Search

The dose-response relationship of enalapril was evaluated in a double- blind, balanced, two-period, incomplete-block study in 91 patients with mild to moderate essential hypertension. Patients were randomly assigned to two of six treatments: placebo, 2.5, 5, 10, 20 and 40 mg/day of enalapril maleate. There were two 3-week treatment periods, each preceded by a 4-week, single-blind placebo washout. Each dose of enalapril produced significant decreases in standing and supine systolic and diastolic blood pressure after 2 and 3 weeks of treatment. There were no significant changes on placebo. There was a significant linear dose response relationship for both mean blood pressure and mean change from baseline in blood pressure (P less than 0.01 for systolic and mean arterial pressure, and P less than 0.05 for diastolic pressure). Enalapril was associated with an increasing dose-response relationship across the 2.5-40 mg/day range. The 2.5 mg/dose is effective in some patients; however, doses greater than or equal to 10 mg/day may be necessary to achieve satisfactory blood pressure control. [ABSTRACT FROM AUTHOR]

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase. [ABSTRACT FROM AUTHOR]

1 Two single doses of 10 mg each of the converting enzyme inhibitor enalapril maleate or MK-421 and of its lysine analogue (MK-521) were administered p.o. to twelve male volunteers. 2 The active diacid metabolite of MK-421 and the lysine analogue were determined by radioimmunoassay and MK-421 by the active metabolite method following in vitro hydrolysis. 3 Peak serum levels of MK-421, active metabolite and lysine analogue were reached within 1, 3 to 4, and 6 h respectively. Practically all MK-421 had disappeared from serum within 4 h. 4 A close correlation between percent inhibition of plasma converting enzyme activity and the serum concentration of active metabolite was observed (r = 0.98, n = 171, P less than 0.001). Similarly, converting enzyme blockade as expressed by the ratio plasma angiotensin II/angiotensin I was closely correlated with serum active metabolite levels (r = 0.93, n = 15, P less than 0.001). [ABSTRACT FROM AUTHOR]

1 The disposition of two angiotensin converting-enzyme inhibitor drugs was studied in normal volunteers. One drug was enalapril maleate (MK- 421), which requires in vivo esterolysis to yield active inhibitor (MK- 422). The other was a lysine analogue of MK-422 (MK-521), which requires no bioactivation. 2 Absorption of enalapril maleate (10 mg, p.o.) was rapid, with peak serum concentrations of enalapril observed 0.5-1.5 h after administration. Based upon urinary recovery of total drug (enalapril plus MK-422), absorption was at least 61%. Bioactivation appeared to be largely post-absorptive. From the ratio of MK-422 to total drug in urine, the minimum extent of bioactivation was estimated at 0.7. 3 A similar dose of MK-521 was absorbed more slowly, reaching peak serum concentrations 6-8 h following drug administration. Minimum absorption, based upon urinary recovery, was 29%. 4 Serum concentration v time profiles for both drugs were polyphasic and exhibited prolonged terminal phases. 5 Recovery in urine and faeces of administered enalapril maleate (intact and as MK-422) was 94%. Recovery of MK-521 was 97%. These results indicate lack of significant metabolism of these agents, apart from the bioactivation of enalapril. [ABSTRACT FROM AUTHOR]

1. This was a multicentre, double-blind, parallel study in 216 patients with mild to moderate (supine diastolic blood pressure = 95-115 mm Hg) essential hypertension. 2. After a 4-week placebo washout, patients were randomized to placebo or lisinopril 1.25, 5.20 or 80 mg once daily for 6 consecutive weeks. Supine and erect blood pressure was measured 24 h postdose at the end of weeks -2, 0, 2, 4, and 6. 3. There was a linear dose-response relationship for both supine and erect blood pressure. Diastolic blood pressure reductions in the lisinopril 20 and 80 mg day-1 groups were significantly greater than in the placebo or lisinopril 1.25 and 5 mg day-1 groups. 4. Lisinopril, at doses up to 80 mg day-1, was well tolerated. [ABSTRACT FROM AUTHOR]

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two-period, crossover design in 12 in-patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state. [ABSTRACT FROM AUTHOR]

