enalapril and Cough

Both enalapril and losartan are effective and widely used in patients with chronic kidney disease (CKD). This review aimed to evaluate the benefits of enalapril and losartan in adults with CKD.. PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, without language limitations, for randomized controlled trials (RCT), in which enalapril and losartan were compared in adults with CKD. Standard methods, consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, were used. Reviewer Manager software, ver. 5.2, was used for meta-analysis.. Of 318 citations retrieved, 17 RCT (14 parallel-group and three cross-over) met our inclusion criteria. The pooled analysis for parallel RCT showed that the effects of enalapril and losartan on blood pressure, renal function and serum uric acid (UA) were similar. Meta-analysis indicated that patients taking enalapril had a higher risk of dry cough (risk ratio, 2.88; 95% CI, 1.11-7.48; P=0.03). Sensitivity analysis showed good robustness of these findings.. Enalapril has similar effects to losartan on systemic blood pressure, renal function and serum UA in patients with CKD, but carries a higher risk of dry cough. Larger trials are required to evaluate the effects of these medications on clinical outcomes.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Pressure; Chi-Square Distribution; Cough; Creatinine; Enalapril; Female; Humans; Kidney; Losartan; Male; Middle Aged; Odds Ratio; Renal Insufficiency, Chronic; Renin-Angiotensin System; Risk Factors; Treatment Outcome; Uric Acid

Dry cough is a common, annoying adverse effect of all angiotensin-converting enzyme (ACE) inhibitors. The present study was designed to compare the rate of coughs reported in the literature with reported rates in the Physicians' Desk Reference (PDR)/drug label.. We searched MEDLINE/EMBASE/CENTRAL for articles published from 1990 to the present about randomized clinical trials (RCTs) of ACE inhibitors with a sample size of at least 100 patients in the ACE inhibitors arm with follow-up for at least 3 months and reporting the incidence or withdrawal rates due to cough. Baseline characteristics, cohort enrolled, metrics used to assess cough, incidence, and withdrawal rates due to cough were abstracted.. One hundred twenty-five studies that satisfied our inclusion criteria enrolled 198,130 patients. The pooled weighted incidence of cough for enalapril was 11.48% (95% confidence interval [CI], 9.54% to 13.41%), which was ninefold greater compared to the reported rate in the PDR/drug label (1.3%). The pooled weighted withdrawal rate due to cough for enalapril was 2.57% (95% CI, 2.40-2.74), which was 31-fold greater compared to the reported rate in the PDR/drug label (0.1%). The incidence of cough has increased progressively over the last 2 decades with accumulating data, but it has been reported consistently several-fold less in the PDR compared to the RCTs. The results were similar for most other ACE inhibitors.. The incidence of ACE inhibitor-associated cough and the withdrawal rate (the more objective metric) due to cough is significantly greater in the literature than reported in the PDR/drug label and is likely to be even greater in the real world when compared with the data from RCTs. There exists a gap between the data available from the literature and that which is presented to the consumers (prescribing physicians and patients).

Topics: Angiotensin-Converting Enzyme Inhibitors; Confidence Intervals; Cough; Drug Labeling; Enalapril; Humans; Incidence; Patient Dropouts; Randomized Controlled Trials as Topic; Reference Books, Medical

Eprosartan is an angiotensin II receptor antagonist (angiotensin II receptor blocker [ARB]) used in the treatment of hypertension. In large, randomized trials, eprosartan (with or without hydrochlorothiazide [HCTZ]) demonstrated superior antihypertensive efficacy to that of placebo and, when administered at comparable dosage regimens, had similar blood pressure-lowering effects to enalapril. Eprosartan was generally well tolerated in clinical trials and had a lower incidence of persistent dry cough than enalapril. Eprosartan has a neutral effect on metabolic parameters, such as serum lipid levels and glucose homeostasis, and a low propensity for pharmacokinetic drug interactions. The use of eprosartan or other ARBs in combination with HCTZ tends to reverse the potassium loss associated with thiazide diuretics. Independent of its antihypertensive effects, eprosartan was associated with improved clinical outcomes (primary composite endpoint of all causes of mortality and all cardiovascular and cerebrovascular events, including all recurrent events) compared with nitrendipine in a randomized, secondary prevention trial in hypertensive patients with previous cerebrovascular events (MOSES trial). Eprosartan also reduced blood pressure and was associated with a modest improvement in cognitive function in a large observational study in patients > or =50 years of age with newly diagnosed hypertension (OSCAR study). In both of these trials, additional antihypertensive therapy, such as HCTZ, was permitted. Therefore, eprosartan is a useful treatment option in the management of a broad range of patients with hypertension, and its use with HCTZ provides a rational combination regimen.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Clinical Trials as Topic; Cough; Enalapril; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Incidence; Nitrendipine; Randomized Controlled Trials as Topic; Receptors, Angiotensin; Recurrence; Risk Factors; Sodium Chloride Symporter Inhibitors; Thiophenes; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Enalapril; Female; Humans; Hypertension; Middle Aged

This report reviews the tolerability profile of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, in the treatment of patients with congestive heart failure. Data have been collected from 546 patients treated with enalapril for up to 9 months in clinical trials other than the Cooperative North Scandinavian Enalapril Survival Study. Results in patients treated with enalapril (n = 193) or placebo (n = 195) in double-blind, controlled clinical trials show that the incidences of death, serious adverse experiences, and adverse experiences requiring discontinuation of double-blind therapy, as well as the overall incidence of such experiences, were similar in the 2 groups. However, certain adverse experiences that are related to the mechanism of action of ACE inhibitors were seen more often after enalapril than after placebo treatment. Dizziness and hypotension were the most frequent adverse experiences reported in patients with heart failure treated with enalapril. The most frequent laboratory adverse experiences were increases in blood urea nitrogen and serum creatinine levels. hyperkalemia was also seen in patients receiving enalapril. It is possible to identify patients at risk of these experiences before initiating treatment with enalapril and to take certain measures (such as withholding or reducing the dose of diuretic drugs and discontinuing potassium supplements or potassium-sparing diuretic drugs) to reduce the likelihood that hypotension, increases in blood urea nitrogen and serum creatinine levels, or hyperkalemia will occur. Angioedema, a recognized adverse effect of ACE inhibitors, was not seen in the clinical trials reviewed here. Cough , another recognized adverse effect of these agents, was seen infrequently and rarely resulted in the discontinuation of enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angioedema; Blood Urea Nitrogen; Cough; Creatinine; Drug Tolerance; Enalapril; Heart Failure; Humans; Hyperkalemia; Hypotension

The PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) found a combination drug containing sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II receptor blocker) superior to enalapril (an angiotensin-converting enzyme inhibitor) in patients with systolic heart failure. Recently approved by the US Food and Drug Administration, sacubitril-valsartan is the first new drug in over a decade to decrease death rates in patients with systolic heart failure.

Topics: Aminobutyrates; Angioedema; Angiotensin Receptor Antagonists; Biphenyl Compounds; Cardiovascular Diseases; Cough; Double-Blind Method; Drug Combinations; Enalapril; Female; Heart Failure, Systolic; Hospitalization; Humans; Hyperkalemia; Hypotension; Male; Middle Aged; Neprilysin; Renal Insufficiency; Tetrazoles; Valsartan

The incidence of enalapril-induced cough was evaluated in 199 patients with congestive heart failure. Cough was more frequent in class I or II patients (28%) than in class III (4.1%, p<0.01) and class IV (0%, p<0.01) patients. Brain natriuretic peptide level was lower in patients in the cough (+) group than in the cough (-) group (170+/-107 vs. 538+/-637 pg/ml, p<0.01). The incidence of enalapril-induced cough is low in patients with severe congestive heart failure and a cough can be a marker of non-severe heart failure.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Cough; Enalapril; Female; Heart Failure; Humans; Incidence; Male; Middle Aged; Severity of Illness Index

To assess the clinical effects and safety profile of initial monotherapy with either bisoprolol or enalapril in elderly patients with heart failure (HF).. In CIBIS III, 1010 patients with mild to moderate HF and age>or=65 years were randomized to monotherapy with either bisoprolol or enalapril for 6 months.. Bisoprolol had a similar effect as enalapril on the combined end-point of all-cause mortality or hospitalization (HR 1.02; p=0.90), as well as on each of the individual end-points. A trend towards fewer sudden deaths was observed with bisoprolol (NS). On the other hand, more cases of worsening HF requiring hospitalization or occurring while in hospital were observed in the bisoprolol group (HR 1.67; p=0.03). The two groups were similar with regard to treatment cessations and early introduction of the second drug.. Bisoprolol and enalapril had a similar effect on the combined end-point of mortality or hospitalization during 6 months monotherapy. However, more worsening HF events were observed in the bisoprolol group.

Topics: Aged; Antihypertensive Agents; Bisoprolol; Blood Pressure; Bradycardia; Chronic Disease; Cough; Drug Administration Schedule; Enalapril; Female; Heart Failure; Heart Rate; Humans; Hypotension; Kaplan-Meier Estimate; Male; Prospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome; Withholding Treatment

To determine the incidence of cough secondary to (1) Cilazapril, (2) Enalapril, (3) Imidapril, and (4) Perindopril and their efficacy in the control of hypertension.. Randomized double-blind study conducted in selected medical centers in the Philippines from the first quarter of 1999 to March, 2001.. A total of 301 patients, aged 28-86 years with stage I or II hypertension were included. Patients were randomized to Cilazapril 2.5-5.0 mg/day (n=70), Enalapril 10-20 mg/day (n=82), Perindoril 4-8 mg/day (n=73), or Imidapril 10-20 mg/day (n=76). Hydrochlorothiazide 12.5 mg/day was added if needed. Using a dechallenge and rechallenge method, a strict criteria to attribute cough to angiotensin converting enzyme inhibitors (ACE-Is) not yet used in previous reports, the cough incidence were as follows: (1) Cilazapril--22.86% (16/70), (2) Enalapril--21.95% (18/82), (3) Perindopril--10.96% (6/73), and (4) Imidapril--13.16% (10/76) (P=0.041). Control of hypertension was significantly better with Enalapril during the first follow-up period.. Statistically significant differences in the incidence of cough among the studied ACE-Is were noted. Control of hypertension was observed to be better in those with a higher incidence of cough; however, the mean change of both systolic and diastolic blood pressure levels were not significantly different.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cilazapril; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Imidazolidines; Incidence; Male; Middle Aged; Perindopril; Philippines; Treatment Outcome

This study compared the efficacy and tolerability of eplerenone and enalapril in 499 patients with stage 1 or 2 hypertension who were randomized to receive eplerenone or enalapril for 6 months in a 3-step titration-to-effect study. After 6 months, patients whose diastolic blood pressure (BP) was <90 mm Hg had their dosages down-titrated were followed for an additional 6 months. Diastolic BP was the primary end point. Eplerenone was as effective as enalapril in reducing both systolic BP (eplerenone, -14.5 mm Hg; enalapril, -12.7 mm Hg; p = 0.199) and diastolic BP (eplerenone, -11.2 mm Hg; enalapril, -11.3 mm Hg; p = 0.910) at 6 months. BP reductions at 12 months were also similar between groups (-16.5/-13.3 mm Hg for eplerenone, -14.8/-14.1 mm Hg for enalapril; p = 0.251 and 0.331, respectively). Withdrawal rates for adverse events (eplerenone 7.9%, enalapril 9.3% at 6 months) and treatment failures (eplerenone 23.3%, enalapril 22.8% at 6 months) were also equivalent. Approximately 2/3 of each group had normal BP with monotherapy treatment at 6 months. BP response was independent of renin levels in the eplerenone group, but not in the enalapril group. Both agents reduced albuminuria in patients who had an elevated value at baseline, with significantly greater improvement in patients treated with eplerenone versus enalapril (-61.5% vs -25.7%; p = 0.01). Both agents were similarly well tolerated, and there was no increased incidence of any sexual adverse events in the eplerenone group. Patients taking enalapril had a higher rate of cough. Both agents increased serum potassium levels, but <1% in each group reported adverse events from hyperkalemia. Eplerenone was as effective as enalapril as monotherapy in patients with stage 1 or 2 hypertension, was more effective in reducing albuminuria, and was well tolerated for 12 months.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Antihypertensive Agents; Blood Pressure; Cough; Drug Tolerance; Enalapril; Eplerenone; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Renin-Angiotensin System; Spironolactone

Microalbuminuria in diabetes is a risk factor for early death and an indicator for aggressive blood pressure (BP) lowering. We compared a combination of 2 mg perindopril/0.625 mg indapamide with enalapril monotherapy on albumin excretion rate (AER) in patients with type 2 diabetes, albuminuria, and hypertension in a 12-month, randomized, double-blind, parallel-group international multicenter study. Four hundred eighty-one patients with type 2 diabetes and hypertension (systolic BP > or =140 mm Hg, <180 mm Hg, diastolic BP <110 mm Hg) were randomly assigned (age 59+/-9 years, 77% previously treated for hypertension). Results from 457 patients (intention-to-treat analysis) were available. After a 4-week placebo period, patients with albuminuria >20 and <500 microg/min were randomly assigned to a combination of 2 mg perindopril/0.625 mg indapamide or to 10 mg daily enalapril. After week 12, doses were adjusted on the basis of BP to a maximum of 8 mg perindopril/2.5 mg indapamide or 40 mg enalapril. The main outcome measures were overnight AER and supine BP. Both treatments reduced BP. Perindopril/indapamide treatment resulted in a statistically significant higher fall in both BP (-3.0 [95% CI -5.6, -0.4], P=0.012; systolic BP -1.5 [95% CI -3.0, -0.1] diastolic BP P=0.019) and AER -42% (95% CI -50%, -33%) versus -27% (95% CI -37%, -16%) with enalapril. The greater AER reduction remained significant after adjustment for mean BP. Adverse events were similar in the 2 groups. Thus, first-line treatment with low-dose combination perindopril/indapamide induces a greater decrease in albuminuria than enalapril, partially independent of BP reduction. A BP-independent effect of the combination may increase renal protection.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Cough; Diabetes Mellitus, Type 2; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Indapamide; Male; Middle Aged; Perindopril; Treatment Outcome

The objective of this study was to compare quality of life and incidence of dry persistent cough among patients treated with eprosartan and enalapril for mild-moderate hypertension. This was a randomised 26-week double-blind controlled trial carried out in clinics in nine countries of North America, Europe and South Africa. A total of 529 patients aged 18 and over with diastolic blood pressure between 95 mm Hg and 114 mm Hg were studied. Treatment comprised of eprosartan or enalapril monotherapy for 12 weeks with the option of hydrochlorothiazide addition for the remaining 14 weeks. The primary outcome measures were cough and the Psychological General Wellbeing Index (PGWB) total and subscales (anxiety, self-control, depression, general health, positive wellbeing and vitality). The results were that 17.8% of enalapril patients and 13.2% of eprosartan patients withdrew from randomised treatment. Those on enalapril were twice as likely to have gained a definite or possible cough by study end point as those on eprosartan (7.6% vs 3.2%) P = 0.099. At monotherapy end point the differences were greater (9.9% vs 2.1%) and of statistical significance, P = 0.001. Patients treated with enalapril, however, had small but significant improvements in measures of self-control and total PGWB compared with those on eprosartan. The effect sizes of 0.2 or less indicated that there were small differences. In conclusion eprosartan was associated with fewer coughs than enalapril but it performed less well on some aspects of quality of life.

