One year experience of elderly hypertensive patients with isradipine therapy.

This is the first report of long-term use (one year) of isradipine, a new dihydropyridine calcium channel blocker, in the treatment of elderly patients with essential hypertension. Patients completing a three month, double-blind, multicentre study comparing isradipine to hydrochlorothiazide (HCTZ) were eligible to enroll in this open-label, continuation study. At initial baseline, patients were at least 60 years of age and had DBP from 95 mmHg to 120 mmHg. Patients were titrated when necessary every two weeks with isradipine, 5 mg to 15 mg once daily or 2.5 mg to 10 mg twice daily, to maintain sitting DBP < or = 90 mmHg. HCTZ, 12.5 mg to 50 mg once daily, could be added for better BP control. A total of 136 patients completed the one year, open-label phase. One hundred and fourteen patients (84%) received isradipine as monotherapy (mean dose, 9.7 mg/day); 22 received concomitant HCTZ therapy at one year. Reduction in DBP was significant and similar among all age groups and races (mean change of -19 mmHg). Reduction in SBP was similar among all age groups. Ninety-four per cent of those receiving isradipine monotherapy achieved BP control during the last four months of treatment. Twenty-six patients (16%) withdrew from the study: 11 (7%) had adverse reactions (one with headache, two with pedal oedema, eight with other problems); 11 (7%) had nondrug-related problems; and in four (2%), the drugs were ineffective. Based on these observations, isradipine is a well-tolerated, safe and effective agent for long-term BP control in elderly patients with essential hypertension.

The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate essential hypertension: a multicenter study.

Benazepril hydrochloride is a new angiotensin-converting enzyme inhibitor. In a multicenter study, 206 patients with mild to moderate hypertension were randomized to receive benazepril at a dose of 2, 5, 10, or 20 mg, hydrochlorothiazide, 25 mg, or placebo once daily for 4 weeks. The 20 mg dosage of benazepril lowered blood pressure to a degree equal to that of 25 mg hydrochlorothiazide: -12.2/7.7 mm Hg and -13.4/-7.5 mm Hg, respectively. Hydrochlorothiazide proved to be more effective in black subjects. At lower dosage levels of benazepril (2, 5, and 10 mg), blood pressure reduction was not significantly different from that with placebo. In those patients who failed to achieve goal diastolic blood pressure of less than 90 mm Hg with monotherapy after 4 weeks, the addition of open-label hydrochlorothiazide (25 mg/day) to benazepril, hydrochlorothiazide, or placebo produced a substantial additional decrease in blood pressure over a 2-week period. No definite adverse effects on hematologic measurements, serum biochemistry test results, or urinalyses were noted. Subjective adverse experiences were common in all groups but except in three or possibly four instances were not considered causally related to the study drug.

Placebo-controlled trial of once-a-day isradipine monotherapy in mild to moderately severe hypertension.

The efficacy and safety of once-daily dosing of isradipine, a new calcium antagonist vasodilator, was evaluated in a multicenter, placebo-controlled trial in hypertensive patients who had supine diastolic blood pressure (SDBP) 100-119 mm Hg. After a 3-week single-blind placebo washout patients randomly received either isradipine, 5 mg once daily, or a matching placebo; if SDBP remained greater than or equal to 95 mm Hg or less than or equal to 10 mm Hg below baseline at four weekly clinic visits, isradipine was increased at weekly intervals by 5 mg once daily up to 20 mg and maintained during weeks 5 and 6. At week 6 mean supine blood pressure 24 hours after dosing had declined from 163 +/- 20/105 +/- 5 (N = 78) to 146 +/- 17/92 +/- 7 mm Hg (N = 60) on isradipine, 14.5 mg once daily, and from 163 +/- 20/105 +/- 6 (N = 85) to 157 +/- 18/99 +/- 10 mm Hg (N = 64) on placebo (P less than .001 between groups). Standing blood pressure decreased from 159 +/- 20/104 +/- 8 to 144 +/- 18/93 +/- 11 mm Hg with isradipine and from 160 +/- 22/105 +/- 9 to 154 +/- 19/101 +/- 11 mm Hg with placebo (P less than .001 between groups) without signs or symptoms of postural hypotension. A SDBP less than or equal to 90 mm Hg or a greater than or equal to 10 mm Hg fall below baseline was achieved in 41 of 78 isradipine-treated (53%) and 18 of 85 placebo-treated subjects (21%).(ABSTRACT TRUNCATED AT 250 WORDS)

