be concluded to be effective and not to cause additional alterations of liver function in patients with liver cirrhosis.
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PMID:[Evaluation of the total hepatic function after treatment with fosinopril in hypertensive patients with liver cirrhosis]. 772 Mar 55

Angiotensin converting enzyme inhibitors are effective in the treatment of hypertension and congestive heart failure. Within the past two years, four new agents in this class-benazepril, fosinopril, quinapril and ramipril--have been approved in the United States for use in the treatment of hypertension. These agents have been shown to be as effective as the older angiotensin converting enzyme inhibitors in treating hypertension and, in limited trials, congestive heart failure. The side effect profiles of the new agents are similar to those of other agents in this class that do not contain a sulfhydryl group. Fosinopril has a unique route of elimination that may make it the preferred agent in patients with renal failure. Otherwise, the new angiotensin converting enzyme inhibitors have no proven clinical advantages over other available agents. However, at moderate to high doses, the new agents may be substantially less expensive.
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PMID:ACE inhibitors: review of four new agents. 821 15

Fosinopril is a phosphinic acid derivative which undergoes rapid hydrolysis after oral administration to the active diacid ACE inhibitor fosinoprilat. Cardiotropic effects have been associated with the drug, and the compensatory dual elimination route of fosinopril via renal and hepatic systems offers an opportunity for ACE inhibitor treatment of hypertension in patients with renal or hepatic impairment. Comparative trials of monotherapy with fosinopril 10 to 40 mg/day have demonstrated antihypertensive efficacy equivalent to that of sustained release nifedipine 40 mg/day, hydrochlorothiazide 25 to 50 mg/day, enalapril 5 to 10 mg/day amlodipine 5 to 10 mg/day and sustained release verapamil 240 to 480 mg/day, and superior to that of isradipine 5 mg/day. The efficacy of combination therapy with fosinopril 10 to 20 mg/day and hydrochlorothiazide 12.5 mg/day was significantly superior to that of hydrochlorothiazide alone, tended to be superior to that of fosinopril 20 mg/day alone and was similar to that of sustained release nifedipine 40 mg/day alone. The combination of fosinopril/chlorthalidone 20 to 40/25 mg/day was as effective as propranolol/chlorthalidone 80 to 160/25 mg/day. The incidence of adverse effects associated with fosinopril is low, and cough may possibly occur less often with this drug than with other ACE inhibitors. Fosinopril thus offers an effective and well tolerated option for the treatment of hypertension in adult and elderly patients, including those with renal or hepatic impairment.
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PMID:Fosinopril: a reappraisal of its pharmacology and therapeutic efficacy in essential hypertension. 886 47


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