Topics: Acrylates; Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Double-Blind Method; Drug Administration Schedule; Enalapril; Europe; Female; Follow-Up Studies; Humans; Hypertension; Imidazoles; Incidence; Male; Middle Aged; North America; Probability; Prospective Studies; Quality of Life; Risk Factors; Severity of Illness Index; South Africa; Thiophenes; Treatment Outcome

The objective of this study was to compare the quality of life and incidence of dry cough with the angiotensin II antagonist eprosartan, the ACE-inhibitor enalapril, and placebo, in hypertensive patients with a history of ACE-inhibitor cough. The study was a multicentre, randomised, double-blind, parallel group controlled trial. A total of 136 patients judged to have ACE-inhibitor cough during single-blind enalapril treatment which was lost during a subsequent placebo washout phase, were randomised to receive either eprosartan 300 mg twice daily, or enalapril 20 mg once daily, or placebo for 6 weeks. Self-completion questionnaires assessing quality of life and cough were examined at baseline and end of study. At study end point 23% of patients in the enalapril group and 5% in the eprosartan and placebo groups reported cough (which included definite, probable and possible coughs) (P = 0.02). After adjusting for multiple comparisons, the eprosartan group was not significantly different from either placebo or enalapril. There were no significant differences in the Psychological General Wellbeing Index (PGWB). In conclusion the incidence of self-reported cough on eprosartan was similar to that on placebo, and lower than on enalapril but this difference was not significant when adjustments were made for multiple comparisons. There were no differences in quality of life.

Topics: Acrylates; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Double-Blind Method; Drug Administration Schedule; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Imidazoles; Incidence; Male; Middle Aged; Probability; Quality of Life; Reference Values; Risk Assessment; Severity of Illness Index; Thiophenes; Treatment Outcome

The aim of this study was to evaluate the occurrence of dry cough during treatment with candesartan cilexetil, enalapril, or placebo in patients with hypertension and a history of angiotensin converting enzyme (ACE)-inhibitor-related cough. Patients with confirmed cough during an enalapril (10 mg) challenge period, followed by no cough during a placebo dechallenge period were randomized to 8 weeks of double-blind treatment with candesartan cilexetil (8 mg) (n = 62), enalapril (10 mg) (n = 66), or placebo (n = 26). Incidence and severity of dry cough was evaluated by the symptom assessment questionnaire, frequency of dry cough by a visual analog scale, and the possible impact on quality of life by the minor symptom evaluation (MSE) profile. The percentage of patients with cough was significantly lower with candesartan cilexetil (35.5%) than with enalapril (68.2%, P < .001), and did not differ between candesartan cilexetil and placebo (26.9%, P > .20). Patients coughed less frequently and with less severe cough with candesartan cilexetil than with enalapril, and similarly with candesartan cilexetil and placebo. Changes in the MSE profile were minor, although candesartan cilexetil had better scores for contentment than placebo (P = .03), and also tended to be associated with better sleep than enalapril (P = .08). In hypertensive patients with ACE-inhibitor-induced cough, the incidence, frequency, and severity of dry cough was significantly lower with candesartan cilexetil than with enalapril, and no different from that found with placebo.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Quality of Life; Safety; Surveys and Questionnaires; Tetrazoles; Treatment Outcome

A double-blind comparator study was performed in 528 hypertensive patients [baseline sitting diastolic blood pressure (SitDBP) 95-114 mmHg]. The primary objective was to compare the incidence of drug-related cough in patients treated with enalapril and eprosartan. The secondary objective was to compare antihypertensive efficacy between treatments. This paper reports the results of a prespecified subgroup analysis performed in the patients under and over 65 years of age recruited into the study. Eprosartan was titrated from 200 mg b.i.d. to 300 mg b.i.d. and enalapril from 5 mg o.d. to 20 mg o.d. over 12 weeks. Hydrochlorothiazide (HCTZ) 12.5-25 mg o.d. could be added where required to the treatment for the final 6 weeks of the titration phase if SitDBP > or = 90 mmHg. Patients received the maximum titrated dosage during the maintenance phase. In the study overall, the incidence of cough at monotherapy endpoint was significantly higher in the enalapril-treated group than in the eprosartan-treated group (p = 0.018). Similar mean changes in blood pressure from baseline were evident with each treatment. The elderly subpopulation mirrored the response of the study as a whole. Both treatments lowered BP with a further reduction evident following the addition of HCTZ at week 18. In conclusion, eprosartan is effective and safe in elderly hypertensive patients. The combination of eprosartan and HCTZ is also well tolerated and provided additional efficacy in those patients not responding to eprosartan alone. Compared with eprosartan enalapril was associated with an increased risk of cough. These results suggest that, irrespective of age, patients may be less likely to discontinue treatment with eprosartan than with an ACE inhibitor.

Topics: Acrylates; Age Factors; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Consumer Product Safety; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Imidazoles; Male; Thiophenes

A double-blind comparator study was performed in 528 hypertensive patients [baseline sitting diastolic blood pressure (SitDBP) 95-114 mmHg]. The primary objective was to compare the incidence of drug-related cough in patients treated with enalapril and eprosartan. The secondary objective was to compare antihypertensive efficacy between treatments. This paper reports the results of a prespecified subgroup analysis performed in the 40 black patients recruited into the study. Eprosartan was titrated from 200 mg b.i.d. to 300 mg b.i.d. and enalapril from 5 mg o.d. to 20 mg o.d. over 12 weeks. Hydrochlorothiazide (HCTZ) 12.5-25 mg o.d. could be added where required to the treatment for the final six weeks of the titration phase if SitDBP > or = 90 mmHg. Patients received the maximum titrated dosage during the maintenance phase. In the study overall, the incidence of cough at monotherapy endpoint was significantly higher in the enalapril-treated group than in the eprosartan-treated group (p = 0.018). This trend was reflected in the black subgroup but the numbers were too small to confirm significance. At study endpoint the mean change in SitDBP was -10.5 +/- 1.9 mmHg and -9.6 +/- 2.4 mmHg for eprosartan-treated and enalapril-treated patients, respectively. The mean change in SitSBP for eprosartan-treated black patients was -18.8 +/- 3.5 mmHg and for enalapril-treated patients was -10.5 +/- 3.7 mmHg. The black subpopulation mirrored the response of the study as a whole. Both treatments lowered BP with a further reduction evident following the addition of HCTZ at week 18. In conclusion, eprosartan is effective and appears to be safe in black hypertensive patients. The combination of eprosartan and HCTZ was also well tolerated and provided additional efficacy in those patients not responding to eprosartan alone. The incidence of treatment-associated cough in the black subgroup was low, but there were no apparent differences between treatment groups.

Topics: Acrylates; Adult; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black People; Blood Pressure; Consumer Product Safety; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Imidazoles; Male; Middle Aged; Thiophenes

The effects of a new angiotensin receptor antagonist, eprosartan (200 or 300 mg b.i.d.) and enalapril (5-20 mg u.i.d.) on cough and blood pressure were compared in a 26-week, double-blind, randomised, parallel-group, multicentre, international study involving 528 patients with hypertension. Uptitration of doses was based on clinic blood pressure measurements during the first 12 weeks, after which hydrochlorothiazide (12.5-25 mg/day) could be added. The frequency and intensity of cough was assessed by a standardised questionnaire administered at each clinic visit. The primary end-point was the incidence of persistent, dry cough not due to upper respiratory infection; change in sitting diastolic blood pressure and overall incidence of cough were secondary end-points. During the first 12 weeks of double-blind therapy, enalapril treatment was associated with a 3.45-fold higher risk of definite cough (14/261 vs 4/259, P = 0.018). Overall cough incidence (from spontaneous reports from patients, or investigator's observation) was also more frequent with enalapril, as compared to eprosartan. Both agents reduced blood pressure significantly compared to baseline, although the eprosartan-treated group had a slightly higher response rate (defined as sitting diastolic blood pressure <90 mm Hg, or at least a 10 mm Hg reduction from baseline), both at end of titration (70.3% vs 62.6%, P < 0.05) and after 26 weeks (81.7% vs 73.5%, P= 0.018). These data suggest that, in unselected hypertensive patients, eprosartan is associated with less cough and a somewhat higher responder rate than enalapril.

Topics: Acrylates; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cough; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Incidence; Male; Middle Aged; Risk Factors; Single-Blind Method; Sodium Chloride Symporter Inhibitors; Surveys and Questionnaires; Thiophenes; Treatment Outcome

To compare the incidence of cough between two angiotensin converting enzyme (ACE) inhibitors, imidapril and enalapril, comparative crossover study was performed in 489 patients (228 men and 261 females) with essential or renal parenchymal hypertension. Patients were randomly assigned to one of two treatment groups, a group receiving imidapril for 12 wk (Period I) followed by enalapril for 12 wk (Period II), and a group in which the order of drugs was reversed. The occurrence of cough during treatment was monitored by questionnaire in all cases. There were no differences in background characteristics between the two groups. The incidence of cough during Period I was 15.2% (32/210) in the group initially treated with imidapril (Group IE) and 38.6% (85/220) in the group initially treated with enalapril (Group EI), the difference being statistically significant (p < 0.001). During Period I, decrease in blood pressure was observed in 63.9% (115/180) of Group IE and 64.6% (115/178) of Group EI patients. In approximately half of the patients in Group EI who developed cough during Period I and in whom the treatment was subsequently switched to imidapril, cough subsequently disappeared. It was concluded that the incidence of cough was significantly less under imidapril than under enalapril treatment, while there was no difference in the antihypertensive effects of the two ACE inhibitors.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Enalapril; Female; Humans; Hypertension; Imidazoles; Imidazolidines; Male; Treatment Outcome

The increased prostaglandin synthesis that might follow stimulation of the arachidonic acid cascade by angiotensin-converting-enzyme inhibition (ACE-I) has been suggested to underlie the appearance of cough on ACE-I treatment. We investigated whether the prostanoid thromboxane was involved.. Nine patients with essential hypertension who had cough after enalapril 20 mg once a day (coughers) were treated, while continuing the enalapril, in a double-blind crossover study with placebo or picotamide, 600 mg twice daily. Picotamide is a platelet antiaggregant that acts through both inhibition of thromboxane synthase and thromboxane-receptor antagonism. Thirteen hypertensive patients with no history of ACE-I-induced cough were also treated with enalapril and served as controls. Cough frequency was measured by a visual analogue scale and by a daily cough diary. 24 h urinary recovery of 11-dehydro-thromboxane-B2 and 6-keto-PGF1 alpha were measured to assess any changes in endoperoxide metabolism during the study periods.. 11-dehydro-thromboxane-B2 (TXB2) recovery was significantly reduced by picotamide, which led to the disappearance of cough in eight patients within 72 h. Picotamide urinary recovery data suggested incomplete absorption in the non-responder. At baseline and after rechallenge with enalapril, 11-dehydro-TXB2 excretion was in the same range in the controls and in the coughers, but the latter showed significantly lower excretion of 6-keto-PGF1 alpha, and their ratio of 11-dehydroTXB2 to 6-keto-PGF1 alpha was twice that of the controls (1.40 [95% CI 0.86-1.95] vs 0.61 [0.37-0.84]).. A thromboxane antagonist is effective in ACE-I-induced cough. An imbalance between thromboxane and prostacyclin may represent a marker of patients susceptible to ACE-I-induced cough.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Double-Blind Method; Enalapril; Humans; Hypertension; Middle Aged; Phthalic Acids; Platelet Aggregation Inhibitors; Thromboxane B2; Thromboxanes

In the Studies of Left Ventricular Dysfunction (LVD), enalapril or placebo was administered in a double-blind fashion to 6797 participants with ejection fraction < or = 0.35. During 40 months' average follow-up, 28.1% of participants randomized to enalapril reported side effects compared with 16.0% in the placebo group (p < 0.0001). Enalapril use was associated with a higher rate of symptoms related to hypotension (14.8% vs 7.1%, p < 0.0001), azotemia (3.8% vs 1.6%, p < 0.0001), cough (5.0% vs 2.0%, p < 0.0001), fatigue (5.8% vs 3.5%, p < 0.0001), hyperkalemia (1.2% vs 0.4%, p = 0.0002), and angioedema (0.4% vs 0.1%, p < 0.05). Side effects resulted in discontinuation of blinded therapy in 15.2% of the enalapril group compared with 8.6% in the placebo group (p < 0.0001). Thus enalapril is well tolerated by patients with LVD; however, hypotension, azotemia, cough, fatigue, and other side effects result in discontinuation of therapy in a significant minority of patients.