1. The dose-peak effect relationship of lisinopril was evaluated in a double-blind, parallel study in 83 patients with mild to moderate essential hypertension (supine diastolic blood pressure = 95-115 mm Hg). 2. After a 4 week placebo washout, patients were randomly assigned to one of four treatments: lisinopril 2.5, 10, 20 or 80 mg day-1 for 1 week. 3. Lisinopril 10 and 20 mg day-1 produced similar peak antihypertensive effects which were greater than that produced by 2.5 mg day-1, but less than that of 80 mg day-1. If the incidence of first- dose symptomatic hypotension is related to the peak effect, then an initial lisinopril dose of 20 mg should not pose any greater risk than a 10 mg dose. 4. The magnitude of antihypertensive response at 24 h postdrug appeared to be dose related across the 2.5 to 80 mg day-1 range. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Twelve healthy male volunteers received single daily oral doses of enalapril (EN) 10 mg for 8 consecutive days. Serum samples for prolactin (PRL) assay were taken on day 0 (baseline) at 12.00 h and 16.00 h, and on days 1 and 8 at 08.00 h (pre-drug), 12.00 h and 16.00 h. The 08.00 h values on day 1 served as the pre-drug baseline. There were no significant changes from baseline in serum PRL levels on days 1 and 8. All mean serum PRL levels on day 8 were significantly (P less than 0.01) lower than the upper limit of the normal range (2-15 ng/ml) found for healthy males in this laboratory. It is concluded that therapeutic doses of EN (10 mg/day, p.o.) for 8 consecutive days do not raise mean serum PRL levels above the normal range in healthy male volunteers. [ABSTRACT FROM AUTHOR]

Anti-neoplastic agents for cancer treatment utilize many different mechanisms of action and, when combined, can result in potent inhibition of cancer growth. Combination therapies can result in long-term, durable remission or even cure; however, too many times, these anti-neoplastic agents lose their efficacy due to the development of acquired drug resistance (ADR). In this review, we evaluate the scientific and medical literature that elucidate STAT3-mediated mechanisms of resistance to cancer therapeutics. Herein, we have found that at least 24 different anti-neoplastic agents-standard toxic chemotherapeutic agents, targeted kinase inhibitors, anti-hormonal agents, and monoclonal antibodies-that utilize the STAT3 signaling pathway as one mechanism of developing therapeutic resistance. Targeting STAT3, in combination with existing anti-neoplastic agents, may prove to be a successful therapeutic strategy to either prevent or even overcome ADR to standard and novel cancer therapies.

Statin use is associated with a variety of overtly related muscle symptoms including muscle pain, myalgia, creatine kinase elevations without pain with myolysis and myositis (rhabdomyolysis), a potentially fatal side effect that led to the withdrawal of cerivastatin in 2001. Unintended drug response phenotypes have an impact on patient compliance and sometimes patient health and the assessment of risk on an individual basis could enhance therapeutic benefit. We therefore investigated whether common single nucleotide polymorphisms were associated with the expression of broadly grouped atorvastatin-induced muscle events in a case-control study (n=263 samples, n=388 SNPs). Of a number of associations identified in a discovery sample (51 atorvastatin-induced muscle and 55 normal) only those corresponding to the CYP2D6*4 allele were significantly associated in the sample (24 atorvastatin-induced muscle and 133 normal) (Discovery P=0.004, odds ratio=3.6; Validation P=0.036, odds ratio=2.7; total P=0.001, odds ratio=2.5). The frequency of the CYP2D6*4 allele was about 50% in atorvastatin-induced muscle patients but only 28% in controls, similar to that of other patient types (28.5%). The association was independent of various demographic variables and not explained by gross demographic, clinical or population-structure differences among cases and controls. Surprisingly, the CYP2D6*4 allele appeared similarly distributed among controls and patients expressing simvastatin-induced muscle events (n=169, frequency in case participants=49.2%, P=0.067, odds ratio=1.7). Our results suggest that the CYP2D6*4 allele is associated with broadly related muscle events caused by at least two structurally dissimilar HMG-CoA reductase inhibitors, and as such, may have implications for a better understanding of this statin-wide phenomena.

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.

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.

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.

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.

