Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor.

The concept of initiating treatment of mild-to-moderate hypertension with a low-dose combination of reserpine and the thiazide clopamide in comparison to monotherapy with an ACE inhibitor was investigated. A total of 127 adult outpatients with diastolic blood pressure between 100 and 114 mmHg were randomized into this double-blind, parallel group study. After a 2-week wash-out period and a subsequent 2-week placebo run-in period, they were allocated to once-daily treatment with 0.1 mg reserpine plus 5 mg clopamide (R/C), or 5 mg enalapril. If diastolic blood pressure was not normalized after 3 weeks of therapy (i.e. DBP < 90 mmHg), the dosage was doubled from week 4 to 6. The primary efficacy variables were the change from baseline in mean sitting diastolic and systolic blood pressure (DBP/SBP) after 3 weeks of therapy. Secondary variables included the change in DBP and SBP after 6 weeks of therapy, the BP normalization rates at 3 and 6 weeks and, concerning tolerability, the rates of adverse events after 6 weeks of therapy. An intent-to-treat analysis was performed. The reserpine/ clopamide and enalapril groups did not differ with regard to demographic and baseline characteristics (mean age 57 or 58 years, respectively; 63% or 56% males, respectively; mean SBP/DBP after the 2-week placebo period = 156 mmHg/104 mmHg in both groups). After 3 weeks of treatment with one capsule daily, mean SBP/DBP reduction from baseline (24 h after last medication intake) in the R/C combination group was -19.6/ -17.0 mmHg, in the enalapril group -6.1/ -9.5 mmHg (between-group comparison: 2p < 0.01 for both parameters). The normalization rates for DBP (< 90 mmHg) were 64.1% (R/C) and 28.6% (enalapril) (2p < 0.01). Adverse events that were considered possibly or definitely drug-related by the investigator were noted in 11 patients (17.2%) in the R/C group and in 9 patients (14.3%) in the enalapril group (NS). Two patients in the enalapril group discontinued the study prematurely due to adverse events (cough; skin eruption). In the treatment of mild-to-moderate hypertension, a low-dose combination of reserpine and clopamide once a day is considerably more effective than, and as tolerable as, 5-10 mg of enalapril once a day. These findings suggest that treatment with a combination of different antihypertensives with different modes of action in low doses is a rational alternative to conventional monotherapy in the first-line treatment of hypertension. Besides, the "old" reserpine-diuretic regimen also in these days appears to be a rational alternative to "modern" monotherapies.

Different concepts in first-line treatment of essential hypertension. Comparison of a low-dose reserpine-thiazide combination with nitrendipine monotherapy. German Reserpine in Hypertension Study Group.

Low-dose combination therapy has been proposed as a rational first-line approach to hypertension treatment. We compared the efficacy and tolerability of the fixed combination of reserpine (0.1 mg) plus the thiazide clopamid (5 mg) with its single components and the calcium-antagonist nitrendipine (20 mg) in a randomized, double-blind, parallel study of 273 hypertensive patients with diastolic blood pressure (BP) between 100 and 114 mm Hg. The four groups did not differ regarding baseline characteristics (mean age, 58 years; 51% men; mean BP after a 2-week placebo period, 158 to 160/103 to 104 mm Hg). After 6 weeks of treatment with one capsule daily, mean reductions in sitting BP from baseline at 24 hours after dosing in the reserpine-clopamid combination, reserpine, clopamid, and nitrendipine groups were -23.0/-17.1, -14.0/-11.7, -13.6/-11.9, and -11.6/-12.3 mm Hg, respectively (2P < .01). The corresponding normalization rates (diastolic BP < 90 mm Hg) were 55%, 40%, 36%, and 33% (2P = .11). All patients whose BP had not been normalized at this point received two capsules of the respective medication once daily from weeks 7 to 12. At week 12, mean BP reductions were -25.7/-18.1, -14.6/-12.2, -17.7/-13.4, and -14.9/-15.3 mm Hg in the four groups, respectively (2P < .01). The respective normalization rates were 69%, 35%, 39%, and 45% (2P < .0001). Linear regression modeling indicated that reserpine and clopamid combined acted more than additively. As regards tolerability, adverse experiences were observed in 27%, 28%, 29%, and 48% of patients, respectively (2P < .05). The respective rates of premature discontinuation because of adverse effects were 3%, 3%, 7%, and 13% (2P = .06). In conclusion, a low-dose combination of reserpine and clopamid lowered BP significantly more than both the components alone and nitrendipine. Moreover, the combination was tolerated as well as its components and significantly better than nitrendipine. Thus, the use of this low-dose reserpine-thiazide combination appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension.