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Cough; Double-Blind Method; Enalapril; Fatigue; Female; Follow-Up Studies; Heart Failure; Humans; Hyperkalemia; Hypotension; Male; Middle Aged; Sex Factors; Time Factors; Uremia; Ventricular Dysfunction, Left

An important aspect of antihypertensive drug treatment is quality of life (QL) which should at least not be negatively affected. In this study, the QL during treatment with carvedilol (C), a beta-blocker with vasodilating properties due to alpha-1-receptor blockade, was compared to that of enalapril (E) in patients who had responded to the treatment.. Patients with mild to moderate hypertension (diastolic blood pressure 95-115 mmHg) were randomised to receive either E(n = 119) of C(n = 129) in a double-blind multicenter study. The starting doses were 12.5 (C) and 10 (E) mg with doubling of the dose if necessary at 3-week intervals. If insufficient blood pressure (BP) control was found at 50 mg C or 40 mg E, 12.5 mg of hydrochlorothiazide was added. After having reached the goal BP the patients entered a 5-months maintenance period. General well-being was evaluated by the "Göteborg Quality of Life Questionnaire".. Equally many patients in the respective treatment groups responded at the different dose levels. Diastolic BP after 5 months in the maintenance period was similar on C and E, respectively. For most items, QL was not affected by the treatments. An increased incidence of cough was perceived in the E group (p < 0.001). None of the C treated patients reported frequent cough at the end of the study compared with 12% of E treated patients.. C and E had similar BP lowering effects. Neither treatment seemed to affect the patients QL adversely. Cough, although seldom leading to withdrawal from the therapy, may be more common than is commonly recognised during treatment with ACE-inhibitors.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Carbazoles; Carvedilol; Cough; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hypertension; Lipids; Male; Middle Aged; Propanolamines; Quality of Life

1. In nine hypertensive patients with enalapril-induced cough the effect of altering the dose of enalapril on subjective cough and the cough response to inhaled capsaicin was examined in a random single-blind balanced cross-over study. They received three doses of enalapril, each for 3 weeks; the dose at entry (mean 10 mg daily); double this dose (mean 20 mg daily); and half this dose (mean 5 mg daily). 2. The cough response to inhaled capsaicin was also measured in two control groups: hypertensive patients on long-term enalapril treatment with no cough (n = 18), and hypertensive patients taking nifedipine (n = 17). 3. In patients with enalapril-induced cough there were significant dose-responses for enalapril as regards severity of cough (P < 0.05) and night time waking by cough (P < 0.05), but not for frequency of cough. Although the cough was less severe (P < 0.02) and caused less night time waking (P < 0.03) on the lowest dose of enalapril (mean 5 mg daily) it did not disappear completely in any patient. 4. The sensitivity to inhaled capsaicin did not differ significantly on the three doses of enalapril. The relative potency of capsaicin on enalapril 20 mg compared with enalapril 5 mg was 1.0 (95% CI 0.4-2.2). The wide confidence limits indicate that an important dose-dependent shift in capsaicin sensitivity is not excluded. 5. The sensitivity to inhaled capsaicin differed significantly between patients with enalapril-induced cough and both control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Adult; Aged; Analysis of Variance; Capsaicin; Cough; Cross-Over Studies; Dose-Response Relationship, Drug; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Prospective Studies; Single-Blind Method

1. The reproducibility of angiotensin converting enzyme inhibitor induced cough was examined in a double-blind cross over study in patients previously shown to have exhibited this side effect. 2. Ninety-seven patients who had experienced angiotensin converting enzyme inhibitor cough within the last 2 years were challenged with enalapril 20 mg daily for 4 weeks to establish eligibility. Eighty-eight of 97 (91%) patients experienced a repeat of their cough symptoms. Sixty-four patients entered the double-blind part of the study where they were treated with enalapril 20 mg and a renin inhibitor for up to 4 weeks in random order. These periods were separated by a minimum 4 week placebo wash out. 3. Of 59 evaluable patients who received enalapril a second time, 37 (62.7%) experienced cough again. Of 62 patients on the renin inhibitor 16 (25.8%) experienced cough, however as it was not equi-efficacious to enalapril no valid comparison could be made. 4. Angiotensin converting enzyme inhibitor cough is not reproducible within patients, as other factors are involved in the aetiology. Objective testing with blinded assessment together with symptom reporting, would give a more accurate measure of the incidence, and mechanism of this side effect.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Double-Blind Method; Enalapril; Female; Humans; Male; Middle Aged; Renin; Reproducibility of Results

1. Angiotensin converting enzyme (ACE) inhibitors are in common use for the treatment of hypertension and heart failure. Whereas they are, in general, well tolerated, a dry cough can develop which, on occasion, requires termination of therapy. The reported prevalence of cough with ACE inhibitor therapy has varied from 0.2 to 25%, depending upon methods of data collection, analysis and symptom reporting. 2. To evaluate the prevalence of cough in Chinese patients receiving ACE inhibitors, interviews were carried out in 191 patients in Hong Kong who were taking therapy which included captopril or enalapril for hypertension or heart failure, and 382 patients matched for sex and age receiving alternative medications which excluded an ACE inhibitor (controls). Patients and controls were interviewed in a blinded manner by the same interviewer using a common adverse-effect questionnaire. 3. Persistent cough was reported in 44% of patients taking an ACE inhibitor (46% of those receiving captopril and 41.8% of patients taking enalapril), and in 11.1% of the controls (P < 0.001). The prevalence of other adverse reactions was similar, with no significant difference between the two treatment groups. The complication of cough was not related significantly to age, sex, underlying disease, drug dosage or smoking status. 4. This study indicates that cough is a common side effect of treatment with ACE inhibitors in Hong Kong Chinese, although in most patients cessation of therapy is not required. Whether Chinese are particularly susceptible to ACE-inhibitor cough requires a formal prospective study comparing Chinese and non-Chinese patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Chi-Square Distribution; Coronary Disease; Cough; Enalapril; Female; Hong Kong; Humans; Hypertension; Male; Middle Aged; New Zealand

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E2 (PGE2), which are likely to be involved in the mechanism of enalapril-induced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE2 did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be diminished or eliminated by a switch to night-time administration.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Cough; Dinoprostone; Enalapril; Enalaprilat; Female; Half-Life; Humans; Hypertension; Male; Middle Aged; Substance P

1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Capsaicin; Cough; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Substance P

To evaluate the blood pressure lowering efficacy as well as tolerability and safety of the angiotensin II antagonist losartan compared with that of the angiotensin converting enzyme inhibitor enalapril in patients with mild-to-moderate essential hypertension.. The study was a multicentre, double-blind, double-dummy, randomized, parallel study. Patients (n = 407) with diastolic blood pressure > or = 95 and < or = 120 mmHg at the end of a 2-week baseline placebo period were randomly allocated to receive either 50 mg losartan once a day or 20 mg enalapril once a day for 12 weeks. Blood pressure, clinical and laboratory safety, specific symptoms including coughing determined using a symptoms questionnaire and metabolic variables were examined at baseline and at weeks 6 and 12.. Both losartan and enalapril decreased systolic and diastolic blood pressure from baseline at weeks 6 and 12. Blood pressure changes from baseline at trough (22-26 h after the dose) did not differ between the two groups in the per-protocol analysis. Response to treatment at trough was excellent or good (diastolic blood pressure < 90 mmHg or reduction in diastolic blood pressure of 10 mmHg) in 51 and 53% of the patients in the losartan and enalapril groups, respectively. Enalapril administration increased dry coughing symptoms whereas losartan did not. The incidence of dry coughing was 1.0 and 12.2% as a spontaneously reported discomfort at week 12 and 3.0 and 15.1% as a clinical adverse experience in the losartan and enalapril groups, respectively. The difference from baseline at week 12 in the incidence of dry coughing between the two groups was 14.9% as a specific symptom in the symptoms questionnaire. Losartan reduced serum uric acid concentration, whereas effects on other metabolic parameters did not differ between the groups.. Losartan is an effective and well-tolerated antihypertensive drug showing similar blood-pressure-lowering efficacy to that of enalapril at trough. However, in contrast to enalapril, losartan does not increase the incidence of dry coughing. Thus, the angiotensin II antagonist losartan provides a promising new approach to treatment of hypertension.

Topics: Adult; Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Blood Pressure; Cough; Diastole; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Imidazoles; Losartan; Male; Middle Aged; Systole; Tetrazoles

Topics: Adult; Aged; Captopril; Cilazapril; Cough; Dose-Response Relationship, Drug; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

Topics: Angiotensin-Converting Enzyme Inhibitors; Cough; Double-Blind Method; Enalapril; Female; Humans; Lisinopril; Male; Sex Factors

Two randomised, double-blind, cross-over studies in healthy volunteers given captopril 50 mg b.d. (n = 37; Study I) or enalapril 20 mg o.d. (n = 40; Study 2) and placebo for 2 weeks have been done to examine general well-being. Subjective experiences were evaluated using the standardised, Minor Symptoms Evaluation-profile (MSEP), which was completed during Run-in and on Days 1, 4, 7 and 14 in the morning. In comparison to placebo and the Run-in period, neither captopril nor enalapril affected the MSEP dimensions of Vitality, Contentment and Sleep. Captopril treatment was also assessed by applying the Quality of Life Clinical Questionnaire during Run-in and on Days 7 and 14. No improvement in the quality of life was demonstrated during treatment in comparison with the placebo or the Run-in period. Thus, no mood elevating effect of the ACE-inhibitors captopril and enalapril was demonstrated in healthy volunteers. Cough, which is believed to be a common adverse effect of ACE-inhibitors, was no more frequent during the treatment with captopril or enalapril than with placebo. It is concluded, that short-term treatment with captopril or enalapril is not perceived differently by healthy volunteers than placebo or no treatment at all. Furthermore, the cough associated with ACE-inhibition may be dependent on the duration of treatment, and two weeks was apparently too short for it to emerge.

Topics: Adult; Affect; Captopril; Cough; Double-Blind Method; Enalapril; Female; Health Status; Humans; Male; Middle Aged; Quality of Life; Surveys and Questionnaires; Time Factors

Twenty-one subjects with known bronchial hyperreactivity were prospectively randomized in double-blind fashion to receive one of two angiotensin-converting enzyme inhibitors (ACE-I), enalapril or spirapril, for three weeks. Spirometry and methacholine provocation were performed prior to, during, and following ACE-I usage. Three of 21 subjects developed a nonproductive cough. However, only one subject wheezed slightly. Spirometry and bronchial reactivity (PD20) were unchanged throughout the study.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cough; Double-Blind Method; Drug Tolerance; Enalapril; Female; Humans; Male; Methacholine Chloride; Middle Aged; Prospective Studies; Single-Blind Method

Topics: Adult; Aged; Bronchodilator Agents; Cough; Enalapril; Female; Humans; Male; Middle Aged; Phthalazines; Sulindac

The efficacy and tolerability of combination therapy using Lisinopril (5-20 mg om) and Isradipine (1.25 mg-2.50 mg bd) was assessed in 29/50 Chinese subjects, whose blood pressures were not controlled on Isradipine alone. The addition of Lisinopril produced approximately two-fold reductions in blood pressure compared to Isradipine alone, increasing the responder rate of the original cohort of 50 subjects by 18% and normalization rate, by 32%. No significant changes in haematological or biochemical parameters, CXR or ECG, were observed. However, use of Lisinopril in our subjects was associated with a high incidence of cough (48%), possibly limiting its use in this population.

Topics: Adult; Aged; Antihypertensive Agents; Cough; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Lisinopril; Male; Middle Aged

We studied the effects of angiotensin converting enzyme (ACE) inhibitors on cough responses to bradykinin (BK), substance P (SP) and citric acid in a double blind, random study on 10 hypertensive patients receiving ACE inhibitors. Of these patients, five had reported cough with ACE inhibitors. Cough responses to citric acid were similar between patients with and without cough, and SP up to 10(-5) M did not cause cough in any of the subjects. BK caused cough at 13.4 +/- 1.2 (-log M) in 5 patients with cough associated with ACE inhibitors, but it did not cause cough at concentrations up to 10(-5) M in other 5 patients. One month after the withdrawal of ACE inhibitors, 5 patients were free from cough symptoms, and BK did not cause cough up to 10(-5) M in these patients, except for one who coughed at 10(-9) M, without changes in responses to citric acid. BK caused cough at 14.3 +/- 0.7 (-log M) although BK1-7, a major metabolite of BK by ACE, caused cough at 5.7 +/- 0.7 (-log M) in another 3 patients with cough associated with ACE inhibitor. These results suggest that impaired metabolism of BK induced by ACE inhibitors may relate to the manifestation of cough in hypertensive patients receiving ACE inhibitors.