Multicenter comparison of once- and twice-daily isradipine to hydrochlorothiazide for the treatment of hypertension in elderly patients.

After 8 weeks of isradipine, a twice-a-day dihydropyridine calcium channel blocker, 49% of elderly patients showed a complete response (sitting diastolic blood pressure less than or equal to 85 mm Hg) and 36% showed a partial response (sitting diastolic blood pressure decrease greater than or equal to 10 mm Hg) for an 85% total response rate. Hydrochlorothiazide gave a complete response in 36% of the patients and a partial response in 33%, for a 69% total response rate (p less than 0.0046). Because elderly subjects have reduced clearance for many drugs, we determined how those who responded to twice-a-day administration would respond to once-a-day administration. After 4 weeks of isradipine administered once a day, 54% of the patients showed a complete or partial response, whereas 38% of the patients who were changed to placebo showed a response. In contrast, 82% of patients receiving hydrochlorothiazide once a day showed a response, whereas 60% of patients who were changed to placebo showed a response. These data indicate that the standard formulation of isradipine was not effective when administered once a day.

Low-dose captopril in mild to moderate geriatric hypertension.

The safety and efficacy of captopril in geriatric patients with mild to moderate hypertension was examined in an eight-week multicenter study of 99 patients. Following a placebo period, patients were treated with captopril 25 mg twice daily. Patients who were uncontrolled after two weeks of active therapy were randomized to either captopril 25 mg plus hydrochlorothiazide 15 mg or captopril 50 mg twice daily. The average decrease in blood pressure at study completion was--16.9/11.9 mmHg. At the conclusion of the trial, 75.8% of patients responded to therapy. Captopril was well tolerated and believed to be a good therapeutic alternative for treating hypertension in the elderly population.

Treatment of hypertension in the elderly.

Investigation of preventive measures for hypertension and atherosclerosis is a geriatric medicine priority. While the causes of both isolated systolic hypertension and conventional systolic and diastolic hypertension in the elderly are well defined, the benefits of lowering blood pressure are not. Evidence to support the treatment of symptomatic hypertension is convincing for men 60 years of age; it is not for women in this age group. The need to treat hypertension, particularly isolated systolic hypertension in patients above 75 years old, is still not resolved. Isolated systolic hypertension in older patients is at least as strong a risk factor for cardiovascular disease as is diastolic hypertension. Ongoing trials may answer these questions; in the meantime, drug therapy in this group will vary widely. The elderly hypertensive is more likely than the younger hypertensive to have other diseases; diagnosis of these disorders is crucial. Hypertension arising de novo late in life warrants a search for underlying and possibly remedial causes. Antihypertensive drug therapy to relieve symptoms is difficult to justify, because most elderly hypertensive patients are asymptomatic; however, it has been shown to delay morbid and fatal complications of hypertension. Appropriate therapy for the elderly hypertensive must be individualized and should be associated with few or no side effects. The thiazides are the preferred diuretics for long-term treatment of hypertension in the elderly. Beta blockers are attractive because they are cardioprotective, counter the end organ effect of catecholamines and reduce angina; however, some decrease cardiac output, increase peripheral resistance, decrease renal blood flow and cause fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)

Lichenoid eruption produced by captopril.

