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Development and validation of a stability indicating HPLC method for determination of lisinopril, lisinopril degradation product and parabens in the lisinopril extemporaneous formulation.

The purpose of the research described herein was to develop and validate a stability-indicating HPLC method for lisinopril, lisinopril degradation product (DKP), methyl paraben and propyl paraben in a lisinopril extemporaneous formulation. The method developed in this report is selective for the components listed above, in the presence of the complex and chromatographically rich matrix presented by the Bicitra and Ora-Sweet SF formulation diluents. The method was also shown to have adequate sensitivity with a detection limit of 0.0075 microg/mL (0.03% of lisinopril method concentration). The validation elements investigated showed that the method has acceptable specificity, recovery, linearity, solution stability, and method precision. Acceptable robustness indicates that the assay method remains unaffected by small but deliberate variations, which are described in ICH Q2A and Q2B guidelines.

Chemistry, Pharmaceutical↗

Antihypertensive efficacy of candesartan-lisinopril in combination vs. up-titration of lisinopril: the AMAZE trials.

The AMAZE (A Multicenter Trial Using Atacand and Zestril vs. Zestril to Evaluate the Effects on Lowering Blood Pressure) program included two identical studies sponsored by AstraZeneca LP. The oral form of candesartan is candesartan cilexetil; for simplicity, the term "candesartan" is used throughout this manuscript. Two identical multicenter, randomized, double-blind studies were performed to determine if addition of the angiotensin receptor blocker candesartan was more effective in lowering blood pressure than up-titration of lisinopril. Hypertensive patients (N=1,096) who were uncontrolled on lisinopril 20 mg daily were randomized (1:1) to receive either 8 weeks of high-dose lisinopril (40 mg) or the addition of candesartan (16 mg) for 2 weeks followed by 32 mg for 6 weeks. Study 1 (n=538) demonstrated decreases in trough sitting systolic/diastolic blood pressures at Week 8 by 6.2/5.9 mm Hg, respectively, for the lisinopril up-titration treatment group and by 11.6/8.3 mm Hg, respectively, for the lisinopril plus candesartan treatment group (p<0.01 in comparing both blood pressures reductions between the two treatment groups). Corresponding results for Study 2 (n=558) are reductions of 8.7/6.2 mm Hg and 9.5/7.4 mm Hg, respectively, for each of the two treatment groups. For Study 2, comparisons of systolic/diastolic blood pressures between the two treatment groups were not statistically significantly different (p=0.51/p=0.08, respectively). Post hoc pooled analysis (N=1,096) demonstrated a slightly greater blood pressure reduction with lisinopril plus candesartan compared with lisinopril (3.1/1.7 mm Hg). A 95% confidence interval limit for the difference in least squares mean change from baseline in systolic blood pressure between the two treatment groups is -4.8 to -1.5 and is -2.8 to -0.7 in mm Hg for diastolic blood pressure. The blood pressure control rates (<140/<90 mm Hg) were 42.7% and 36.9%, respectively. Both treatment regimens were well tolerated in all groups. In conclusion, for hypertensive patients not controlled by lisinopril 20 mg once daily, addition of candesartan (32 mg once daily) or doubling the dose of lisinopril provides safe, additional reduction of blood pressure.

Aged↗

Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study.