Topics: Adult; Aerosols; Aged; Bradykinin; Captopril; Citrates; Citric Acid; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Reflex; Respiratory Function Tests; Substance P

To compare the effects of three different angiotensin converting enzyme (ACE) inhibitors on the cough reflex, capsaicin and citric acid challenge tests were done in normal subjects and hypertensive patients before and after administration of delapril, captopril, or enalapril. Two groups of 7 normal subjects (single dose study: 15 mg delapril v 18.75 mg captopril or 2.5 mg enalapril) and a group of 6 mildly hypertensive patients (1 week study: cross-over administration of 30 mg/day delapril, 37.5 mg/day captopril, or 5 mg/day enalapril) were studied. Another group of 6 patients with essential hypertension was treated with three ACE inhibitors for 4 weeks in a randomized order, with a 2 week washout period between active therapies. Aerosols of 1 mumol/L and 3 mumol/L capsaicin and 0.68% citric acid in 0.9% NaCl were generated by an ultrasonic nebulizer, and the frequency of cough was counted during inhalation. Delapril treatment resulted in substantially fewer patients with a significant increase (greater than or equal to 4 coughs during treatment than during the control period) in the frequency of cough than did captopril treatment. In the 1 and 4 week studies, enalapril and captopril had substantially more occurrences of significantly increased capsaicin-induced cough than did delapril. These results indicate that delapril has the least cough stimulatory effect among these ACE inhibitors, which may be clinically beneficial.

Topics: Administration, Inhalation; Adult; Angiotensin-Converting Enzyme Inhibitors; Capsaicin; Captopril; Citrates; Citric Acid; Cough; Enalapril; Humans; Hypertension; Indans; Male; Middle Aged; Reference Values; Reflex

The incidence and prevalence of cough related to enalapril was assessed by spontaneous reporting and a visual analogue scale during a 6 month random double-blind parallel-group study comparing enalapril with nifedipine. Cough was reported spontaneously by 6.2% of enalapril-treated patients, and by none on nifedipine (NS). No patient had to discontinue enalapril because of cough. After 24 weeks treatment increases in visual analogue scale scores for cough frequency greater than or equal to 8 mm were more common for enalapril than nifedipine (difference 21.5%, 95% CI 7.3-35.7%). Increased cough frequency by visual analogue scale was present throughout the study in women, but less consistently in men. High scores for cough were not related to the dose of enalapril. Cough with enalapril was not an important problem during the 6 months of treatment. However increased cough frequency could be detected by visual analogue scale, with a frequency consistent with that observed in open clinic-based studies of longer duration. These findings suggest that ACE inhibitor-induced cough may increase in severity over time, and that even a period of 6 months treatment is too short to evaluate this side-effect adequately.

Topics: Adult; Aged; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine

The aim of this study was to investigate whether ACE-inhibitors could influence bronchial reactivity and interfere with inflammatory skin responses. Ten hypertensive subjects, who had reacted with coughs during ACE-inhibitor therapy, were treated in a double-blind crossover fashion for two weeks with enalapril and with placebo. Enalapril reduced the PC20 value for histamine and augmented the dermal response. Circulating eosinophilic leukocyte level in venous blood dropped markedly after the histamine bronchoprovocation performed during enalapril treatment. Plasma substance P was reduced after histamine provocation performed during placebo treatment, whereas this reduction was abolished by enalapril. In this study, we have demonstrated ACE-inhibitor-induction of moderately increased bronchial reactivity in subjects with suspected ACE-inhibitor-elicited coughs. It is suggested that coughing during ACE-inhibitor therapy is due to an increased inflammatory state in the airways.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Bronchi; Bronchial Provocation Tests; Cough; Double-Blind Method; Drug Eruptions; Enalapril; Eosinophils; Female; Humans; Hypertension; Injections, Intradermal; Male; Middle Aged; Random Allocation; Renin

To find out whether enalapril or ramipril causes the sensitivity of the cough reflex to change or symptomatic cough to develop in patients with hypertension.. Prospective, placebo controlled, double blind, randomised crossover study.. Academic units of clinical pharmacology and medicine.. 20 Patients (nine men and 11 women) who needed to take angiotensin converting enzyme inhibitors to control hypertension.. All patients received enalapril 10 mg daily, ramipril 10 mg daily, or placebo daily for one week in random order, with a washout period of at least one week between treatments. For assessment of sensitivity of the cough reflex the patients inhaled various concentrations of capsaicin solution in random order.. Measurement of the doses of capsaicin required to cause two or more and five or more coughs or the development of a symptomatic cough.. Blood pressure, symptoms of cough, and the sensitivity of the cough reflex to inhaled capsaicin were recorded at the start of the study and before and at the end of each treatment period. Plasma urea and creatinine concentrations and angiotensin converting enzyme activity were measured at the start of the study and the end of each treatment period. Data were analysed by two way analysis of variance. Mean blood pressure was 159/97 mm Hg at the start of the study and 152/92, 143/88, and 147/86 mm Hg after treatment with placebo, enalapril, and ramipril respectively. Mean (SE) plasma angiotensin converting enzyme activity was 2.2 (0.2) mmol/l/h after treatment with placebo and fell significantly to 1.3 (0.1) mmol/l/h and to 0.4 (0.1) mmol/l/h after treatment with enalapril and ramipril respectively. No patient complained of cough while taking placebo but three women complained of cough when taking both enalapril and ramipril. The mean (95% confidence interval) lowest dose of capsaicin causing two or more coughs was 2.4 (1.5 to 4.0), 1.8 (1.12 to 2.82), and 2.2 (1.7 to 3.0) nmol after treatment with placebo, enalapril, and ramipril respectively; none of these changes were significant. The lowest dose of capsaicin causing five or more coughs was 18.9 (13.9 to 25.8), 14.4 (8.4 to 24.5), and 15.3 (10.8 to 21.2) nmol respectively; none of these changes were significant. The three patients who complained of cough had normal sensitivity to capsaicin after treatment with placebo but had a considerably increased sensitivity after treatment with enalapril and ramipril.. Both enalapril and ramipril increase the sensitivity of the cough reflex appreciably in patients who complain of cough during treatment, but they do not change the se

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Clinical Trials as Topic; Cough; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Ramipril; Random Allocation; Reflex

Development of the secondary to ACEI cough leads to discontinuation of the drugs of this group. Assessing the safety of the ACEIs with further development of customized approaches for their administration is a major scientific and practical problem. The objective of this study was to assess the association of the genetic markers with the development of the adverse drug reaction in the form of secondary to enalapril dry cough in the patients with essential arterial hypertension.. Study involved 113 patients with the secondary to enalapril cough and 104 patients without development of the secondary to enalapril adverse drug reaction.. The patients carriers of the genotype AA rs2306283 of gene SLCO1B1 had 2-fold higher odds of developing the dry cough than those with the genotypes AG and GG (ОR=2.01, 95%CI=1.10-3.66, р=0.023). Similarly, the patients heterozygous for rs8176746 of gene АВО had 2.3-fold higher odds of developing the ADR in the form of dry cough than the carriers of the genotypes GG and TT (ОR=2.30, 95%CI=1.24-4.29, р=0.008).. Statistically significant association between the development of the ADR in the form of secondary to enalapril dry cough and polymorphisms rs2306283 of gene SLCO1B1 and rs8176746 of gene ABO was revealed.

Topics: Cough; Enalapril; Genotype; Humans; Hypertension; Liver-Specific Organic Anion Transporter 1; Pharmacogenetics

Cough may be associated with complications such as syncope, urinary incontinence, pneumothorax, and less frequently, pulmonary hernia and costal fractures. Chronic cough is a cause of rib fractures and when they occur it is likely to affect more than one rib. We report a 53 year-old obese male in treatment with enalapril 10 mg for hypertension with a dry cough lasting five months. He consulted for bilateral chest pain and a Chest X ray examination showed symmetrical fractures in the seventh left and right ribs. Enalapril was discontinued, cough and pain subsided in two weeks.

Topics: Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Cough; Enalapril; Humans; Hypertension; Male; Middle Aged; Rib Fractures; Tomography, X-Ray Computed

Clinical observations suggest that incidence of cough in Chinese taking angiotensin converting enzyme inhibitors is much higher than other racial groups. Cough is the most common adverse reaction of enalapril. We investigate whether SLCO1B1 genetic polymorphisms, previously reported to be important determinants of inter-individual variability in enalapril pharmacokinetics, are associated with the enalapril-induced cough. A cohort of 450 patients with essential hypertension taking 10 mg enalapril maleate were genotyped for the functional SLCO1B1 variants, 388A > G (Asn130Asp, rs2306283) and 521T > C (Val174Ala, rs4149056). The primary endpoint was cough, which was recorded when participants were bothered by cough and respiratory symptoms during enalapril treatment without an identifiable cause. SLCO1B1 521C allele conferred a 2-fold relative risk of enalapril-induced cough (95% confidence interval [CI] = 1.34-3.04, P = 6.2 × 10(-4)), and haplotype analysis suggested the relative risk of cough was 6.94-fold (95% CI = 1.30-37.07, P = 0.020) in SLCO1B1*15/*15 carriers. Furthermore, there was strong evidence for a gene-dose effect (percent with cough in those with 0, 1, or 2 copy of the 521C allele: 28.2%, 42.5%, and 71.4%, trend P = 6.6 × 10(-4)). Our study highlights, for the first time, SLCO1B1 variants are strongly associated with an increased risk of enalapril-induced cough. The findings will be useful to provide pharmacogenetic markers for enalapril treatment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Female; Gene Dosage; Genetic Predisposition to Disease; Haplotypes; Humans; Linkage Disequilibrium; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Organic Anion Transporters; Pharmacogenetics; Polymorphism, Single Nucleotide; Risk Factors

ABO genetic polymorphisms have recently been associated with angiotensin-converting enzyme (ACE) activity and inflammation, which play a critical role in the pathogenic mechanism of ACE inhibitor-induced cough. Therefore, the current study determined the association of ABO genetic polymorphisms with enalapril-induced cough in Chinese patients with essential hypertension.. A total of 450 essential hypertensive patients treated with 10 mg of enalapril maleate were genotyped for ABO genetic polymorphisms using the PCR-direct sequencing method. Cough was recorded when patients were bothered by cough and respiratory symptoms during enalapril treatment without an identifiable cause.. The distribution of rs8176740 and rs495828 was different between the coughers and the controls [P=0.039; odds ratio (OR)=0.70, P=0.018; OR=1.41]. The risk of enalapril-induced cough in the rs495828 TT carriers was increased (P=0.008; OR=2.69), which remained significant after false discovery rate correction. The results for the rs8176740 polymorphism were significant in the female subgroup (P=0.027; OR=0.22). Haplotype analysis of the four ABO polymorphisms (rs8176746/rs8176740/rs495828/rs12683493) showed that the frequency of the GATC haplotype was higher in the coughers than those in the controls (26.6 vs. 18.8%, P=0.033; OR=1.43).. The rs495828 polymorphism was associated with enalapril-induced cough and may serve as a useful pharmacogenomics marker of the safety of enalapril in Chinese patients with essential hypertension. The mechanism for the associations may involve the effects of the ABO gene or ABO blood type on ACE activity and inflammation.

Topics: ABO Blood-Group System; Adult; Angiotensin-Converting Enzyme Inhibitors; Asian People; Cough; Enalapril; Essential Hypertension; Female; Genetic Association Studies; Haplotypes; Humans; Hypertension; Male; Middle Aged

Imidapril is an angiotensin converting enzyme (ACE) inhibitor without a sulfhydril group which has been shown from previous study to have low incidence of ACE inhibitor induced cough.. To compare the incidence of cough between two ACE inhibitors, imidapril and enalapril.. A comparative cross over study was performed in 119 patients with hypertension or left ventricular dysfunction. Patients were assigned to one of the two treatment groups, either a group receiving imidapril or enalapril for 4 weeks (Period I) and then these same groups were crossed over to receive either enalapril or imidapril for 4 weeks (Period II). The occurrence of cough during treatment was monitored by interviewing the patients.. The incidence of cough was 44 % while on imidapril treatment and 66% while on enalapril treatment (p = 0.0014). The antihypertensive effects of two drugs were not different.. The incidence of cough was significantly less under imidapril than under enalapril treatment, while there was no difference in the antihypertensive effects between the two ACE inhibitors.

