The antihypertensive and metabolic effects of low and conventional dose cyclopenthiazide in type II diabetics with hypertension.

The antihypertensive efficacy and metabolic effects of cyclopenthiazide 125 micrograms were compared with cyclopenthiazide 500 micrograms in patients with non-insulin dependent diabetes and hypertension in a double blind, randomized crossover study. After a 6-week placebo period 24 patients with non-insulin dependent diabetes mellitus, stabilized on diet or oral hypoglycaemic agents, who had a mean diastolic blood pressure between 90 and 120 mmHg after receiving placebo for 6 weeks were given 125 micrograms or 500 micrograms cyclopenthiazide for 12 weeks. Patients then received placebo for a further 6-week period, following which they received the alternate treatment dosage for 12 weeks. There were no differences between doses in their antihypertensive effects. While 500 micrograms significantly reduced systolic and diastolic blood pressures, only diastolic pressure was significantly reduced by 125 micrograms from pre-treatment values. The higher dose of cyclopenthiazide had greater effects on measures of diabetic control than did the 125 micrograms dose and the rise in blood glucose after 12 weeks' treatment with 500 micrograms was significantly different from pre-treatment values. Cyclopenthiazide 125 micrograms had significantly less effect on triglycerides, potassium and urate, than did 500 micrograms. Cyclopenthiazide 500 micrograms resulted in a significant fall in serum potassium from pre-treatment values. There were no intertreatment differences in the other variables measured. Cyclopenthiazide 125 micrograms is as effective as 500 micrograms in reducing diastolic blood pressure in mildly hypertensive non-insulin dependent diabetic patients. The higher dose had more pronounced adverse effects on glucose control and serum concentrations of triglycerides, potassium and urate.

Low-dose cyclopenthiazide in the treatment of hypertension: a one-year community-based study.

After an 8-week placebo period, 73 patients whose diastolic blood pressures were between 90 and 110 mmHg were randomly assigned to receive 125 micrograms (low dose) or 500 micrograms of cyclopenthiazide (standard dose) for a period of one year. Blood pressure was measured in the patient's home by the same observer at two-weekly intervals during an 8-week placebo run-in period, every 4 weeks for a further 12 weeks and at 24, 36 and 52 weeks thereafter. Serum potassium, urate, glucose, glycosylated haemoglobin, total and HDL cholesterol, and apolipoproteins were measured at the end of the placebo period and at 4, 8, 24 and 52 weeks of active treatment. Twelve of the 73 patients had an inadequate antihypertensive response--five on the higher dose and seven on the lower dose. One patient receiving 500 micrograms was withdrawn because of adverse effects. In the remaining 60 patients, systolic and diastolic blood pressures were significantly reduced when compared with pretreatment values in both treatment groups throughout the one year period. The decreases in blood pressure were not significantly different from each other (p greater than 0.65). Three patients on 500 micrograms required potassium supplements. Maximum decreases in the serum potassium of 0.52 mmol/l (500 micrograms dose) and 0.14 mmol/l (125 micrograms dose) were observed at 24 weeks of treatment in the remaining 57 patients. The differences between the two doses at this time were statistically significant (p less than 0.05), as were the increases in serum urate observed at 4, 8 and 24 weeks (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the haemodynamic and hormonal effects of low and conventional dose cyclopenthiazide in normal volunteers.

In this study we compared low (125 micrograms) and conventional (500 micrograms) doses of cyclopenthiazide on the renin angiotensin system, plasma and extracellular fluid volumes and the pressor responsiveness to angiotensin II since we have previously shown that the two doses have the same antihypertensive effect but different effects on plasma renin activity. Following a two week placebo run-in period, 8 healthy male volunteers received 125 micrograms or 500 micrograms of cyclopenthiazide for 2 treatment periods of 4 weeks as part of a double blind, 2-part crossover study with treatment periods separated by a 4-week placebo washout phase. Measurements were made on two study days at the beginning and end of the active treatment periods. On the first day serum potassium, plasma renin activity and plasma angiotensin II levels were measured after a 1 h period of supine rest. Plasma and extracellular fluid volumes were also measured after appropriate equilibration times. The blood pressure responses to angiotensin II were assessed on day 2. The 500 micrograms dose of cyclopenthiazide had a greater effect than the 125 micrograms dose on plasma renin activity, serum potassium, angiotensin II levels and extracellular fluid volumes. Neither drug had any effect on plasma volume or the responsiveness to infused angiotensin II. Low dose cyclopenthiazide failed to increase angiotensin II levels, contract body fluid volumes or attenuate vascular reactivity in normotensive volunteers.