Captopril, an oral active dipeptidylcarboxypeptidase inhibitor with antihypertensive properties, has been reported to have the following cutaneous side effects: macular and papular skin eruptions, urticaria, angioedema, mouth ulcers, pemphigus, and pityriasis rosea-like eruptions. Here, to the best of our knowledge, is the first case in which a pityriasis rosea-like eruption evolved into a lichenoid drug eruption. Also discussed is the remarkable similarity in the side effects of captopril, gold compounds, d-penicillamine, and organic mercurials.

Pulmonary function in hypertensive patients treated with pindolol: a report of two studies.

Pulmonary function was measured serially in two separate randomized trials of pindolol in the treatment of essential hypertension. Patients with overt obstructive airways disease were excluded. In study 1, 131 hypertensive patients were randomized to placebo (31) and 15 mg (33), 30 mg (33), and 60 mg (34) of pindolol. Pulmonary function was measured before and at weeks 8 and 15 of active medication. Bronchospasm--a 20% increase in forced expiratory volume in 1 second (FEV1) after isoprenaline--developed in three patients on active treatment and one on placebo. In eight patients on pindolol and one on placebo, bronchospasm ceased. Compared to placebo, no deterioration in pulmonary function occurred with pindolol and in three tests--maximum voluntary ventilation (MVV) (L/min), MVV%, midexpiratory flow rate (MEFR) (L/min)--significant improvement occurred. In study 2, 14 hypertensive patients were randomized to pindolol (mean dose 50 mg/day), 15 to propranolol (mean 360 mg/day), and 14 to chlorthalidone (mean 107 mg/day). Pulmonary function was measured after 3 weeks of placebo and again after 6 weeks of active treatment. While propranolol produced slight deterioration in pulmonary function, pindolol and chlorthalidone produced slight but significant improvement (p less than 0.05) with maximum MEFR (L/sec). Pulmonary function tests measured after isoprenaline were significantly worse in patients on propranolol compared to those on placebo, but were unchanged in patients on pindolol or chlorthalidone. The conclusions are: (1) Pindolol in antihypertensive doses does not produce airways obstruction and some improvement in pulmonary function may occur. (2) In comparable doses, pindolol has a positive effect on pulmonary function and propranolol a negative effect which, when summated, is statistically significant. (3) Propranolol, but not pindolol, appears to block the bronchodilator effects of isoprenaline. The lack of pulmonary function impairment may be due to intrinsic sympathomimetic activity properties of pindolol.

Pindolol and systolic time intervals in patients with hypertension.

Two studies of systolic time intervals (STIs) in patients with mild to moderate hypertension (HBP) revealed that no mean change in systolic intervals occurred with pindolol therapy, although some patients had significant alterations in their STIs. Pindolol responders with normal pretreatment preejection period to left ventricular ejection time (PEP/LVET) ratios had a significant increase in this ratio following pindolol therapy, whereas those with abnormal pretreatment PEP/LVET ratios had improvement in this ratio on administration of the drug. Patients on propranolol showed no change in PEP/LVET ratio. Propranolol administration slowed heart rate and lengthened Q-S2, S1-S2, and LVET, however, without altering the Q-S2 and LVET index, indicating that the changes were caused by the effect of propranolol on the heart rate alone. Chlorthalidone in high doses significantly reduced the Q-S2 index and the S1-S2 index, indicating that these changes were not caused by alteration of the heart rate. The second study suggests that STIs may provide a predictive clue for clinical response to pindolol. Patients with normal cardiac function (group I) are more likely to respond to pindolol than are those with abnormal cardiac function (group II). Directionally opposite changes in STIs in the two subgroups suggest different mechanisms for changing cardiac function. Pindolol's dual role as a beta-blocking agent with intrinsic sympathomimetic activity is proposed as a possible explanation, beta-blocking effects predominating in group I and sympathomimetic activity balancing the beta effect in group II.

Capoten-induced juxtaglomerular hyperplasia in rabbits.