Topics: Administration, Oral; Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Cross-Over Studies; Enalapril; Female; Humans; Hypertension; Imidazolidines; Incidence; Male; Middle Aged; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Aged, 80 and over; Anti-Bacterial Agents; Antihypertensive Agents; Antiprotozoal Agents; Clostridioides difficile; Connecticut; Cough; Drug Administration Schedule; Dysentery; Emigrants and Immigrants; Enalapril; Female; Humans; Japan; Polypharmacy

Cough is an adverse event associated with the angiotensin-converting enzyme (AA inhibitor drugs. ACE inhibitor-induced cough is believed to be related to the accumulation of bradykinin,substance P,and prostaglandins resulting from the inhibition of ACE.Angiotensin-receptor blockers (AARBs) do not have any effect on ACE and theoretically might not cause cough. Therefore, a proposed option in patients suffering with ACE inhibitor-induced cough is to try an ARB. However,this report describes the reverse: a case of losartan-induced cough th hat co om completely resolved after it was substituted with an ACE inhibitor, enalapril.. A 23-year-old, nonsmoking white woman, weighing 73.55 kg, ACE inhibitor naive (before admission), presented to the emergency department at Imam Referral Hospital, Tehran, Iran,with hypertension,proteinuria, and hyperlipidemia. The patient was admitted to the nephrology ward. She was prescribed hydrochlorothiazide 12.55 mg/d, furosemide 20 mg BID, and simvastatin 20 mg/d. The patient had no respiratory illnesses. The patient experienced cough 3 days following the initiation of losartan treatment. The cough continued in this patient for the 2-week duration of losartan treatment; however, 1 week after substitution of losartan with enalapril (22.5 mg/d),the cough resolved completely.. This report describes a young woman who developed cough while receiving losartan treatment,which resolved after substitution with the ACE inhibitor enalapril.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Female; Humans; Hypertension; Losartan

Angiotensin Converting Enzyme Inhibitors (ACEIs) like enalapril are extremely effective in the treatment of hypertension and heart failure. One of the most important side-effects of these drugs which can lead to cessation of therapy is a persistant dry cough, induced because of increased bradykinin levels in the lung. Although antitussive alkaloids like codeine are effective in suppressing this cough, they too present a wide range of side-effects, most notably addiction.. In a previous work we were able to show that noscapine, a non-narcotic antitussive agent, was able to decrease enalapril induced cough in guinea pigs. In this work, papaverine, another non-narcotic alkaloid found in opium latex was tested in the guinea pig model for antitussive activity.. Cough was induced in enalapril pretreated guinea pigs by forcing the animals to inspire capsaicin aerosol in an air-tight chamber. Coughs were recorded in control animals and in those which had received different doses of papaverine. Characteristic changes in chamber air pressure, were detected by a pressure transducer.. . At low doses (0.5 and 0.25 mg/kg) papaverine was able to decrease enalapril induced cough. CONCLUSION. This effect was not mediated by the action of the drug on mu receptors and was only observed in animals treated with enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cough; Enalapril; Guinea Pigs; Male; Papaverine; Vasodilator Agents

A persistent, chronic dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors therapy. The mechanism of this respiratory adverse effect is related to the inhibition of ACE and the accumulation of bradykinin, substance P, prostanoids and other inflammatory neuropeptides in the airways. The aim of this study was to follow the relationship between 15-day administration of enalapril and the defense reflexes (cough and bronchoconstriction) of the airways in experimental animals, as well as the possibility of their pharmacological restriction with simultaneous diltiazem administration. Cough reflex was investigated by the method of mechanical irritation of laryngopharyngeal and tracheobronchial area in non-anesthetized cats. The reactivity of tracheal smooth muscles of the airways to bronchoconstrictor mediators (histamine 10 nM - 1 mM, acetylcholine 10 nM - 1 mM and KCl 1 mM - 100 mM) was evaluated by an in vitro method in guinea pigs. Enalapril 5 mg/kg/day and diltiazem 30 mg/kg/day were administered perorally for 15 days. The results showed that long-lasting administration of enalapril resulted in a significant increase of measured cough parameters and increased reactivity of tracheal smooth muscle to histamine and KCl. Simultaneous administration of enalapril together with diltiazem significantly decreased the enalapril induced cough, and decreased enalapril induced hyperreactivity of tracheal smooth muscles to KCl. The results showed a partially protective effect of diltiazem and enalapril co-administration on the respiratory adverse effects induced by enalapril therapy.

Topics: Animals; Bronchoconstriction; Calcium Channel Blockers; Cats; Cough; Diltiazem; Drug Combinations; Enalapril; Female; Guinea Pigs; Male; Muscle, Smooth, Vascular; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

It has been reported that the incidence of angiotensin-converting enzyme (ACE) inhibitor-related dry cough is significantly less with the ACE inhibitor imidapril than with the ACE inhibitor enalapril in hypertensive patients. Bradykinin (BK) in the trachea is believed to play some role in this adverse effect. The present study was undertaken to evaluate the effects of imidapril and enalapril on the activity of aminopeptidase P (APP), one of the BK-metabolizing enzymes, in the mouse trachea. Imidapril (0.5 mg/kg) or enalapril (0.5 mg/ kg) was given orally to mice once daily for 7 days. Drug concentrations and APP activity in the trachea were determined at the end of the experiment. Active metabolites (imidaprilat and enalaprilat), but not parent drugs (imidapril and enalapril) were detected in the trachea after a repeated dose for 7 days. Tissue concentrations of imidaprilat and enalaprilat did not significantly differ. The APP activity in the trachea did not significantly change after the 7th dose of imidapril. However, the enzyme activity was significantly inhibited after the final dose of enalapril. Thus, the present study showed that enalapril, but not imidapril inhibited the airway APP activity during repeated dosing. This finding is compatible with previous reports that the incidence of dry cough is lower with imidapril than with enalapril, and with the hypothesis that the dry cough induced by ACE inhibitors may be related to accumulation of BK in the trachea.

Topics: Aminopeptidases; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cough; Enalapril; Enzyme Activation; Imidazolidines; Male; Mice; Mice, Inbred ICR; Trachea

Angiotensin Converting Enzyme Inhibitors (ACEI) like captopril and enalapril, can induce persistant cough in man. Noscapine, an antitussive alkaloid, can be used to suppress ACEI-induced cough. Some workers have suggested a role for bradykinin in precipitation of ACE-induced cough. Work carried out in our laboratory has shown noscapine to be a non-competitive inhibitor of bradykinin in guinea pig ileum. It is therefore possible that noscapine suppresses cough by blocking the effect of bradykinin receptor activation in the airways. Guinea pigs were placed in a cough-chamber connected to an air pump and a pressure transducer. Capsaicin was sprayed into the chamber and cough was recorded as a distinctive change in air pressure inside the cough-chamber. Animals treated with 1 mg/kg captopril and enalapril for 7 days, showed increased cough response. Ten microgram/kg FR190997, a non-peptide agonist of the bradykinin B2 receptor, also increased the cough response. Noscapine at 0.5, 1 and 2 mg/kg was able to reverse the effects of ACEI and FR190997. Naloxone, a specific opioid receptor inhibitor, did not block the antitussive effects of noscapine in enalapril or FR190997 treated guinea pigs. This antitussive effect of noscapine is not mediated via the mu, kappa or delta opioid receptors. It is therefore possible that noscapine exerts its antitussive action by interfering with the bradykinin cough mediation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antitussive Agents; Bradykinin; Capsaicin; Captopril; Cough; Dose-Response Relationship, Drug; Drug Interactions; Enalapril; Guinea Pigs; Male; Naloxone; Narcotic Antagonists; Noscapine; Quinolines; Receptor, Bradykinin B2

Studies of angiotensin-converting enzyme inhibitor-induced cough have involved extensive use of experimental models in which guinea pigs are exposed to an inhaled stimulus such as capsaicin or citric acid. In the present study, we examined enalapril-induced potentiation of spontaneous cough in guinea pigs, without an inhaled stimulus. Daily oral administration of enalapril (3 mg/kg) for 20 to 30 days enhanced spontaneous cough. This enhancement of cough was inhibited by the bradykinin B(1) receptor antagonist des-Arg(10)-[Leu(9)]kallidin, but not by the bradykinin B(2) receptor antagonist icatibant. The amount of the bradykinin B(1) receptor agonist [3H]des-Arg(10)-kallidin specifically bound to membrane fractions from the trachea and larynx was increased by prolongation of the enalapril treatment, and positively correlated well with coughing frequency. In conclusion, the present results indicate that enalapril-induced cough is mediated by up-regulation of bradykinin B(1) receptors.

Topics: Animals; Bradykinin; Bradykinin B1 Receptor Antagonists; Cough; Dose-Response Relationship, Drug; Enalapril; Guinea Pigs; Larynx; Male; Protein Binding; Receptor, Bradykinin B1; Trachea; Up-Regulation

86 patients with chronic obstructive pulmonary diseases (COPD) and tuberculosis in combination with COPD complicated by chronic pulmonary heart (CPH) received a 18-month continuous treatment with enalapril (enap, D. Reddis Laboratories). It was found that the addition of enap, an inhibitor of ACE, to combined therapy of CPH patients is pathogenetic as it results in lowering of blood pressure in pulmonary artery, remodeling of hypertrophic right ventricle of the heart and decline of left ventricular dysfunction, in improvement of functional state of the lungs, in arrest of progression of cardiac failure. Long-term administration of the drug induced no serious side effects and is well tolerated.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Combined Modality Therapy; Cough; Enalapril; Humans; Hyperventilation; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Heart Disease; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary; Ventricular Remodeling

Angioedema and cough are known side effects of angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme is a potent inhibitor of kinase II, which facilitates the breakdown of bradykinin. An increase in bradykinin levels results in continued prostaglandin E2 synthesis, vasodilation, increased vascular permeability, and increased interstitial fluid. In contrast, the angiotensin II receptor blockers (ARBs) do not increase bradykinin levels. Angioedema as a complication of ACE inhibitor therapy is not widely recognized; this complication is even less recognized with second-line ARBs. We report angioedema associated with losartan (an ARB) in a patient who had experienced angioedema secondary to enalapril (an ACE inhibitor). Almost half of patients with ARB-associated angioedema also had developed angioedema while receiving ACE inhibitor therapy. Clinicians should exercise caution when using ARBs in patients with a history of angioedema secondary to ACE inhibitors.

Topics: Adult; Angioedema; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Diabetes Mellitus, Type 1; Enalapril; Female; Humans; Losartan; Pharyngitis

Topics: Adult; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Arthralgia; Cough; Drug Tolerance; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Polycystic Kidney Diseases

Angiotensin-converting enzyme (ACE) inhibitors are among the first-choice drugs for treating hypertension and congestive heart disease. It has been reported, however, that these drugs could induce chronic cough and airway hyperresponsiveness. The aim of this work was to assess in pigs the effects of bradykinin and tachykinins on citric-acid-induced coughing after ACE inhibitor pretreatment. Coughing was induced by challenging pigs with an aerosol of 0.8 M citric acid over 15 min. Coughs were counted by a trained observer for 30 min. The animals underwent two cough induction tests two days apart (days 1 and 3), the first being taken as a control. All drugs were injected intravenously 30 min before the second challenge. In the control group, no difference was observed between days 1 and 3. The ACE inhibitor enalapril (7.5 and 15 microg/kg) caused the cough frequency to increase significantly. In contrast, a dose-related decrease was observed with Hoe140 (icatibant), a bradykinin B2 receptor antagonist (0.5 and 1 mg/kg). When both drugs were administered simultaneously (15 microg/kg for enalapril and 1 mg/kg for Hoe140), a significant increase was observed as compared with the control value obtained on day 1. When enalapril was combined with the three tachykinin receptor antagonists SR 140333 (NK1 receptor antagonist), SR 48968 (NK2 receptor antagonist) and SR 142801 (NK3 receptor antagonist), a significant decrease was observed as compared with control value obtained on day 1; the percentage of variation was also significantly different as compared with those observed in enalapril groups at both doses. These data suggest that ACE-inhibitor-induced enhancement of the cough reflex is mainly due to tachykinins and not to bradykinin in our pig model. Bradykinin, however, plays a major role in coughing induced by citric acid alone.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antitussive Agents; Bradykinin; Citric Acid; Cough; Dose-Response Relationship, Drug; Drug Synergism; Enalapril; Female; Male; Receptors, Tachykinin; Swine; Tachykinins

A persistent, chronic dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors therapy. The mechanism of this respiratory adverse effect is related to the inhibition of ACE and the accumulation of bradykinin, substance P, prostanoids and inflammatory neuropeptides in the airways.. The aim of this study was to follow the relationship between 15-days administration of enalapril and the defence reflexes of the airways of experimental animals and possibility of pharmacological restriction with inhaled furosemide.. From the defence reflexes of the airways the changes of the parameters of a mechanically induced cough in nonanaesthetized cats were measured. The reactivity of the smooth muscle of the airways to the bronchoconstrictor mediator was evaluated by in vitro method. The enalapril was administered for 15-days in the dosage of 5 mg/kg b.w. p.o., inhaled furosemide for 15-days in the dosage 10 mg/kg b.w.. The results suggested that long-lasting administration of enalapril resulted in a significant increase of measured cough parameters and increased reactivity of tracheal smooth muscle to the histamine. The reactivity of the lung smooth muscle was not influenced significantly after enalapril treatment. Inhaled furosemide administered with enalapril significantly decreased the enalapril induced cough and decreased enalapril potentiated reactivity of the tracheal smooth muscle to the histamine.. The results showed the protective effect of inhaled furosemide against the respiratory adverse effects induced by ACE-inhibitors administration.