The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide.

In a double blind placebo controlled randomised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were evaluated in patients with mild essential hypertension that had been recently diagnosed or was being treated with a single drug. After a four week placebo washout period 53 patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to 50, 125, or 500 micrograms cyclopenthiazide or matching placebo for an eight week period of treatment. Blood pressure was measured in the patients' homes by the same observer every two weeks. Serum urea, electrolytes, urate, and creatinine concentrations and 24 hour urinary sodium excretion were monitored every four weeks and serum magnesium concentration and plasma renin activity at the end of the washout and treatment periods. After eight weeks of treatment systolic and diastolic blood pressures were significantly reduced in patients taking 125 and 500 micrograms cyclopenthiazide when compared with those taking placebo. The decrement in serum potassium concentration (0.6 mmol/l) and increase in serum urate concentration 0.06 mmol/l) were greatest with the 500 micrograms dose, the increase in serum urate concentration alone being significant. No change in serum magnesium concentration or 24 hour urinary sodium excretion was noted with any dose of cyclopenthiazide. Only the 500 micrograms dose of cyclopenthiazide significantly increased the mean plasma renin activity (1.8 (95% confidence interval 0.2 to 3.4)-5.4 (3.9 to 6.8) nmol angiotensin I/l/h); the other doses like the placebo had no effect. Cyclopenthiazide 125 micrograms, a dose lower than is currently marketed, produced a similar hypotensive response to 500 micrograms of the drug without upsetting the biochemical profile.

Effect of low versus conventional dose cyclopenthiazide on platelet intracellular calcium in mild essential hypertension.

Platelet free intracellular calcium levels were measured during a double-blind, placebo-controlled parallel study to investigate the antihypertensive activity of 50 micrograms, 125 micrograms, and 500 micrograms cyclopenthiazide, in mild essential hypertension. Cytosolic free calcium levels were significantly higher in established hypertensive patients (135 +/- 28 nmol/l, P less than 0.001) but not in borderline hypertensive patients (123 +/- 26 nmol/l) compared with normotensive controls (111 +/- 9 nmol/l). A positive correlation between platelet free calcium level and systolic and diastolic blood pressure was confirmed (n = 68; r = 0.309 P = 0.01; r = 0.405 P less than 0.001, respectively). The 125-micrograms and 500-microgram doses of cyclopenthiazide produced mean decrements in blood pressure of 18/10 mmHg and 23/8 mmHg, respectively, (P less than 0.05 for both), after 8 weeks of therapy. The 50-microgram dose displayed no useful antihypertensive activity. Platelet free calcium levels fell by a similar amount in the four groups. The fall in blood pressure produced by the 125 and 500-microgram doses of cyclopenthiazide did not correlate with changes in platelet [Ca2+]i (r = 0.166 systolic and r = 0.169 diastolic). These findings do not support the hypothesis that changes in platelet cytosolic calcium levels are determined by the same factors that control blood pressure.

A comparative study of frusemide-amiloride and cyclopenthiazide-potassium chloride in the treatment of congestive cardiac failure in general practice.

Forty-seven patients entered this comparison of frusemide-amiloride and cyclopenthiazide-potassium chloride in the treatment of congestive cardiac failure in general practice. Frusemide-amiloride was 'very satisfactory' in 92% of the patients compared to only 55% who took cyclopenthiazide-potassium chloride. Significantly more patients were free of paroxysmal nocturnal dyspnoea and orthopnoea after taking frusemide-amiloride.

[The stability of hydrochlorothiazide and cyclopenthiazide in various dosage forms. 4. Stability of hydrochlorothiazide injection solutions II]. / Untersuchungen zur Stabilität von Hydrochlorothiazid und Cyclopenthiazid in unterschiedlichen Arzneiformen. 4. Mitteilung: Stabilität von Hydrochlorothiazid-Injektionslösungen II.

The hydrolytic decomposition of hydrochlorothiazide (1) in an optimized dispensing with polyethyleneglycol 400/ethanol as solvent led to an equilibrium in the isothermic short-term test as well as in the long-term stability test. Corresponding equilibrium concentrations were obtained for forward and back reaction. When comparing the precalculated equilibrium values with the long-term results the evaluation after Van't Hoff proved superior compared with an evaluation after the Arrhenius plot which is only applicable when the equilibrium concentrations are taken into consideration. By adding the decomposition product aminodisulfamide (2) the hydrolysis of 1 can be inhibited completely.