BACKGROUND: The goal of antihypertensive therapy is to provide good blood pressure (BP) control without eliciting adverse effects. OBJECTIVE: This study compared the risk-benefit profile of the angiotensin II receptor blocker valsartan with that of the angiotensin-converting enzyme inhibitor lisinopril in patients with mild to severe hypertension. The primary objective was to show that the equipotent BP-lowering effect of the valsartan-based treatment is accompanied by a better tolerability profile. METHODS: This 16-week, randomized, double-blind, parallel-group study was conducted at 88 outpatient centers across Italy. After a 2-week placebo run-in period, patients aged > or = 18 years with mild to severe hypertension (systolic BP [SBP], 160-220 mm Hg; diastolic BP [DBP], 95-110 mm Hg) were eligible. Patients were randomized to receive once-daily, oral, self-administered treatment with valsartan 160-mg capsules or lisinopril 20-mg capsules under double-blind conditions for 4 weeks. Responders continued monotherapy, whereas nonresponders had hydrochlorothiazide 12.5 mg added for the final 12 weeks of the study. The 2 primary variables used to assess the equivalence of therapeutic efficacy of the 2 regimens were sitting SBP and sitting DBP, which were measured at weeks 0 (baseline), 4, 8, and 16. The rate of drug-related adverse events (AEs) was used to assess whether 1 treatment had a better tolerability profile than the other. Tolerability was assessed by collecting information about AEs by means of questioning the patient or physical examination at each visit. RESULTS: A total of 1213 patients were enrolled (635 men, 578 women; mean [SD] age, 54.5 [10.1] years [range, 28-78 years]). The study was completed by 1100 patients (553 receiving valsartan and 547 receiving lisinopril). Fifty-one patients (8.4%) treated with valsartan and 62 (10.2%) [corrected] treated with lisinopril withdrew, mainly because of AEs (9 [1.5%] and 23 patients [3.8%], respectively). The valsartan- and lisinopril-based treatments were similarly effective in reducing sitting BP, with mean SBP/DBP reductions of 31.2/15.9 mm Hg and 31.4/15.9 mm Hg, respectively. At the end of the study, BP was controlled in 82.6% [corrected] of the patients receiving valsartan and 81.6% of those receiving lisinopril. AEs were experienced by 5.1% of the patients treated with valsartan and 10.7% of those treated with lisinopril (P=.0001), with dry cough observed in 1.0% and 7.2% of patients, respectively (P<0.001). CONCLUSIONS: Valsartan and lisinopril were both highly effective in controlling BP in these patients with mild to severe hypertension, but valsartan was associated with a significantly reduced risk for AEs, especially cough.

Adult↗

Comparison of lisinopril versus digoxin for congestive heart failure during maintenance diuretic therapy. The Lisinopril-Digoxin Study Group.

Lisinopril 5-20 mg once daily was compared with digoxin 0.125-0.375 mg once daily in a double-blind, randomized, parallel-group study involving 217 patients with mild-to-moderate heart failure (New York Heart Association [NYHA] grades II-III) who were maintained on optimized diuretic therapy. After 6 weeks of treatment, digoxin and lisinopril had increased exercise duration by 18 seconds (p = 0.015) and 32 seconds (p = 0.0007), respectively, versus the baseline run-in period. The difference between treatments was not statistically significant (p = 0.1343). After 12 weeks, digoxin and lisinopril had increased exercise duration by 29 seconds and 51 seconds, respectively. The effect of digoxin compared with the baseline value was not significant but that for lisinopril was (p = 0.0027). The difference between treatments approached statistical significance (p = 0.0813). There was no difference between lisinopril and digoxin with regard to their effects on the frequency of ventricular ectopic counts, couplets, or nonsustained ventricular tachycardia. Blood pressures were not significantly different between treatments, although both systolic and diastolic blood pressure were consistently lower in the lisinopril group throughout randomized treatment. The proportions of patients demonstrating an improvement in NYHA grading were similar for both lisinopril and digoxin. Both treatments had similar effects on the symptoms of heart failure. Both drugs appeared to be equally well tolerated with a similar frequency of adverse events reported for both drugs (30% for lisinopril vs 29% for digoxin). Withdrawals from treatment were of a similar frequency for both treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. The Multicenter Lisinopril-Captopril Congestive Heart Failure Study Group.