Changes in urinary enzyme levels following the use of antihypertensive agents in patients with essential hypertension.

When choosing antihypertensive agents for the treatment of hypertension, it is necessary to consider the predisposition of individuals to renal damage, which may be associated with the long-term effect of such agents. In this respect, this study examined the effect of two commonly used antihypertensive drugs (Brinerdin and Minizide) on renal function over 24 months in patients diagnosed as having essential hypertension. We utilized urinary enzyme studies, which are indicators of subtle renal dysfunction. Other parameters of glomerular and tubular function were also determined in the pretreatment period, as well as during and at the end of treatment of 28 patients (16 males and 12 females) with therapeutic doses of Brinerdin and 22 patients (12 males and 10 females) with conventional doses of Minizide. During the follow-up period, blood pressure (BP) fell from a mean of 160/108 +/- 9/4 (SD) mmHg to 130/90 +/- 7/4 on Brinerdin and from a mean of 160/106 +/- 5/2 (SD) mmHg to 130/90 +/- 8/5 on Minizide. There was no significant difference in the levels of BP between the patients taking Minizide and those taking Brinerdin before, during, and at the end of treatment. Significant elevation (p < 0.05) of the levels of urinary protein, lactate dehydrogenase (LDH), and N-acetyl-B-D-glycosaminidase (NAG) was observed in patients on Minizide during treatment, and these levels remained elevated during the latter part of the study. Normotensive, untreated, age- and sex-matched control subjects showed no such urinary parameter changes.(ABSTRACT TRUNCATED AT 250 WORDS)

[Combined uni- and multicenter double-blind studies in hypertensive patients. Comparison of blood pressure measurements]. / Kombinierte uni- und multizentrische Doppelblindstudie bei Hypertonikern. Vergleich der Blutdruckmessungen.

In a double-blind study to investigate the antihypertensive effect of a fixed triple combination with 0.05 mg reserpine, 2.5 mg clopamide and 0.4 mg dihydroergocristine in comparison to a fixed double combination with 0.05 mg reserpine and 2.5 mg clopamide, a patient subgroup of 34 patients followed a unicenter (central unit, 'institute') as well as a multicenter (established physicians) study design. The patients visited both investigation units on the day of admission to the study (week 0), after four weeks and after eight weeks of therapy (after the morning intake of the drugs). The paper in hand looks at the results of this subgroup with respect to the conformity of blood pressure values in the two investigative units. The analyses confirm the already published results of the entire study: Both combinations proved to be highly effective antihypertensive drugs. The triple combination showed therapeutical advantages for systolic blood pressure after four weeks, for diastolic pressure after eight weeks of therapy at the 'institute' as well as, although less distinct, in the medical offices. A comparison of the individual values did not show a convincing coherence of the measurements between institute and offices. All investigated possible systematic sources of error (different methods of measurement, days or times of measurement) could be excluded by correlation statistics as a reason for the divergences. The results show the necessity--particularly in multicenter studies--of a careful documentation of all accompanying data (e.g. method or time of measurement) as well as a greatest possible standardization of investigation (e.g. identical measuring apparatus and investigator.)

[Evaluation of hemodynamic changes in patients with primary arterial hypertension after treatment with a combination of pindolol and clopamide (Viskaldix)]. / Ocena zmian w dynamice krazenia u chorych z pierwotnym nadcisnieniem tetniczym po leczeniu trwalym polaczeniem pindololu z klopamidem (Viskaldix).

In 35 patients with mild essential hypertension the influence of 9 week Viskaldix therapy on hemodynamics was evaluated. Twelve of them underwent repeated hemodynamic examinations after mean 13 months treatment. Viskaldix therapy lowered total peripheral resistance --TPR and there was no significant influence on the heart rate, stroke volume, and cardiac output. It was demonstrated that decrease of total peripheral resistance after treatment with Viskaldix was directly proportional to the initial values of TPR.