Topics: Administration, Inhalation; Angiotensin-Converting Enzyme Inhibitors; Animals; Cats; Cough; Diuretics; Enalapril; Furosemide; Lung; Muscle, Smooth; Trachea

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Captopril; Child; Child, Preschool; Cough; Enalapril; Female; Humans; Infant; Kidney Diseases; Male; Perindopril; Time Factors

Cough is one of the most frequent side effects associated with angiotensin converting enzyme inhibitors (ACEIs) but is not thought to be associated with losartan, an angiotensin II receptor antagonist (ARA). This study compares reports of cough with losartan and three ACEIs used in general practice.. Studies have been conducted for losartan, and three ACEIs enalapril, lisinopril and perindopril, using the technique of Prescription-Event Monitoring. Patients were identified using dispensed prescription data. Questionnaires were sent to patients' general practitioners 6 months after the date of first prescription. Cases of cough within the first 60 days of treatment with losartan resulting in withdrawal of the drug were followed up with additional questionnaires. Incidence rates for reports of cough were calculated. In order to reduce the impact of carry-over effects, rate ratios were calculated for first reports of cough between days 8 and 60 using losartan as the index drug.. The cohort for each drug exceeded 9000 patients. Age and sex distributions and indications for prescribing the four drugs were similar. Cough was the most frequent reason for discontinuation of losartan and the most frequently reported event in the first month of treatment with this drug. When reports of cough between days 1-7 were excluded, rates of cough were significantly higher for the three ACEIs when compared with losartan (rate ratios 1.5, 4.8 and 5.7, all P<0.03). 101 patients had discontinued losartan due to cough. 91% of these had previously been prescribed an ACEI and 86% had previously experienced ACEI cough.. Carry-over accounted for the observed excess of reports of cough with losartan. Rates of cough between days 8 and 60 were significantly higher for the three ACEIs compared with losartan. Confounding factors associated with comparative observational cohort studies are discussed.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Confounding Factors, Epidemiologic; Cough; Data Collection; Drug Monitoring; Enalapril; Female; Humans; Indoles; Lisinopril; Losartan; Male; Middle Aged; Perindopril

The efficacy and tolerability of spirapril were evaluated in a prospective, multicentre, post-marketing surveillance study on the treatment of arterial hypertension in 5000 patients, most of whom had received a single daily dose of 6 mg spirapril. The study was carried out by internists and general practitioners. In accordance with placebo-controlled clinical trials, spirapril was proven to be a very effective antihypertensive drug, in respect of both the mean reduction in systolic and diastolic blood pressure achieved as well as the responder rate of 89.4% and 85.4% for systolic and diastolic blood pressure, respectively. Efficacy was equally good in single drug treatment and combination treatment. Differentiated evaluation of blood pressure values in respect of the severity of hypertension on the basis of the World Health Organization classification showed a clear relationship between the baseline blood pressure and the reduction in blood pressure. The higher the baseline blood pressure, the more pronounced was the antihypertensive efficacy; a particular reduction in diastolic blood pressure being observed. Tolerability was also good, with an incidence of side effects of only 2.9%. Coughing was observed in only 0.88% of patients. Thus spirapril is seen to be an effective and well-tolerated antihypertensive drug whose efficacy is clearly related to baseline blood pressure and thus is also very effective in the treatment of severe forms of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Cough; Enalapril; Hemodynamics; Humans; Hypertension; Polypharmacy; Product Surveillance, Postmarketing

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Cough; Enalapril; Female; Humans

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Benzamides; Citric Acid; Cough; Dose-Response Relationship, Drug; Enalapril; Female; Male; Nebulizers and Vaporizers; Piperidines; Receptors, Neurokinin-2; Swine

Several antihypertensive medications affect lower urinary tract function and may cause urinary incontinence.. A 59-year-old woman on doxazosin mesylate for control of her hypertension presented with stress urinary incontinence. Because this drug is known to cause loss of urethral tone leading to stress incontinence in some patients, she was switched to enalapril maleate, an angiotensin converting enzyme inhibitor. Her incontinence improved on the new medication, but she developed a persistent dry cough that continued to cause episodic stress incontinence. Because a persistent cough is a known side effect of angiotensin converting enzyme inhibitors, her medication was changed to a calcium channel blocker, amlodipine besylate. Her cough resolved, and her stress incontinence was no longer a clinical problem.. Gynecologists should be aware of the unexpected side effects of medications on the lower urinary tract.

Topics: Adrenergic alpha-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cough; Doxazosin; Enalapril; Female; Humans; Middle Aged; Urinary Incontinence, Stress

Cough is an important side effect of Angiotensin Converting Enzyme Inhibitor (ACEI) therapy. The incidence of cough was investigated in a prospective 8 week study in 250 hypertensive patients receiving ACEI alone or in combination with other agents. Enalapril (5-20 mg/day), Lisinopril (5-20 mg/day), Captopril (25-75 mg/day) or Ramipril (5-15 mg/day) was prescribed to patients, who were followed up at weekly visits. Cough developed in 73 of the 250 patients i.e. an incidence of 29.2%. Females had a higher incidence of cough as compared to males--37.9% versus 15.5% (p < 0.001) and there was no significant difference in the cough incidence in the various age groups. A dry, non-productive cough developed in all patients within 4 weeks of ACEI initiation. Increased nocturnal intensity of cough was reported by 79.4% patients. Cough incidence was 34.4%, 24.3% and 18.1% in patients on Enalapril, Ramipril and Lisinopril, respectively. Cough was not dose related and was not related to smoking. There was no statistically significant difference among patients on ACEI alone or in combination with beta blockers, calcium channel blockers or diuretics. Of the 18 patients with ACEI induced cough who received Indomethacin, 50 mg bid, 8 reported complete cure and cough was reduced in intensity in the remaining ten.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Incidence; India; Indomethacin; Lisinopril; Male; Middle Aged; Prospective Studies; Ramipril; Risk Assessment

OBJECTIVE. This study examines cough recorded in Prescription-Event Monitoring (PEM) of four ACE-inhibitors. Particular attention was paid to the study of enalapril because the drug was monitored before the causal relationship between cough and ACE-inhibitors had been widely accepted. RESULTS. Several factors which had obscured the causal relationship in the individual cases were found to be also an obstacle in PEM. For example, cough was a common and non-serious event and was under-reported in the PEM study of enalapril and the rate was not strikingly different from that recorded for other drugs. Cough induced by ACE-inhibitors has several characteristics which reduce the chance of a recognisable "signal'. The original questionnaires returned from doctors in the PEM study of enalapril have been reexamined. The observation that the rate of cough diminished after enalapril had been stopped rather than increased after starting, provided the best evidence of causality, because this was not affected by many biases such as the publicity that had occurred prior to doctors participating in PEM completed later reports.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cohort Studies; Cough; Enalapril; Female; Humans; Indoles; Lisinopril; Male; Middle Aged; Perindopril; Product Surveillance, Postmarketing; Ramipril; Structure-Activity Relationship; Surveys and Questionnaires

Angiotensin converting enzyme (ACE) inhibitors cause coughing in 5-10% of patients, but the exact mechanisms of this effect are still unclear. In the airways ACE degrades substance P so the cough mechanism may be related to this peptide.. Nine patients who developed a cough and five patients who did not develop a cough when taking the ACE inhibitor enalapril (2.5 or 5.0 mg/day) for hypertension were enrolled in the study. No subjects had respiratory disease and the respiratory function of all subjects was normal. One month after stopping enalapril, inhalation of hypertonic saline (4%) was performed using an ultrasonic nebuliser for 15-30 minutes to induce sputum. The concentration of substance P in the sputum sample was measured by radioimmunoassay. In four of the nine cases with a cough enalapril was given again for 1-2 weeks and the concentration of substance P in the induced sputum was again measured.. One month after stopping enalapril the mean (SE) concentration of substance P in the sputum of the group with a cough was 16.6 (3.0) fmol/ml, significantly higher than that in the subjects without a cough (0.9 (0.5) fmol/ml). All four subjects in the group with a cough who were given a repeat dose of enalapril developed a cough again, but the concentrations of substance P in the induced sputum while taking enalapril (17.9 (3.2) fmol/ml) were similar to the values whilst off enalapril (20.0 (2.5) fmol/ml).. The mechanisms of ACE inhibitor-induced coughing may involve substance P mediated airway priming. However, the final triggering of the ACE inhibitor-induced coughing is unlikely to be due to this peptide.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Sputum; Substance P; Time Factors

Topics: Adolescent; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Child; Cough; Enalapril; Female; Humans; Imidazoles; Losartan; Male; Renin-Angiotensin System; Tetrazoles

The effect of moguisteine, a novel peripherally acting non-narcotic antitussive drug, on coughs associated with enalapril was examined in guinea-pigs. Chronic treatment with enalapril markedly enhanced the number of capsaicin-induced coughs. Moguisteine dose-dependently suppressed the number of coughs at doses between 3-30 mg/kg p.o., in both vehicle-treated and enalapril-treated animals. There was no significant difference in the antitussive ED50 (95% confidence limit) value of moguisteine between vehicle-treated (16.4 (13.7-19.7) mg/kg) and enalapril-treated (13.7 (3.9-47.6) mg/kg) animals. On the other hand, dihydrocodeine also dose-dependently suppressed the number of coughs in the same dose range as moguisteine in both vehicle-treated and enalapril-treated animals. There was no significant difference in the antitussive ED50 (95% confidence limit) of dihydrocodeine between vehicle-treated (11.7 (4.9-28.3) mg/kg) and enalapril-treated (11.2 (9.4-13.3) mg/kg) animals. Furthermore, the antitussive effect of moguisteine was identical to that of dihydrocodeine in both vehicle-treated and enalapril-treated animals. On the other hand, while chronic co-treatment with moguisteine significantly reduced the number of enhanced coughs associated with enalapril, chronic co-treatment with dihydrocodeine had no significant effect on the number of enhanced coughs associated with enalapril treatment. These results suggest that moguisteine may have a therapeutical benefit in reducing the coughing associated with treatment with inhibitors of angiotensin-converting enzyme.

Topics: Animals; Antitussive Agents; Capsaicin; Cough; Enalapril; Guinea Pigs; Male; Thiazoles; Thiazolidines

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Dose-Response Relationship, Drug; Enalapril; Humans; Hypertension; Isoquinolines; Kidney Diseases; Lisinopril; Otolaryngology; Quinapril; Tetrahydroisoquinolines

1. We report a controlled retrospective cohort study of respiratory adverse reactions to ACE inhibitors. Bronchospasm and cough occurred at a higher rate in patients treated with ACE inhibitors, no links with sex, past history of bronchospasm, drug type or dose were found. 2. Cohorts of 1013 patients on angiotensin converting enzyme (ACE) inhibitors and 1017 patients on lipid lowering drugs (LLDs) were compared for the occurrence of new bronchospasm, relapse of previous bronchospasm, increase of current bronchospasm, and cough. 3. The prevalence of bronchospasm was 5.5% for patients on ACE inhibitors and 2.3% for patients on LLDs, P < 0.001. The relative risk of a bronchospasm adverse reaction for a patient on an ACE inhibitor compared with a patient on a LLD was 2.39, 95% confidence interval 1.47 to 3.90. 4. No ACE inhibitor specificity, or significant sex differences were found in the prevalence of bronchospasm or cough after correcting for bias implicit in the original cohorts. The bronchospastic reactions were not dose dependent. 5. The prevalence of a past history of bronchospasm in patients reporting ACE inhibitor-induced bronchospasm (16%) was not significantly different from the prevalence in patients on ACE inhibitors without an adverse reaction (13%), P = 0.447. 6. The prevalence of ACE inhibitor cohort cough was 12.3% and 2.7% in the patients on LLDs, P < 0.0001. Cough did not occur more commonly in patients on ACE inhibitors who had experienced any bronchospasm (28%) than in patients on LLDs with bronchospasm (27%).

Topics: Aged; Bronchial Spasm; Captopril; Chi-Square Distribution; Cohort Studies; Computer Simulation; Cough; Enalapril; Female; Humans; Hypolipidemic Agents; Lisinopril; Male; Middle Aged; Prevalence; Retrospective Studies; Sex Factors; Surveys and Questionnaires

Topics: Angiotensin-Converting Enzyme Inhibitors; Asian People; Captopril; Case-Control Studies; China; Cough; Double-Blind Method; Enalapril; Female; Humans; Incidence; Male; Middle Aged; Prospective Studies; White People

The objectives of this study were to determine the risk for coughing as an adverse reaction to angiotensin converting enzyme (ACE) inhibitors under everyday circumstances in a large population and to study whether this adverse effect is more common in women. A population-based case-control study was used. The study was set in the practices of 161 Dutch general practitioners (GPs), in which all consultations, morbidity, mortality, medical interventions and prescriptions were registered during 4 consecutive 3-month periods in 4 consecutive groups of 40-41 GPs. The subjects were 2436 patients with incident coughing and up to 3 controls per case were obtained (total group: 7348 controls), matched for GP and a contemporary consultation in the same 3 months. All cases and controls were 20 years or older and had no notification of respiratory infections, influenza, tuberculosis, asthma, chronic bronchitis, emphysema, congestive heart failure, sinusitis, laryngitis, haemoptysis or respiratory neoplasms during the 3-month period. The results showed that cases were 3.6 times as likely as controls to have been exposed to ACE inhibitors (95% CI: 2.4-5.5) but after adjustment for potential confounders the odds ratio was 2.5 (95% CI: 1.6-3.9). The crude odds ratio for males was 2.7 (95% CI: 1.4-5.1) and for females 4.2 (95% CI: 2.4-7.5). The adjusted odds ratio for males was 1.8 (95% CI: 0.9-3.5) and for females 2.7 (95% CI: 1.5-4.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Captopril; Case-Control Studies; Cough; Enalapril; Female; Humans; Male; Middle Aged; Netherlands; Odds Ratio; Pharmacoepidemiology; Risk Factors

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cough; Drug Tolerance; Enalapril; Female; Follow-Up Studies; Headache; Humans; Hypertension; Male; Middle Aged; Sex Factors

We examined the effect of trandolapril ((-)-(2S, 3aR, 7aS)-1-[(S)-N-[(S)-1-ethoxycarbonyl-3- phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid), a potent angiotensin converting enzyme (ACE) inhibitor, on the number of capsaicin-induced coughs in guinea pigs and compared it with that of enalapril. Chronic treatment with enalapril, at a dose of 3 mg/kg, p.o., significantly enhanced the number of capsaicin-induced coughs. Chronic treatment with trandolapril, at doses of 1 and 3 mg/kg, p.o., slightly enhanced the number of capsaicin-induced coughs. However, there were no significant differences in the number of capsaicin-induced coughs between trandolapril-treated and vehicle-treated animals. These results suggest that cough induced activity, one of the most serious side effects associated with chronic treatment with ACE inhibitors, of trandolapril is relatively lower than that of enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Capsaicin; Cough; Enalapril; Guinea Pigs; Indoles; Male