Three new angiotensin converting-enzyme inhibitors were given orally to 20 men in single doses ranging from 1.25 to 40 mg. Two of them induced comparable marked inhibition of both the blood pressure response to exogenous angiotensin I and plasma converting-enzyme activity. Onset of action was relatively slow, but 21 to 24 hr after drug plasma converting-enzyme activity was still clearly reduced. The third was less active. There was a close correlation between blood pressure response on administration of angiotensin I and plasma converting-enzyme activity. There were no adverse effects. These new drugs are interesting because of their long duration of action. The measurement of plasma converting-enzyme activity seems useful for monitoring efficacy of converting-enzyme blockade and compliance to therapy.

The renal site of the natriuretic effect of human, atrial natriuretic peptide (hANP) was studied using clearance techniques in eight salt-loaded normal volunteers undergoing maximal water diuresis. Lithium was used as a marker of proximal sodium reabsorption. According to a two-way, single blind, crossover design, hANP (Met12-(3-28)-eicosahexapeptide, (2 micrograms/min) or its vehicle (Ve) were infused for two hours, followed by a two-hour recovery period. Blood pressure, heart rate and insulin clearance remained unchanged. During hANP infusion, the filtration fraction increased slightly from 19.6 to 24.3% (P less than 0.001), fractional water excretion rose transiently at the beginning of the infusion. Fractional excretion of sodium increased markedly from 2.2% to 7.4% (P less than 0.001) but remained unchanged with Ve. ANP increased fractional excretion of lithium slightly from 46 to 58% (P less than 0.01), while it remained stable at 47% during Ve. The distal tubular rejection fraction of sodium calculated from sodium and lithium clearances rose markedly from 4.7 to 13% (P less than 0.001) and returned to 6.2% at the end of the recovery period. Thus, under salt loading and water diuresis conditions, hANP infusion did not alter GFR, but reduced proximal reabsorption of sodium, and markedly enhanced the fraction of sodium escaping distal tubular reabsorption, suggesting that hANP-induced natriuresis is due, for an important part, to inhibition of sodium reabsorption in the distal nephron.

Lisinopril is an orally active, nonsulfhydryl angiotensin-converting-enzyme (ACE) inhibitor that is not metabolized or bound to protein. Peak serum concentrations occur 6-8 h after oral dosing. Lisinopril bioavailability (approximately 25%) is not significantly affected by food, age, or coadministration of hydrochlorothiazide (HCTZ), propranolol, digoxin, and glibenclamide. Lisinopril is excreted unchanged in the urine. Steady state is achieved in 2-3 days with little accumulation. Significant accumulation occurs in patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min). Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity. Lisinopril produces a smooth, gradual blood pressure (BP) reduction in hypertensive patients without affecting heart rate or cardiovascular reflexes. The antihypertensive effect begins within 2 h, peaks around 6 h, and lasts for at least 24 h. Lisinopril produces greater systolic and diastolic BP reductions than HCTZ. Lisinopril is similar to atenolol and metoprolol in reducing diastolic BP, but superior in systolic BP reduction. Lisinopril and nifedipine produce comparable reductions in systolic and diastolic BP. When lisinopril is given once daily as monotherapy, the range of BP reductions is 11-15% in systolic and 13-17% in diastolic. HCTZ addition enhances its antihypertensive effect. Lisinopril does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia. Lisinopril has natriuretic properties; renal blood flow remains stable or increases. Lisinopril increases cardiac output, and decreases pulmonary capillary wedge pressure and mean arterial pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Human experience to date (2,800 patients/subjects) indicates that lisinopril is well tolerated and has a good safety profile.

Enalapril, a long-acting, non-sulfhydryl, angiotensin converting enzyme (ACE) inhibitor, is well absorbed after oral administration, and hydrolised to its bioactive form, enalaprilic acid (EA). Administration with food does not affect its bioavailability; elimination is predominantly renal. Peak serum EA concentrations occur 4 h after an oral dose; its serum half-life is approximately 35 h, and steady state is achieved by the fourth day of treatment. Enalapril controls blood pressure in essential and renovascular hypertension without affecting heart rate or cardiovascular reflexes. It also decreases serum concentrations of ACE (for greater than 24 h), angiotensin II and aldosterone, and increases plasma renin activity. Once and twice-daily regimens are equally effective. In patients with congestive heart failure refractory to digitalis and diuretics, enalapril increases cardiac output and decreases pulmonary capillary wedge pressure. Long-term treatment produces improvement in NYHA functional classification, exercise capacity and ejection fraction. Human experience to date indicates that enalapril is safe and well tolerated.