A randomized, parallel, double-blind study was performed with lisinopril, a long-acting angiotensin-converting enzyme inhibitor, versus captopril, a shorter-acting angiotensin-converting enzyme inhibitor, in the treatment of congestive heart failure. All patients were in New York Heart Association class II, III or IV and had remained symptomatic despite therapy with digoxin and diuretics. After a 4 to 14 day placebo baseline period, patients were randomized to receive either lisinopril, 5 mg orally once per day (n = 94), or captopril, 12.5 mg orally three times per day (n = 95), in addition to continuation of digoxin and diuretics. The dose of study drug could be doubled at 4 week intervals for a total of 12 weeks of double-blind therapy. The maximal dose was 20 mg once per day of lisinopril or 50 mg three times per day of captopril. The addition of either lisinopril or captopril to a regimen of diuretics or digoxin, or both, caused an increase in exercise duration as assessed on a motorized treadmill. When protocol violators were excluded, patients receiving lisinopril had a statistically greater increase in exercise duration than that of patients receiving captopril. In patients with renal impairment (serum creatinine greater than 1.6 mg/dl at baseline), lisinopril was superior to captopril in improving exercise duration. Lisinopril, but not captopril, increased left ventricular ejection fraction in patients with moderately to severely (less than 35%) decreased function (p less than 0.05). Improvement in functional capacity and quality of life, as assessed by the Yale Scale dyspnea/fatigue index, was significantly greater for the lisinopril group.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

Lisinopril versus placebo in the treatment of heart failure: the Lisinopril Heart Failure Study Group.

Lisinopril, a long-acting, angiotensin-converting enzyme inhibitor, was compared with placebo in a randomized, parallel, double-blind, 12-week study of 193 patients with heart failure. All patients were New York Heart Association Functional Class II, III, or IV and had remained symptomatic despite optimal dosing with digoxin and diuretics. After 12 weeks of therapy, the improvement in treadmill exercise duration was greater in the lisinopril group (113 seconds) compared with the placebo group (86 seconds). This improvement in exercise duration was particularly evident in patients with left ventricular ejection fractions less than 35% (lisinopril = 130 seconds; placebo = 94 seconds). In patients receiving lisinopril, the increase in exercise duration was accompanied by an improvement in quality of life as measured by the Yale Scale Dyspnea/Fatigue Index and in signs and symptoms of heart failure. In addition, the lisinopril group had a larger mean increase (3.7%) in left ventricular ejection fraction when compared with the placebo group (1.3%). Thus, lisinopril, administered once daily for 12 weeks, was well tolerated and efficacious in the treatment of heart failure when used concomitantly with diuretics and digoxin.

Aged↗

Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus.

BACKGROUND: Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes. METHODS: As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20-59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-level scale (none to proliferative). FINDINGS: The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p = 0.2). Patients on lisinopril had significantly lower HbA1c at baseline than those on placebo (6.9% vs 7.3 p = 0.05). Retinopathy progressed by at least one level in 21 (13.2%) of 159 patients on lisinopril and 39 (23.4%) of 166 patients on placebo (odds ratio 0.50 [95% CI 0.28-0.89], p = 0.02). This 50% reduction was the same when adjusted for centre and glycaemic control (0.55 [0.30-1.03], p = 0.06). Lisinopril also decreased progression by two or more grades (0.27 [0.07-1.00], p = 0.05), and progression to proliferative retinopathy (0.18 [0.04-0.82], p = 0.03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0.69 [0.30-1.59], p = 0.4). INTERPRETATION: Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated.

Adult↗

Lisinopril versus lisinopril plus hydrochlorothiazide in essential hypertension.

The efficacy of a new angiotensin converting enzyme inhibitor, lisinopril, used alone (group A) was compared with lisinopril plus hydrochlorothiazide (group B) in 26 patients with essential hypertension. Therapy with both regimens was equally effective in lowering blood pressure compared to placebo. Mean antihypertensive dose of lisinopril was lower when given in combination with hydrochlorothiazide than when given alone (48 +/- 6 vs 68 +/- 12 mg daily). Plasma renin activity increased in both groups of patients, but more in group B (p less than 0.05). Plasma aldosterone concentrations and serum uric acid levels were also higher in the group receiving lisinopril plus hydrochlorothiazide (p less than 0.05). Serum potassium concentrations were unaffected in either group. The incidence of side effects was similar in groups A and B (44% and 38%, respectively). This study suggests that lisinopril alone or in combination with hydrochlorothiazide effectively lowers blood pressure in patients with essential hypertension without any major side effects.

Angiotensin-Converting Enzyme Inhibitors↗

[Evaluation of lisinopril and lisinopril-hydrochlorothiazide combination in mild to moderate arterial hypertension].