Probably the most common and irritating side effect of angiotensin-converting enzyme (ACE) inhibitors is cough. In this retrospective study the incidence of cough was investigated in 1113 patients with arterial hypertension who were receiving ACE inhibitors alone or in combination with other antihypertensive agents. Patients were treated with one of the following ACE inhibitors: enalapril 10-20 mg/day (n:668), captopril 25-75 mg/day (n:234), perindopril 2-8 mg/day (n:90), or lisinopril 5-20 mg/day (n:121). Mean follow-up periods were twenty-six months with enalapril, twenty-nine months with captopril, eleven months with perindopril, and thirteen months with lisinopril. Spontaneously declared cough incidence in enalapril, captopril, perindopril, and lisinopril groups were 7%, 5.1%, 2.2%, and 1.6%, respectively. Cough was not dose related. Treatment was stopped in all patients with cough. In 59% of patients the onset of cough occurred after the first month of treatment (thirty to one hundred eighty days). Cough decreased by 50% within three days of drug cessation and disappeared in ten days. Mean age of patients with cough was 58.7 years and 79% of them were women. In patients without cough, mean age was 57.8 years and 56% of them were women. There was no significant difference between the two groups regarding mean age, but the sex difference between groups was statistically significant (P < 0.05). In conclusion, although cough may occur with all four types of ACE inhibitors, the incidence of this side effect was higher during enalapril and captopril treatment than during lisinopril and perindopril treatment. The incidence was also greater in women than in men.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Indoles; Lisinopril; Male; Middle Aged; Perindopril; Retrospective Studies

To evaluate the occurrence of asthma and dyspnoea precipitated or worsened by angiotensin converting enzyme inhibitors.. Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation's international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised.. Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions.. Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea.. In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had adverse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dyspnoea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors.. Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Asthma; Bronchial Spasm; Captopril; Cough; Dyspnea; Enalapril; Female; Humans; Lisinopril; Male; Middle Aged; Ramipril

1. We examined the effect of spirapril, a potent angiotensin converting enzyme (ACE) inhibitor, on the number of capsaicin-induced coughs in rats and compared with that of enalapril. 2. Chronic treatment with enalapril, at doses of 1 and 3 mg/kg, p.o., significantly and dose-dependently enhanced the number of capsaicin-induced coughs. 3. Chronic treatment with higher dose of spirapril (3 mg/kg, p.o.) also significantly enhanced the number of capsaicin-induced coughs. However, lower dose (1 mg/kg, p.o.) of spirapril had no significant effect on the number of capsaicin-induced coughs. 4. These results suggest that cough induced activity, one of the most serious side effects associated with chronic treatment with ACE inhibitors, of spirapril is relatively lower than that of enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cough; Enalapril; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Reflex

Topics: Cough; Enalapril; Humans; Hypertension

Topics: Acrylates; Acute Kidney Injury; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Cough; Dogs; Enalapril; Female; Glomerular Filtration Rate; Imidazoles; Male; Renal Circulation; Thiophenes

Topics: Cough; Enalapril; Humans; Hypertension; Male; Middle Aged; Syncope

Topics: Aged; Captopril; Cilazapril; Cough; Enalapril; Female; Heart Failure; Humans; Hypertension; Long-Term Care; Male; Middle Aged

The files of 172 consecutive hypertensive patients who received captopril or enalapril have been reviewed and the patients questioned on the development of chronic dry cough, persisting for at least two months. Forty patients had cough that was attributed to the drugs. Thirteen of them discontinued the drugs because of this adverse effect. In 15 of the 27 patients (55%) who continued receiving ACE inhibitors (7 males, 8 females, aged 65.4 +/- 9.9 years) the cough had spontaneously disappeared after 3.9 +/- 1.9 months of continued unaltered administration of these drugs and without any treatment aimed against this symptom. All patients were followed for at least four months after disappearance of cough, without recurrences. This finding may discourage withdrawal of ACE inhibitors from many patients who develop cough. Continuation of ACE inhibitors for at least several months, despite cough, (if the cough is not too severe) is probably justifiable.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Remission, Spontaneous

The effect of hydrochlorothiazide, a diuretic which is used in the treatment not only of edema but also of hypertension, on coughs associated with treatment with enalapril was studied in guinea pigs. Chronic treatment with enalapril markedly and dose dependently enhanced the number of capsaicin-induced coughs. However, chronic treatment with hydrochlorothiazide significantly reduced the number of coughs associated with enalapril treatment, also in a dose-dependent manner. These results suggest that diuretics might be used to reduce the coughing associated with treatment with inhibitors of angiotensin-converting enzyme in patients with hypertension.

Topics: Animals; Capsaicin; Cough; Dose-Response Relationship, Drug; Enalapril; Guinea Pigs; Hydrochlorothiazide; Male

Persisting cough developed in three children treated with converting enzyme inhibitors. The symptoms disappeared within 3-7 days after withdrawing medication. These observations in children complement previous reports in adults and indicate that cough may be induced by treatment with these agents.

Topics: Adolescent; Captopril; Child; Cough; Enalapril; Female; Humans; Infant; Male

Topics: Black People; Cough; Drug Tolerance; Enalapril; Humans; Male; Middle Aged

Topics: Aged; Bronchial Hyperreactivity; Cough; Enalapril; Female; Humans; Hypertension; Middle Aged

Topics: Aged; Captopril; Cough; Enalapril; Female; Humans; Male; Middle Aged; Remission, Spontaneous

Cough is a recognised side effect of angiotensin converting enzyme (ACE) inhibitors although its exact mechanism is still unknown. Reports on the side effect of ACE inhibitors on asthma have been conflicting. These drugs either had no effect on bronchial reactivity or resulted in an increase in pre-existing hyperreactivity. We report a case of a non-asthmatic patient who had lisinopril-induced cough and bronchial hyperreactivity.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Enalapril; Humans; Lisinopril; Male

Topics: Aged; Cough; Enalapril; Humans; Male

The prevalence and severity of cough during long-term enalapril treatment were examined by comparing a cohort of 136 hypertensive patients who started treatment with enalapril with consecutive age and sex-matched patients who commenced nifedipine therapy during the same period. Cough and other symptoms were assessed by a questionnaire designed to avoid bias towards reporting cough. After a mean of 27 months' treatment patients on enalapril had an excess of persistent cough (16 per cent, 95 per cent CI 7-25, p less than 0.01), voice change (14 per cent, 95 per cent CI 2-27, p less than 0.05) and sore throat (10 per cent, 95 per cent CI -0.1 to 20.3 per cent, p less than 0.01) when compared to nifedipine-treated patients. The cough was usually dry, moderate or severe, paroxysmal, and troublesome at night. Cough tended to be more common in women (23 per cent vs. 7.2 per cent), non-smokers, and at higher doses of enalapril, but was not related to age, duration of treatment, or chronic respiratory disease. Dry cough commonly persists as a troublesome side-effect during long-term enalapril treatment, and is often associated with voice change and sore throat.

Topics: Cough; Enalapril; Female; Humans; Hypertension; Larynx; Male; Middle Aged; Nifedipine; Prevalence; Time Factors

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Female; Humans

Topics: Aged; Cough; Enalapril; Female; Humans

Since dry cough has recently been recognized as a side effect of angiotensin converting enzyme (ACE) inhibitors employed in the treatment of hypertension or congestive heart failure, the incidence of dry cough in elderly patients receiving ACE inhibitors was investigated. There were 237 out-patients on either captopril, enalapril, or delapril, in August and November 1989. Questionnaires concerning dry cough and smoking were completed by 184 patients. Patients either less than 50 years of age, or with chronic pulmonary disease were excluded. The remaining 168 patients, 63 males, 105 females, with a mean age of 73 years were analyzed for the incidence of a dry cough in relation to age, sex, smoking, and type of drugs. The overall incidence of a dry cough was 21/168 (12.5%), 7/63 (11.1%) for males and 14/105 (13.3%) for females, and was less frequent with advancing age; in the 51-60 age group 4/11 (36.4%), in the 61-70 age group 5/39 (12.8%), in the 71-80 age group 9/75 (12.0%), in the 81-90 age group 3/40 (7.5%), in the 91- age group 0/3 (0%). Enalapril showed significantly higher incidence of dry cough than captopril (16/93, 17.2% vs 7/88, 8.0%, p less than 0.05). Delapril showed an incidence 4/11, 36.4%, however, 9 out of the 11 patients who were given delapril had had a history of a dry cough with captopril or enalapril, and in 4 out of these 9 patients the dry cough disappeared by replacement of captopril or enalapril by delapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Female; Heart Failure; Humans; Hypertension; Indans; Male; Smoking; Surveys and Questionnaires

Cough is one of the possible untoward adverse drug effects of angiotensin converting enzyme inhibitors. We describe the available information on 50 cough episodes attributable to captopril and 18 episodes attributable to enalapril reported to the Spanish Drug Surveillance System. Cough represented 37% and 39% of the reports of side effects of captopril and enalapril, respectively. There was a remarkable female predominance among the patients with cough. Cough developed at very low doses (15 mg of captopril and 5 mg of enalapril daily), although the patients on captopril who developed cough were receiving higher doses than those who presented other side effects. A high proportion of patients (29%) continued with the drug for more than six months after cough had developed, suggesting the need for a wider knowledge of this side effect.

Topics: Aged; Captopril; Cough; Enalapril; Humans; Middle Aged; Product Surveillance, Postmarketing

Topics: Aged; Captopril; Cough; Enalapril; Female; Humans; Pancreatitis

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Humans; Hypertension; Male; Middle Aged; Reflex; Risk Factors

The ACE-inhibiting drugs enalapril and captopril may result in a chronic and sometimes severe cough for which no pathologic cause can be found. Drug-induced cough should therefore be considered in any symptomatic patient taking these medications. In such cases, prompt withdrawal of the drug and substitution of a non-ACE inhibitor is curative and conserves the time and resources of the patient and the physician by avoiding unnecessary diagnostic and therapeutic measures.

Topics: Aged; Chronic Disease; Cough; Dose-Response Relationship, Drug; Enalapril; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged

In a cohort of 136 hypertensive patients started consecutively on enalapril the incidence of persistent dry cough by life-table analysis was 14.6% (95% CI 10.2-19.0%). The incidence in women (19.2%; 95% CI 11.3-27.1%) was twice that in men (9.7%; 95% CI 6.6-12.8%). Dry cough was unrelated to age, smoking habit, renal function, or the dose and duration of enalapril treatment. In one half of patients who developed cough enalapril had to be stopped. The incidence of withdrawal due to cough was 6.0% (95% CI 4.5-7.5%), and cough was by far the most common reason for discontinuing enalapril treatment. Reviewing previous studies of enalapril-induced cough, it is evident that postmarketing surveillance studies have grossly underestimated the incidence and importance of this side-effect. Surveys in hospital clinics have slightly underestimated the true incidence through failure to use life-table methods of analysis.

Topics: Adult; Aged; Cohort Studies; Cough; Enalapril; Female; Humans; Hypertension; Incidence; Life Tables; Male; Middle Aged

Physicians should suspect ACE inhibitors as the cause of cough in patients whose symptom begins soon after the institution of therapy with this class of drugs. This is particularly important in patients without a personal or family history of atopy, with normal physical findings, chest radiographs, and lung function tests. Rather than subjecting the patient to an extensive workup, substitution of a different antihypertensive agent is an inexpensive way to show whether the ACE inhibitor is the cause of the chronic cough.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Cough; Enalapril; Female; Humans; Hypertension; Middle Aged

Topics: Adult; Cough; Enalapril; Female; Humans

Seventeen patients using angiotensin-converting enzyme (ACE) inhibitors for hypertension were evaluated with baseline spirometry followed by determination of bronchial reactivity by challenge with methacholine. There were nine coughers and eight noncoughers in the study. Among the nine coughers, eight demonstrated bronchial hyperreactivity. Conversely, none of the noncoughers disclosed bronchial hyperreactivity. Eight of the nine coughers were rechallenged two to six months following cessation of ACE inhibitor therapy. Six of these eight showed persistent bronchial hyperreactivity. We conclude that cough is associated with the use of ACE inhibitors in patients with underlying bronchial hyperreactivity. The findings indicate caution in administration of ACE inhibitors in asthmatic patients and those with known bronchial hyperreactivity.

Topics: Asthma; Bronchi; Bronchial Provocation Tests; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Male; Maximal Expiratory Flow Rate; Methacholine Chloride; Methacholine Compounds; Middle Aged; Spirometry; Vital Capacity

Topics: Captopril; Cough; Enalapril; Humans

A 65-year-old woman started taking enalapril 2.5 mg daily for hypertension. Twelve days later she complained of a persistent, dry cough. Due to the coughing and a preexisting cystocele, she developed stress incontinence and a marked decline in her functional status. The coughing and incontinence resolved with the discontinuation of enalapril. During a subsequent hospitalization the patient received captopril 6.25 mg twice daily for congestive heart failure. Within 24 hours the dry cough recurred. It resolved with the discontinuation of the drug. Cough is a symptom that is generally not recognized as a drug side effect. However, increasing numbers of case reports document angiotensin-converting enzyme inhibitor-induced cough. Although the actual frequency and mechanism are currently unknown, the dry cough typically begins early in the course of therapy. It may be specific to this pharmacologic class rather than to one individual agent. Age and sex may be contributing factors. While cough has been considered a minor side effect, unnecessary hospitalizations and inappropriate treatments may easily result. Even minor adverse reactions may have an impact on a patient's quality of life.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Female; Humans

We report a 68 yr old woman with hypertension who developed a dry cough on enalapril but not on captopril therapy. Pulmonary function tests, methacholine inhalation challenges, total blood eosinophil counts, and changes in plasma concentrations of prostaglandin E2 and thromboxane B2 did not explain the difference in the adverse reaction between these two angiotensin converting enzyme inhibitors.