Enalapril, an orally-active, long-acting, nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor, is extensively hydrolysed in vivo to enalaprilat, its bioactive form. Bioactivation probably occurs in the liver. Metabolism beyond activation to enalaprilat is not observed in man. Administration with food does not affect the bioavailability of enalapril; excretion of enalapril and enalaprilat is primarily renal. Peak serum enalaprilat concentrations are reached 4 hours post-dose, and the profile is polyphasic with a prolonged terminal half-life (greater than 30 hours) due to the binding of enalaprilat to ACE. Steady-state is achieved by the fourth daily dose, with no evidence of accumulation. The effective accumulation half-life following multiple dosing is 11 hours. Higher serum concentrations and delayed urinary excretion occur in patients with severe renal insufficiency. Enalapril reduces blood pressure in hypertensive patients by decreasing systemic vascular resistance. The blood pressure reduction is not accompanied by an increase in heart rate. Furthermore, cardiac output is slightly increased and cardiovascular reflexes are not impaired. Once- and twice-daily dosage regimens reduce blood pressure to a similar extent. Enalapril increases renal blood flow and decreases renal vascular resistance. Enalapril also augments the glomerular filtration rate in patients with a glomerular filtration rate less than 80 ml/min. Enalapril reduces left ventricular mass, and does not affect cardiac function or myocardial perfusion during exercise. There is no rebound hypertension after enalapril therapy is stopped. Enalapril does not produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. When combined with hydrochlorothiazide, enalapril attenuates the undesirable diuretic-induced metabolic changes. Therapeutic doses of enalapril do not affect serum prolactin and plasma cortisol in healthy volunteers or T3, rT3, T4 and TSH in hypertensive patients. Enalapril has natriuretic and uricosuric properties. The antihypertensive effect of enalapril is potentiated by hydrochlorothiazide, timolol and methyldopa, but unaffected by indomethacin and sulindac. No interactions occur between enalapril and frusemide, hydrochlorothiazide, digoxin and warfarin. The bioavailability of enalapril is slightly reduced when propranolol is coadministered, but this does not appear to be of any clinical significance. Enalapril increases cardiac output and stroke volume and decreases pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

Enalapril, the ethyl ester of a potent angiotensin converting enzyme inhibitor, enalaprilat, was administered to healthy volunteers as a capsule containing 10 mg of the maleate salt, every 24h for eight doses. Serum profiles show little accumulation of enalaprilat following eight daily doses of enalapril maleate. An average effective half-life for accumulation of approximately 11h was calculated from urine data. Comparison of observed 24-h urinary recoveries of enalaprilat to predicted steady-state recovery indicates that an 'average' steady state for enalaprilat is attained by the third or fourth dose of enalapril maleate. Statistical comparison of daily urinary recoveries, as well as Cmin values for enalaprilat, confirm this. Observed fluctuations in serum and urine data during apparent steady state suggest some day-to-day variability in the absorption of enalapril maleate and/or its hydrolysis to enalaprilat. An accumulation ratio of 1.3 for enalaprilat was calculated from the predicted steady-state urinary recovery and observed urinary recovery for dose one.

Following hemodynamic evaluation using invasive and noninvasive methods, 73 patients were treated in an open, uncontrolled, multicenter study with single oral doses of enalapril maleate 1.25 to 40 mg until the optimal dose for each patient (based upon hemodynamic response) was achieved. Diuretics were withheld and reinstituted only if necessary. Hemodynamic measurements were made at 0 (predrug), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdrug. Patients were discharged on their optimal dose, treated 1 to 4 months and then rehospitalized for repeat hemodynamic measurements. The optimal enalapril single dose was associated with the following mean peak responses: increased cardiac index 42% (SE = 6) and decreased pulmonary capillary wedge pressure 40% (SE = 3), systemic vascular resistance 39% (SE = 2), and mean arterial pressure 23% (SE = 1.5). These changes persisted during chronic therapy. Chronic treatment with enalapril also improved exercise capacity 40% (P less than 0.01), ejection fraction 18% (P less than 0.05) and clinical status (N.Y.H.A. functional class, P less than 0.01). Ten and 20 mg/day, taken as once- or twice-daily regimens, were the most commonly effective doses.