The main objective of this multicenter study was to compare the efficacy of an increase in dose and of a synergic combination in the 68 patients out of 126 (54%) with hypertension (DBP between 95 and 120 mm Hg after 2 weeks of placebo) who did not respond (DBP > or = 95 mmHg) to a 4-week treatment of 20 mg per day of lisinopril. Patients were randomized to receive a 4-week double-blind treatment of either 40 mg per day of lisinopril or the combination of 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide per day. Mean reductions of systolic (inter-group comparison: p = 0.08) and diastolic BP (p = 0.006) as well as the proportion of responders (82% versus 45%, p < or = 0.01) were greater with the lisinopril-hydrochlorothiazide combination than with 40 mg of lisinopril. Tolerance was good in the 3 groups. The administration of a synergic combination is justified when hypertension is not controlled by a monotherapy.

Dose-Response Relationship, Drug↗

Low doses vs. high doses of the angiotensin converting-enzyme inhibitor lisinopril in chronic heart failure: a cost-effectiveness analysis based on the Assessment of Treatment with Lisinopril and Survival (ATLAS) study. The ATLAS Study Group.

OBJECTIVE: A cost-effectiveness analysis of high and low doses of the angiotensin-converting enzyme (ACE) inhibitor lisinopril in the treatment of chronic heart failure. METHODS: A cost-effectiveness analysis using data from a randomized controlled trial, ATLAS, where 3164 patients with chronic heart failure were allocated to a high-dose (daily target dose 32.5-35 mg) or low-dose strategy (daily target dose 2.5-5.0 mg) of lisinopril. Differential costs were based on resource use data collected in the trial costed using UK unit costs. Cost-effectiveness analysis related differential costs to differential life-years during a 4-year trial follow-up. RESULTS: The mean total number of hospital in-patient days per patient was 18. 5 in the high dose group and 22.5 in the low dose group. Over the whole duration of the trial, the mean (S.D.) daily dose of lisinopril in the high-dose group was 22.5 mg (15.7 mg) compared to 3.2 mg (2.5 mg) in the low-dose group. The mean difference in cost per patient was pound sterling 397 lower in the high-dose group [95% CI (high-dose-low-dose) - pound sterling 1263 to pound sterling 436]. Mean life-years per patient were 0.085 years higher in the high-dose group [95% CI (high-dose-low-dose) -0.0074 to 0.1706). Based on mean costs and life-years, high-dose therapy dominates low-dose (less costly and more effective). Allowing for uncertainty in mean costs and life-years, the probability of high-dose therapy being less costly than low dose was 82%. If a decision maker is willing to pay at least pound sterling 3600 per life-year gained, the probability of high-dose being more cost-effective was 92%. CONCLUSIONS: The ATLAS Study showed that the treatment of heart failure with high-doses of lisinopril has a high probability of being more cost-effective than low-dose therapy.

Angiotensin-Converting Enzyme Inhibitors↗

Lisinopril combined with atenolol in the treatment of hypertension. Swedish Lisinopril Study Group.

This is a double-blind, randomized parallel-group multicenter study comprising 340 hypertensive patients. All were treated with 50 mg of atenolol once daily. If their recumbent diastolic blood pressure was greater than or equal to 95 and less than or equal to 115 mm Hg after a 4-week open run-in period, patients were randomized to receive additionally, 5, 10, or 20 mg of lisinopril once daily or placebo for a further 8-week period in a double-blind fashion. The additional effects on the trough (24-28 h after tablet intake) diastolic blood pressure of placebo and 5 mg of lisinopril were not statistically significant. Lisinopril at 10 and 20 mg reduced the recumbent diastolic blood pressure by 3.2 and 3.3 mm Hg, respectively, more than placebo (p = 0.010-0.011). The recumbent systolic blood pressure and heart rate did not change. The side effect profile of lisinopril was not different from that of placebo and adverse effects were few and mild.

Adolescent↗

Lisinopril-hydrochlorothiazide combination vs lisinopril for the treatment of hypertension.