Effects of pindolol, or a pindolol/clopamide combination preparation, on plasma lipid levels in essential hypertension. Hunter Hypertension Research Group.

In an open study that was conducted in general practice, 22 patients with previously-untreated mild hypertension received an average daily dose of 11.7 mg of pindolol over a 50-week study period. The total cholesterol, high-density lipoprotein fraction and plasma triglyceride levels showed no significant change from baseline values at the conclusion of this period. A separate group of 18 patients were treated with 10 mg of pindolol a day for 12 weeks, to which regimen was added 5 mg of clopamide for the succeeding 38 weeks. A small rise in total plasma cholesterol levels in this group of patients at both 12 and 50 weeks did not achieve statistical significance, and no change was observed in either the high-density lipoprotein fraction or the plasma triglyceride levels. These results which were obtained in general practice and over a prolonged period of time accord with the general view that the treatment of hypertension with pindolol, a beta-receptor blocking drug with partial agonist activity, is not associated with either the increases in total plasma cholesterol levels or the falls in the high-density lipoprotein fraction that have been reported with other beta-blocking compounds.

Clopamide: plasma concentrations and diuretic effect in humans.

Clopamide pharmacokinetics were determined after oral doses of 5, 10, and 20 mg in normal volunteers. Maximum plasma concentrations occurred within 2 hours and were followed by a monoexponential decline with an elimination half-life of approximately 10 hours. There was an approximately linear relationship between dose and the AUC. Urinary sodium, chloride, and potassium excretion rates indicated that the peak diuretic activity corresponded with peak plasma drug concentrations and probably continued for 12 to 24 hours. There was little difference between the total sodium and chloride output after each dose of clopamide, suggesting that 5 mg may have been close to the top of the dose-response curve. Chlorothiazide, 500 mg, caused less sodium and chloride output with similar potassium loss. During chronic administration to patients with hypertension, hypokalemia was more marked with clopamide, 10 mg daily, than with clopamide, 5 mg, or chlorothiazide, 500 mg daily.

A dose-finding study of the combination of pindolol, clopamide and endralazine in the treatment of moderate-to-severe hypertension.

This study compared the efficacy of a beta-blocker, pindolol, and a diuretic, clopamide, plus a vasodilator, endralazine, in the treatment of 30 patients suffering from moderate-to-severe hypertension. Different doses of endralazine were tested. This study showed that hypertension was controlled in 76,7% of patients receiving a combination of pindolol 10 mg and clopamide 5 mg (Viskaldix; Sandoz) plus endralazine 5 mg, and in 90% it was controlled by a combination of pindolol 10 mg, clopamide 5 mg and endralazine 10 mg daily. In 3 patients it was necessary to give pindolol 10 mg, clopamide 5 mg and endralazine 10 mg twice daily. Side-effects occurred in 5 patients, but they were not sufficiently severe for discontinuation of the therapy. There was no difference as regards the blood pressure response in the 15 Black and 15 Indian patients. Tolerance over a period of 14 weeks did not occur. Results of this study suggest that a fixed drug combination of pindolol 10 mg, clopamide 5 mg and endralazine 10 mg once daily could control blood pressure in about 90% of patients suffering from moderate-to-severe hypertension.

Patients compliance in hypertension--the importance of number of tablets.

The importance of number of tablets for patient compliance was investigated in 160 patients with mild-moderate essential hypertension treated with a beta-adrenoceptor blocker and a thiazide diuretic. Mean BP at entry 146 +/- 16/92 +/- 8 mm Hg. All patients were given pindolol 10 mg and clopamide 5 mg in one combination tablet or in separate tablets for 4 months respectively. Approximately 90% of the patients took greater than 90% of the prescribed dose throughout the study. Mean BP decreased progressively and heart rate increased slightly. Side effects were more frequently reported during the first month of the study than previously, and 30 patients discontinued the treatment. No differences in this respect were seen between 1 and 2 tablets daily. Approximately 75% of the patients preferred 1 tablet daily, but combining two drugs in one tablet had no effect upon compliance.

[Should elderly hypertensive patients be treated with a beta-blocker-diuretic combination?]. / Können ältere Hypertoniker mit einer Betablocker-Diuretika-Kombination behandelt werden?