The effects of the converting enzyme (CE) inhibitor, captopril, on blood pressure, plasma aldosterone, plasma renin activity (PRA), and kidney morphology were studied. Captopril, at a near maximum daily recommended human dose of approximately 5.0 mg/kg, was administered to rabbits over a period of six months. Mean arterial pressure, CE activity, and aldosterone levels were significantly reduced; PRA and renal renin activity were increased. Microscopic examination of the kidney showed marked hyperplasia of the juxtaglomerular apparatus in all of the treated animals.

Pityriasis rosea-like rash from captopril.

Captopril, an orally active dipeptidylcarboxypeptidase inhibitor, is a promising new antihypertensive agent. Cutaneous reactions, including (rarely) a pityriasis rosea-like eruption, are frequently associated with this therapy. Two new cases of a pityriasis rosea-like captopril-induced eruption support a pharmacologic mechanism for the eruption, since it resolved after the dosage of captopril was lowered in one patient and continued when the dosage of captopril remained unchanged in the other patient. However, the eruption later responded to therapy while use of the drug was continued. Captopril should be included among those drugs associated with a pityriasis rosea-like eruption.

Renin as a risk factor for atherogenesis. Part 2. Effects of hypercholesterolemia and hyporeninemia in the rabbit.

Four groups of New Zealand rabbits were used to study the effect of suppressed plasma renin activity (PRA) on atherogenesis. Control groups were fed normal rabbit chow (Group I) or normal chow supplemented with 0.25% cholesterol--0.75% corn oil (Group III). Group II animals were fed normal chow and received periodic injections of 11-desoxycorticosterone (DOC)pivalate and 0.5% saline to drink, while Group IV animals were treated similarly except that they were also fed the atherogenic diet. Blood pressure and blood chemistry measurements were performed monthly over a 7-month period. The blood pressure was unaffected by either the diet or the DOC-saline treatment, however, the PRA was greatly reduced in the animals receiving DOC-saline (Groups II and IV). Similarly, plasma aldosterone was significantly (P less than 0.05) reduced in the DOC-saline-treated animals. No atheromata were observed in the animals consuming the regular diet, regardless of DOC-saline treatment. All of the animals fed the atherogenic diet showed extensive aortic atheromata. However, there was no difference in the lesion index between the animals with normal PRA levels (Group III) and those with suppressed PRA levels (Group IV). Likewise, microscopic evaluation of the aorta, coronary arteries, and renal arteries failed to show a consistent difference in the vascular involvement between animals of Groups III and IV. We therefore conclude that the suppression of PRA does not have a protective effect on atherogenesis in the cholesterol-fed normotensive rabbit.

Renin as a risk factor for atherogenesis. Effects of hypercholesterolemia and two-kidney--one-clip hypertension in the rabbit.

Four groups of New Zealand rabbits were used to study the effect of plasma renin activity (PRA) on atherogenesis. Control groups were fed normal rabbit chow (Group I) or chow supplemented with 0.25% cholesterol and 0.75% corn oil (Group II). The two-kidney--one-clip (2K-1C) hypertensive model was produced in 2 additional groups; Group III (normal diet) and Group IV (atherogenic diet). The latter 2 groups were subgrouped according to PRA levels. Each group was examined over a 7-month period. Group II became hyperlipidemic and developed extensive lipoidal vascular lesions. Mean arterial pressure remained normal throughout the experimental period; PRA fell below normal. Group III and Group IV rabbits developed sustained hypertension irrespective of circulating PRA. The atheromas of Group III were predominantly microscopic and fibromuscular; the extent of aortic and coronary artery involvement was independent of renin response. The most extensive and complicated atheromas were seen in the 2K-1C rabbits consuming the atherogenic diet (Group IV). The lesions were mostly lipoidal, although some were fibromuscular. These results demonstrated that cardiovascular lesions and atherogenesis were exacerbated in the 2K-1C rabbits on a high cholesterol diet; however, PRA was excluded as the cause.