When three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin-converting enzyme (ACE). The half-life for the terminal phase (approximately 40 h) was not predictive of steady-state parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half-life for accumulation was 12.6 h. The mean accumulation ratio was 1.38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.

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.

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.

Synthetic atrial natriuretic peptide, containing 26 amino acids in the rat sequence, L-364, 343 (Ileu-ANP), was infused intravenously at increasing rates (1-40 micrograms/min) into four normal volunteers. Mean intraarterial blood pressure decreased and heart rate increased in cumulative-dose-dependent fashion. Skin blood flow as measured with a laser Doppler device rose already with a cumulative dose of 55 micrograms Ileu-ANP and further rises were directly related to dose. The only side effects observed were those accompanying symptomatic hypotension at higher doses. These findings provide strong evidence that Ileu-ANP acts as a vasodilator in normal volunteers.

To assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 microgram/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of 1 week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 microgram/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p less than 0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.

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 micrograms/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.

The effect of a synthetic analogue of atrial natriuretic peptide (Ileu-ANP) on haemodynamic, hormonal, and electrolyte excretion indices was studied in 7 patients with chronic congestive heart failure. Patients received in random order placebo or Ileu-ANP infusions (5 micrograms/min) for 4 h on 2 separate occasions, at least 1 week apart. Compared with placebo, Ileu-ANP caused significant reductions in mean systemic arterial pressure, mean pulmonary artery pressure, pulmonary diastolic pressure, and right atrial pressure. These changes were sustained for at least 2 h after infusion. Cardiac output increased from 6.2 to 7.4 l/min at 60 min, then returned to pre-infusion levels. Despite considerable falls in systemic pressure there was no significant increase in heart rate or plasma noradrenaline. With Ileu-ANP infusion, plasma renin activity, angiotensin, arginine vasopressin, aldosterone, and cortisol values were not significantly different from placebo values. Plasma cortisol and aldosterone increased after stopping Ileu-ANP. Neither urine volume nor sodium excretion rate was significantly increased by Ileu-ANP.

Angiotensin-converting enzyme inhibitor therapy has been thought to be more effective in hypertensive patients with normal or elevated levels of renin in the plasma. However, several studies have challenged this concept by demonstrating the efficacy of angiotensin-converting enzyme inhibitors (captopril and enalapril) in older patients, among whom a low level of renin activity in the plasma is common, and in other patients with low-renin essential hypertension. Lisinopril, a new long-acting angiotensin-converting enzyme inhibitor, also has been shown to be an effective antihypertensive agent in older patients. This report examines data from 97 older and 710 younger hypertensive patients enrolled in four multicenter trials of eight to 12 weeks' duration. In these trials, the dose of lisinopril was titrated until a diastolic pressure of less than 90 mm Hg was reached, or to a maximal dose of 80 mg per day. In general, the antihypertensive effect achieved in older patients with lisinopril was equal to or greater than that achieved in younger patients. The drug was generally well tolerated. Lisinopril can be expected to be used frequently in older patients.

The acute hypotensive response to oral and parenteral enalapril (E) and lisinopril (LI) was assessed in 24 patients with chronic congestive heart failure in two open, randomized, balanced, crossover studies. In the E study, 12 patients received each of three treatments: a single oral dose of 10 mg E, a single intravenous bolus of 5 mg E, and a single intravenous bolus of 5 mg enalaprilat (ET). In the LI study, 12 patients received each of two treatments: a single oral dose of 10 mg LI and a single intravenous bolus of 5 mg LI. Intraarterial blood pressure was measured continuously. Significant decreases from baseline in mean arterial pressure (MAP) were observed in all cases, starting at 15 min. The maximal hypotensive effect (MAP; mean +/- SD) was greatest and the nadir earliest for intravenous ET (-30 +/- 7 mm Hg at 75 min) compared with oral E (-25 +/- 10 mm Hg at 210 min) and intravenous E (-19 +/- 10 mm Hg at 195 min). Oral E and intravenous E had similar onsets of action. The maximal reduction following oral LI (-19 +/- 13 mm Hg at 210 min) was similar to oral E and intravenous E. The effect of intravenous LI (-25 +/- 9 mm Hg at 105 min) was similar to that of intravenous ET. Among the parenteral treatments, E produced the most gradual and least pronounced reduction in blood pressure, and may be best suited for use in the acute situation to minimize the risk of abrupt hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)