This multicentre, double-blind, randomized, parallel-group study compared the antihypertensive effect of a once-daily fixed-dose combination of lisinopril 20 mg and hydrochlorothiazide 12.5 mg (L/HCTZ) with that of lisinopril 40 mg once-daily (L40), in patients uncontrolled (supine DBP greater than or equal to 91 mm Hg) on lisinopril 20 mg once daily (L20). After 8 weeks of treatment the supine and standing BPs 4-6 hours post dose were 2.7/1.3 mm Hg lower in the L/HCTZ patients than in the L40 patients. However, thee differences did not reach statistical significance. When measured 24-26 hours post dose, no significant difference was observed between the two treatments with respect to change from baseline for supine and standing BPs. There was no significant difference between treatments. Adverse events related to treatment were reported in 13.2% of L/HCTZ and 20.0% of L40 patients (difference not statistically significant), and withdrawals from L/HCTZ and L40 (1.1% and 2.2%) were not significantly different. The results indicate that in patients uncontrolled on L20, switching to L/HCTZ is as effective as increasing the dose of lisinopril to 40 mg once daily.

Adult↗

Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group.

OBJECTIVE: To test the antihypertensive and metabolic effects of lisinopril, 10 mg/d (L); hydrochlorothiazide, 12.5 and 25 mg/d (H12.5 and H25); and its combination with lisinopril (L/H12.5 and L/H25) against placebo in patients with mild to moderate (stage I and stage II) hypertension. DESIGN: Multicenter, double-blind, placebo-controlled outpatient study of 12 weeks' duration. PATIENTS: After 4 weeks of single-blind placebo treatment, 505 patients whose sitting diastolic blood pressure was 100 to 114 mm Hg were randomized into the study--467 patients completed it (placebo, 71; L, 80; H12.5, 79; H25, 77; L/H12.5, 79; and L/H25, 81). The patients were seen in the clinic every 2 weeks, where measurements of their sitting and upright blood pressure and heart rate were taken 24 +/- 2 hours after drug administration. Complete blood cell counts with differential cell counts, blood chemistry studies, urinalyses, and electrocardiograms were done at baseline and during the study. Roentgenograms were done once at baseline. RESULTS: Compared with placebo, all drug regimens decreased sitting and upright blood pressure (P < .001) and had no effect on sitting and upright heart rate. The greatest effect was obtained with the combinations of L/H12.5 and L/H25. There was no difference between L/H12.5 and L/H25 or between H12.5 and H25. There were no serious clinical side effects except cough, which was slightly higher with L, L/H12.5, and L/H25. The only metabolic side effects were in serum potassium level, which was lower with H25 (P < .01), and serum glucose level, which was higher with H25 and L/H25 (P < .01). CONCLUSIONS: The data suggest that (1) monotherapy of hypertension with L, H12.5, H25, L/H12.5, and L/H25 was effective and well tolerated; (2) the best results were achieved with L/H12.5 and L/H25; (3) lower doses of hydrochlorothiazide either alone or in combination with lisinopril were equipotent with higher doses and were free of metabolic side effects.

Blood Pressure↗

Controlled multicenter study of the antihypertensive effects of lisinopril, hydrochlorothiazide, and lisinopril plus hydrochlorothiazide in the treatment of 394 patients with mild to moderate essential hypertension.

Lisinopril (LIS) is a lysine analog of enalaprilat, the active metabolite of enalapril, an angiotensin-converting enzyme inhibitor (ACEI). Unlike enalapril, the precursor of enalaprilat, LIS is not a prodrug but has equal ACEI efficacy and potency and a slightly longer duration of action after oral administration. Short-term (12 weeks) and long-term (24 weeks) blood pressure control has been studied with LIS, hydrochlorothiazide (HCTZ), and LIS + HCTZ when given once a day. Drug treatment had three phases: (i) 2-4 weeks of single-blind placebo washout; (ii) 12 weeks of double-blind comparison therapy with LIS 20, 40, and 80 mg vs. HCTZ 12.5, 25, and 50 mg, vs. LIS + HCTZ 20 + 12.5, 40 + 25, and 80 + 50 mg; (iii) 13-24 weeks single-blind LIS vs. LIS + HCTZ. Starting double-blind therapy at the lowest dose, all three groups doubled the dose at weeks 4 and 8 if BP was not controlled with sitting diastolic BP (SDBP) less than 90 mm Hg. At the end of 12 weeks of double-blind therapy, uncontrolled HCTZ-only and LIS-only treatment groups were advanced to combination LIS + HCTZ therapy but uncontrolled LIS + HCTZ patients were dropped. Mean BP reductions (systolic/diastolic, mm Hg) for all three groups after 12 weeks of double-blind comparison therapy were: (i) LIS (n = 162), -16.6/-12.5; (ii) HCTZ (n = 155), -10.4/-6.8; (iii) LIS + HCTZ (n = 74), -23.9/-18.2 with p less than 0.01 for all groups compared to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Lisinopril. A review of its pharmacology and use in the management of the complications of diabetes mellitus.