Topics: Aged; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Respiratory Function Tests

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Humans; Retrospective Studies

Persistent dry cough is not a known adverse reaction of captopril and enalapril. We present 5 patients with persistent dry cough severe enough to warrant withdrawal of the drug, which resulted in rapid and complete recovery. Challenge with the drugs induced recurrence of cough. The pathogenesis of the reaction is unknown, but possible mediators include bradykinin and prostaglandins.

Topics: Aged; Captopril; Cough; Enalapril; Female; Humans; Male; Middle Aged

A retrospective analysis of records from an outpatient medical practice was undertaken to determine the incidence and features of cough resulting from the use of enalapril maleate. Of 209 patients taking enalapril, 22 (10.5%) required discontinuation of therapy because of an intractable, dry cough. Cough was more than twice as common in women; 16 (14.6%) of 109 women and 6 (6%) of 100 men stopped taking enalapril because of cough. The cough resolved in 21 of 22 patients within 2 weeks of discontinuation of enalapril therapy. When the patients with cough were compared with the others, there was no significant difference in age, smoking status, creatinine levels, enalapril dosage, associated cardiopulmonary disease, or concomitant administration of medications. Among the 187 study patients who did not discontinue taking enalapril because of cough, many developed a persistent, dry cough that to date has not been severe enough to require discontinuation of therapy, after a mean follow-up period of 16 months. The enalapril-induced cough is insidious, dry, persistent, benign, and reversible on discontinuation of therapy. It is important to distinguish enalapril-induced cough from cough resulting from acute illness, reactive airway disease, and congestive heart failure. Optimal clinical application of enalapril in the treatment of hypertension and congestive heart failure will require increased awareness of this incessant cough, which requires discontinuation of the therapy in about 10% of patients.

Topics: Antitussive Agents; Cough; Enalapril; Humans; Retrospective Studies; Sex Factors

The incidence of cough during treatment with angiotensin converting enzyme (ACE) inhibitors was studied using retrospective analysis of outpatient records and a questionnaire; for a more precise evaluation, all reported cases of cough were reviewed according to criteria for the operational assessment of side effects, and those found unrelated were excluded. Cough during treatment with ACE inhibitors appears to be more frequent than previously recorded and substantial differences between patients treated with captopril or enalapril seem unlikely.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Humans; Hypertension; Incidence; Italy; Sex Factors; Surveys and Questionnaires

Topics: Cough; Enalapril; Female; Humans; Middle Aged

Topics: Adrenergic beta-Antagonists; Cough; Drug Therapy, Combination; Enalapril; Humans; Risk Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Humans; Hypertension; Substance P

The first inhibitor of angiotensin converting enzyme (ACE) was found in and isolated from the venom of the South American pit viper Bothrops jararaca. This was done after it was discovered that bites of the pit viper inhibit the breakdown of a proinflammatory peptide, bradykinin, in prey. Treatment with newly developed orally active ACE-inhibitors has been reported to cause symptoms such as adverse skin reactions, angioneurotic oedema, coughs and, in asthmatics, rapidly decreasing lung function. In this thesis the ACE-inhibitor MK 422 (active parent diacid of enalapril) was demonstrated to potentiate wheal and flare reactions induced by allergens, bradykinin or capsaicin, and to increase infiltration of "inflammatory cells", like eosinophils and neutrophils, into inflammatory dermal test sites in sensitized guinea pigs. MK 422 also augmented spontaneous and allergen-triggered histamine release in vitro from guinea pig skin and lung tissue. Capsaicin "desensitization" of guinea pig skin markedly reduced the wheal and flare reactions to allergens and attenuated the proinflammatory effect of the ACE-inhibitor. The histamine release in vitro from capsaicin-pretreated skin was also decreased, and no clear potentiating effect of MK 422 was demonstrated. In man, enalapril augmented anti-IgE-induced wheal and flare responses and increased bronchial reactivity to histamine. The drop of circulating eosinophils in venous blood was more pronounced after the provocations performed during enalapril treatment, and plasma substance P tended to increase. The alpha 2-adrenoceptor agonist clonidine, known to attenuate "neurogenic inflammation", reduced the wheal and flare reactions in guinea pig skin and decreased infiltration of neutrophils and eosinophils into inflammatory test sites. Furthermore, clonidine abolished the proinflammatory effect of MK 422 on the allergen- evoked wheal and flare reactions in guinea pig skin without counteracting the blood pressure lowering effect of the ACE-inhibitor. Contrarily, an additive hypotensive effect was demonstrated when clonidine was combined with MK 422. It is suggested that the proinflammatory properties demonstrated by ACE-inhibitors is due to augmentation of "neurogenic inflammation".

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Capsaicin; Cough; Drug Eruptions; Enalapril; Enalaprilat; Guinea Pigs; Histamine Release; Humans; Injections, Intradermal; Ovalbumin; Skin; Skin Tests

Topics: Aged; Aged, 80 and over; Captopril; Cough; Enalapril; Female; Humans; Male; Middle Aged

Angiotensin converting enzyme inhibitors cause cough in some patients, but the mechanism of this effect is not known. Six patients in whom these inhibitors had caused cough and a further two patients in whom they were suspected to have caused worsening of bronchial asthma were studied. Nine patients in whom angiotensin converting enzyme inhibitors had not been associated with cough served as controls. In the controls lung function and bronchial reactivity were measured once; for the study patients these and the cough index were measured twice before rechallenge for two weeks with an angiotensin enzyme inhibitor and once afterwards. Rechallenge with drug for two weeks caused a significant decrease in the mean concentration of histamine causing a 35% fall in airways conductance and a significant increase in the cough index. Patients with cough showed bronchial hyperactivity compared with the controls, which increased after rechallenge with the inhibitors. Cough associated with converting enzyme inhibitors may be a variant of the cough in asthma.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Asthma; Bronchi; Bronchial Provocation Tests; Captopril; Cough; Enalapril; Female; Histamine; Humans; Hypertension; Male; Middle Aged

Topics: Aged; Cough; Enalapril; Female; Humans

Topics: Adult; Aged; Asthma; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies

Topics: Adult; Aged; Cough; Enalapril; Humans; Middle Aged; Pulmonary Eosinophilia

To identify and measure the incidence of adverse effects of the angiotensin converting enzyme inhibitor enalapril 13,713 patients were studied for one year by prescription-event monitoring. Precise information about the duration of treatment was available for 12,543 patients. The frequency of many events was calculated, including dizziness (483 patients; 3.9%), persistent dry cough (360; 2.9%), headache (310; 2.5%) hypotension (218; 1.7%), and syncope (155; 1.2%). Less common reactions included angioedema, urticaria, and muscle cramps. Altogether 1098 (8%) patients died and the notes of 913 of them (83%) were obtained for detailed scrutiny. With the exception of a few patients with renal failure who deteriorated during treatment (reported on separately), no death was attributed to enalapril. Enalapril was considered to be effective, even in patients with advanced cardiac failure. These results for enalapril are reassuring and provide further evidence of the value of prescription-event monitoring.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Conjunctivitis; Cough; Dizziness; Dysgeusia; Enalapril; Female; Headache; Humans; Hypotension; Male; Middle Aged; Product Surveillance, Postmarketing; Skin Diseases; Syncope

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Female; Humans; Male; Middle Aged

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cilazapril; Cough; Enalapril; Female; Humans; Male; Pharynx; Pyridazines

Topics: Adult; Aged; Cough; Enalapril; Female; Humans; Male

Topics: Aged; Cough; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

Topics: Aged; Aged, 80 and over; Captopril; Cough; Enalapril; Female; Humans; Middle Aged

Topics: Cough; Enalapril; Humans; Male; Middle Aged

Topics: Captopril; Cough; Enalapril; Humans

Topics: Captopril; Cough; Enalapril; Female; Humans

Topics: Aged; Captopril; Cough; Enalapril; Female; Humans; Male; Middle Aged

Topics: Adult; Cough; Diagnosis, Differential; Enalapril; Female; Humans; Hypertension; Nasopharyngitis

Topics: Asthma; Captopril; Cough; Enalapril; Humans; Respiratory Sounds

Topics: Cough; Enalapril; Female; Humans; Middle Aged

Post-marketing surveillance in general practice represents an important part of the monitoring of adverse events associated with newly introduced drugs. Such a study of the angiotensin-converting enzyme inhibitor enalapril maleate has been undertaken in 11 710 patients with essential hypertension. Serious adverse events occurred in 1.7% of patients, though most of these were not thought to be related to the treatment. The incidence rates of death (0.09%), stroke (0.11%) and myocardial infarction (0.15%) were compatible with rates predicted from age, sex and blood pressure considerations. Other events reported were hypotension (0.3%), angioneurotic oedema (0.03%), rash (0.5%), taste disturbance (0.2%) and cough (1.0%). The degree of blood pressure reduction attained was similar to that previously reported from pre-marketing development studies, as was the overall nature and frequency of both serious and non-serious adverse events. The most frequently reported event during enalapril therapy was of an improvement in well-being (19.8%).

Topics: Adolescent; Adult; Aged; Angioedema; Cough; Enalapril; Evaluation Studies as Topic; Family Practice; Female; Humans; Hypertension; Hypotension; Male; Middle Aged; Product Surveillance, Postmarketing; United Kingdom

The relationship between angiotensin converting enzyme inhibitors (ACE inhibitors) and the development of cough was studied in 80 patients. Cough developed in 25 (31%). Seventeen patients had detailed respiratory investigations of whom 12 developed a new cough. Five of the 12 patients had a remission on placebo and recurrence on rechallenge. Cough does occur with ACE inhibitors but there are other possible causes of cough such as asthma, bronchitis, smoking and heart failure. The true incidence of new cough with ACE inhibitors is uncertain at present.

Topics: Adult; Aged; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Retrospective Studies

Since there are isolated case reports linking cough with angiotensin converting-enzyme (ACE) inhibitor treatment, we reviewed the case notes of patients attending a hypertension outpatient clinic. Of 126 patients, 37 were on medications other than ACE inhibitors, and none complained of cough. In contrast, 12 of 89 patients receiving an ACE inhibitor had noted cough. The symptoms remained when one ACE inhibitor was substituted for another, but disappeared when the drug was withdrawn. Cough was sufficiently irritating to require cessation of treatment in two patients. We conclude that cough is not uncommon during treatment with ACE inhibitors.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Male; Middle Aged

Topics: Aged; Captopril; Cough; Enalapril; Female; Humans; Hypertension; Middle Aged

Cough associated with angiotensin-converting enzyme (ACE) inhibitors has long been considered a rare side effect. We report 8 cases, 7 with enalapril (10 to 20 mg/day) 1 with quinapril (40 mg/day) in which cough occurred after a mean duration of treatment of 39 days. In all patients, cough disappeared with a mean delay of 2 days with no other treatment than withdrawal of the drug. In 6 patients, cough was reinduced within less than a day with the same drug; in 5 patients a second reinduction with another ACE inhibitor gave the same result. These data suggest that cough is probably more frequent than it would appear from the literature. In clinical practice, if cough occurs in a patient treated with an ACE inhibitor, the drug may be continued for a few days in order to exclude an acute viral infection; if cough lasts more than a week, specific diagnostic procedures for pulmonary disease should be initiated; if it stops, the patient may be treated either for hypertension or chronic heart failure with another ACE inhibitor.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Female; Humans; Male; Middle Aged

Thirty three reports of cough associated with captopril and 26 associated with enalapril received by the New Zealand intensive medicines monitoring programme were reviewed. The programme is a specialised part of the New Zealand postmarketing surveillance system. Review of these reports showed that the cough was an adverse reaction to the drugs, occurred even with low dose treatment, and was severe enough to warrant withdrawal of the drugs in most of the cases reported. A significant sex difference was shown, with women predominating. The reaction seemed to be a greater problem with enalapril, and in seven patients it occurred with both captopril and enalapril. Withdrawal of treatment resulted in rapid recovery, and no long term effects were shown. The pathogenesis of the reaction is unknown, but possible mediators include bradykinin and prostaglandins.

Topics: Captopril; Cough; Dose-Response Relationship, Drug; Enalapril; Female; Humans; Male; Middle Aged; Product Surveillance, Postmarketing

Topics: Chronic Disease; Cough; Enalapril; Female; Humans; Middle Aged

Topics: Aged; Chronic Disease; Cough; Enalapril; Female; Humans; Middle Aged

Topics: Cough; Enalapril; Humans

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cough; Enalapril; Female; Humans; Male; Middle Aged; Respiratory Sounds

Topics: Cough; Enalapril; Female; Humans; Hypertension; Middle Aged; Posture; Sex Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Cough; Enalapril; Humans; Lisinopril

Topics: Captopril; Cough; Enalapril; Female; Humans; Hypertension, Renal; Middle Aged

Topics: Captopril; Cough; Enalapril; Humans; Hypotension

Topics: Cough; Enalapril; Humans; Lisinopril