30 hypertensive patients aged over 60 years underwent an antihypertensive treatment for a time of 3 months with Viskaldix . There was an excellent hypotensive effect in supine and standing position and no bradycardia or orthostatic dysregulation occurred. Metabolic parameters were not influenced, and this is of great importance in elderly patients. It seems notable that elderly patients may benefit from a beta-blocker therapy, as there is clinical or subclinical coronary heart disease.

Lowering blood pressure in the aged: a 40-month experience.

In the author's experience once a day treatment of the hypertensive aged is feasible. A group of 71 cases with an average BP of 170/95 mm Hg or greater and an average age of 72 years were treated with DH ergocristine-clopamide-reserpine compound or methyldopa. The asymptomatic nature of hypertension and a realization of long-term medication accounted for the withdrawal of 18 cases (25.3%) in the first year. At the end of a 40-month period, 47 cases were still under treatment. The BP had been reduced to normal in 27 cases (57.4%) and significantly lowered in 8 cases (17%). With the exception of 1 case, all tolerated the therapy well and experienced no side effects.

New design for clinical trial of antihypertensive drugs applied to pindolol, clopamide, and combinations thereof.

A beta-blocker (pindolol) and a diuretic (clopamide) were given in different dosages, singly and in two different combinations, to 71 patients with mild to moderate essential hypertension. The trial design was such that patients took both drugs singly and in combination, and in different doses, according to a set plan. The best regimen for each patient was determined by taking into account not only blood pressure but also resting heart-rate, body-weight, serum potassium, and serum urate. For 19 patients (27%) monotherapy was best--pindolol for 16 and clopamide for 3. For the remaining patients, a combination of pindolol 10 mg and clopamide 5 mg was best for 39, and in 35 of these one tablet daily was sufficient. All patients reached the preset target blood-pressure. The differences in proportions responding best to the following pairs of regimens compared--monotherapy vs combination, and combination of clopamide 5 mg and pindolol 5 mg vs combination of clopamide 5 mg and pindolol 10 mg--were significant (2p less than 0.01). The process by which the best treatment is chosen according to this study design resembles much more closely that followed in general medical practice, than does the process in the conventional hypertension trial, in which only average effects are reported and compared.

[Viskaldix in the treatment of arterial hypertension]. / Viskaldix v lechenieto na arterialna khipertoniia.

Viskaldix, a combination of Pindolol (Visken)--10 mg with Clopamide--5 mg, was administered to 15 patients with arterial hypertension. The follow up of the patients was according to a previous plan, the preparation administered according, to a schedule. In the determination of the stage of the disease, consideration was mainly given to the values of the diastolic pressure, measured in a lying position. The patients examined were of the following age: to 40--I patient; to 50-7 patients; to 60--7 patients. Seven patients were at the stage I, 4 patients--stage OII and 4 patients--stage III. Reduction of systolic and diastolic pressure with more than 1.33 kPa (10 mm Hg column) both in a lying and standing position were recorded in 2/3 of the patients with the treatment carried out. The effect on the blood pressure, was noticed to develop in 1/3 of the patients with the administration of 2 tablets daily. The blood pressure of only one patient failed to respond to the treatment.

[Computerized automatic management of the therapy of arterial hypertension]. / Avtomaticheskoe upravlenie lecheniem arterial'noi gipertonii s pomoshch'iu EVM.

On the basis of the propositions of the theory of automatic control and regulation, the authors developed the method, algorithm, and program of automatic controlled treatment of arterial hypertension by means of computers. It was conducted in 160 patients with hypertensive disease. Treatment was accomplished with reserpine, dopegit, hemiton, combination of these agents with each other and with diuretics, and with brinerdin. The effect was good in 70.6% and satisfactory in 21.9% of cases; no effect was produced in 7.5% of cases. The studies showed that the created algorithms and program make it possible to carry out effective controlled hypotensive therapy by means of computers. With the use of the developed method it was found that the tuning coefficients, and consequently, the dosages of the drugs necessary for reducing arterial pressure and its maintenance on the desirable preset level differ with the patients and in one and the same patient on different days of the treatment. Automatic controlled hypotensive therapy employing computers may be accomplished with a single agent and, whenever necessary, with a combination of several agents.