Lisinopril, like other ACE inhibitors, lowers blood pressure and preserves renal function in hypertensive patients with non-insulin-dependent or insulin-dependent diabetes mellitus (NIDDM or IDDM) and early or overt nephropathy, without adversely affecting glycaemic control or lipid profiles. On available evidence, renoprotective effects appear to be greater with lisinopril than with comparator calcium channel blockers, diuretics and beta-blockers, despite similar antihypertensive efficacy. As shown by the EUCLID (EUrodiab Controlled trial of Lisinopril in Insulin-Dependent Diabetes) trial, lisinopril is also renoprotective in normotensive patients with IDDM and microalbuminuria. The effect in normotensive patients with normoalbuminuria was smaller than in those with microalbuminuria, and no conclusions can yet be made about its use in patients with normoalbuminuria. In complications other than nephropathy, lisinopril has shown some benefit. Progression to retinopathy was slowed during 2 years' lisinopril therapy in the EUCLID study. Although not yet fully published, these results provide the most convincing evidence to date for an effect of an ACE inhibitor in retinopathy. The drug may also improve neurological function, but this finding is preliminary. Lastly, post hoc analysis of the GISSI-3 trial indicates that lisinopril reduces 6-week mortality rates in diabetic patients when begun as early treatment after an acute myocardial infarction. The tolerability profile of lisinopril is typical of ACE inhibitors and appears to be similar in diabetic and nondiabetic individuals. Hypoglycaemia has occurred at a similar frequency with lisinopril and placebo, as shown in the EUCLID trial. In addition, the GISSI-3 study indicates that the incidence of persistent hypotension and renal dysfunction is increased with lisinopril in general, but the presence of diabetes does not appear to confer additional risk of these events in diabetic patients with acute myocardial infarction receiving lisinopril. In summary, lisinopril lowers blood pressure and produces a renoprotective effect in patients with IDDM and NIDDM without detriment to glycaemic control or lipid profiles. Like other ACE inhibitors, lisinopril should thus be viewed as a first-line agent for reducing blood pressure and preventing or attenuating nephropathy in hypertensive diabetic patients with IDDM or NIDDM and microalbuminuria or overt renal disease. The EUCLID study, using lisinopril, provides new data supporting an additional place in managing normotensive patients with microalbuminuria and IDDM. These findings, together with some evidence for an effect of lisinopril in delaying progression of retinopathy and in reducing mortality, suggest a broader role for the drug in managing diabetic vascular complications.

Angiotensin-Converting Enzyme Inhibitors↗

Lisinopril: a review of its use in congestive heart failure.

UNLABELLED: The ACE inhibitor lisinopril is a lysine derivative of enalaprilat, the active metabolite of enalapril. In patients with heart failure, maximum pharmacodynamic effects are produced 6 to 8 hours after administration of the drug and persist for 12 to 24 hours. High doses (32.5 to 35mg, administered once daily) of lisinopril in the Assessment of Treatment with Lisinopril and Survival (ATLAS) study demonstrated clinically important advantages over low doses (2.5 to 5mg, administered once daily) of the drug in the treatment of congestive heart failure. High doses of lisinopril were more effective than low doses in reducing the risk of major clinical events in patients with heart failure treated for 39 to 58 months. Compared with recipients of low doses, those receiving high doses of lisinopril had an 8% lower risk of all-cause mortality (p = 0.128), a 12% lower risk of death or hospitalisation for any reason (p = 0.002) and 24% fewer hospitalisations for heart failure (p = 0.002). These benefits were associated with significant cost savings. In short term (generally 12 weeks' duration) randomised, double-blind, parallel-group, multicentre clinical trials, lisinopril was significantly more effective than placebo and was at least as effective as captopril, enalapril, digoxin and irbesartan at improving symptomatic end-points and clinical status in patients with heart failure. Lisinopril is generally well tolerated by patients with heart failure. In controlled clinical trials, the most common adverse events occurring in recipients of the drug were dizziness, headache, hypotension and diarrhoea. Overall adverse event profiles for patients treated with high or low doses of lisinopril in the ATLAS study were similar. However, high doses of lisinopril used in the ATLAS study were associated with a higher incidence of adverse events, importantly hypotension and worsening renal function; nevertheless, these events were generally well managed by altering the dose of lisinopril or concomitant medications. Furthermore, despite the higher incidence of some adverse events with high doses of lisinopril, the frequency of treatment discontinuations because of adverse events was the same in the high and low dose groups. CONCLUSIONS: Lisinopril (when added to diuretics and/or digoxin) provides symptomatic benefits in patients with congestive heart failure. The ATLAS study demonstrated that high doses of lisinopril significantly reduced the risk of the combined end-point of morbidity and mortality compared with low doses of the drug. Importantly, there was no clinically significant decrease in the tolerability of the drug with use of a high dose. Lisinopril is at least as effective and as well tolerated as other members of the ACE inhibitor class for the treatment of congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗

The clinical pharmacology of lisinopril.

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.

Angiotensin-Converting Enzyme Inhibitors↗

Lisinopril. A review of its pharmacology and clinical efficacy in elderly patients.

Lisinopril, the lysine analogue of enalaprilat, is a long-acting angiotensin converting enzyme (ACE) inhibitor which is administered once daily by mouth. The efficacy of lisinopril in reducing blood pressure is well established in younger populations, and many trials now show it to be effective in lowering blood pressure in elderly patients with hypertension. In comparative and non-comparative clinical trials, 68.2 to 89.1% of elderly patients responded (diastolic pressure < or = 90 mm Hg) to > or = 8 weeks' lisinopril treatment. Age-related differences in antihypertensive efficacy do not appear to be clinically significant, and dosages effective in elderly patients tend to range from 2.5 to 40 mg/day. Dosages usually need to be lower in patients with significant renal impairment. In congestive heart failure, lisinopril 2.5 to 20 mg/day increases exercise duration, improves left ventricular ejection fraction and has no significant effect on ventricular ectopic beats. It is similar in efficacy to enalapril and digoxin and similar or superior to captopril on most end-points. Data from the GISSI-3 post-myocardial infarction trial show that lisinopril reduced mortality and left ventricular dysfunction when given for 42 days starting within 24 hours of the onset of infarction symptoms. Results at 6 weeks and 6 months were similar in elderly and younger patients. Elderly patients, however, among other subgroups, exhibited a strong reduction in risk of low ejection fraction after treatment (-25.5%). Economic studies suggest that lisinopril is cost saving compared with other ACE inhibitors in some markets. When given according to the GISSI-3 protocol, lisinopril appears to be one of the less expensive of the successful ACE inhibitor regimens for acute myocardial infarction. In other trials, patients with diabetic nephropathy and hypertension improved or did not deteriorate during lisinopril treatment. Blood pressure was controlled and reductions or trends towards reductions in albuminuria were observed. These reductions were similar to those in diltiazem, nifedipine and verapamil recipients, and greater than those in patients receiving atenolol. Lisinopril appears to reduce mortality in diabetic patients after myocardial infarction and may also improve neuropathy associated with diabetes. Lisinopril is well tolerated and the profile of adverse events seen is typical of ACE inhibitors as a class. There is a tendency for more elderly than younger patients to discontinue treatment, but this trend is not clearly related to the incidence of adverse events in these age groups. Drug interactions occur with few other agents and are usually clinically significant only between lisinopril and either diuretics or lithium. Lisinopril is, thus, an effective treatment for elderly patients with hypertension, congestive heart failure and acute myocardial infarction and has shown promising benefits in patients with diabetic nephropathy.

Aged↗