Comparative clinical trial of bemetizide/triamterene and cyclopenthiazide/potassium chloride combinations in patients with mild to moderate hypertension.

A double-blind trial was carried out to compare the combination of 25 mg bemetizide plus 50 mg triamterene ('Hypertane') and 0.25 mg cyclopenthiazide plus 600 mg potassium chloride ('Navidrex' K) in the treatment of mild to moderate essential hypertension. Two well matched groups of patients were treated for periods of 6 weeks with one or other of the drugs under test. There were 2-week placebo run-in and run-out periods. Blood pressure and laboratory investigations were performed every 2 weeks during the trial period. Both treatments resulted in similar overall statistically significant reductions in blood pressure during the trial. With bemetizide/triamterene, mean lying blood pressure decreased by 11.1/11.2 mmHg and mean standing blood pressure by 15.9/10.3 mmHg; with cyclopenthiazide/potassium chloride the corresponding reductions were 14.9/12.1 mmHg and 9.1/11.7 mmHg. The fact that some of the observed overall reduction seen with both drugs was due to 'placebo effect' is discussed but the clinical importance of overall changes is stressed. There were no significant differences between changes in blood pressure with the two treatments. Biochemical changes were those expected with thiazide diuretics. However, the decrease in potassium and increases in urea and uric acid levels were less with bemetizide/triamterene than with cyclopenthiazide/potassium chloride. Clinical tolerance of both treatments was good.

Do all diuretics have equal hypotensive efficacy?

An open parallel study was carried out in general practice on 70 patients with uncomplicated mild to moderate hypertension to compare the hypotensive efficacy of hydrochlorothiazide/amiloride with that of cyclopenthiazide/potassium. After a 2-week baseline period on placebo, patients were allocated at random to receive treatment with one or other of the diuretics starting with 1 tablet per day and increasing up to a maximum of 4 tablets per day or until their supine diastolic blood pressure was 90 mmHg or less. They were then continued at their optimum dose for a further 4 weeks. Analysis of the results from 62 patients showed that the hydrochlorothiazide/amiloride preparation produced both a greater decrease and better control of blood pressure in a greater percentage of patients that did the comparison diuretic. In addition, the beneficial effects were attained with fewer tablets, of importance for patient compliance.

Comparison of timolol/hydrochlorothiazide/amiloride ('Moducren') with cyclopenthiazide/potassium in mild to moderate hypertension.

An open study was carried out in 641 patients with mild to moderate hypertension seen in general practice to assess the effectiveness of treatment with a timolol/hydrochlorothiazide/amiloride preparation compared with cyclopenthiazide/potassium. The timolol/hydrochlorothiazide/amiloride preparation produced better control of blood pressure in a larger percentage of patients after 2 and 6 weeks of treatment than did the diuretic/potassium preparation, and more patients were maintained on 1 tablet per day. Both treatments reduced the number of symptoms complained of by the patients at the initial visit.

Comparison of the beta-adrenoceptor blocking activity of oxprenolol, slow release oxprenolol and a combined oxprenolol diuretic preparation.

1 Observations were made in five healthy subjects who exercised before and 2, 3, 6, 8 and 24 h after the oral administration on separate occasions of 160 mg oxprenolol, 160 mg slow release oxprenolol, 160 mg slow release oxprenolol with 0.25 mg cyclopenthiazide and placebo. Blood samples were obtained before and at 1, 2, 3, 6, 8, 12 and 24 h after drug administration and assayed for oxprenolol concentration. 2 The three formulations produced maximum reductions of 29% in the exercise tachycardia 3 to 6 h after drug administration. At 24 h the effects of the three preparations were not significantly different from placebo. 3 There were no significant differences in the plasma concentrations produced by the three formulations during the 24 h period. 4 These observations suggest that the slow release formulations of oxprenolol should be given twice daily to maintain cardiac beta-adrenoceptor blockade throughout a period of 24 h.

Oxprenolol slow-release with cyclopenthiazide KCl in the treatment of essential hypertension. A multicentre general practice study.

In part I of this article we report on 89 hypertensive patients who underwent 9 months of treatment with oxprenolol HCl 160 mg in a slow-release formulation plus cyclopenthiazide 0.25 mg and potassium chloride 600 mg (Trasidrex; Ciba-Geigy). Blood pressures, both supine and standing, and pulse rates were consistently controlled by this regimen throughout the 9 months of treatment, regardless of the time of day at which these parameters were measured, i.e. morning or afternoon. Seventy-six patients completed the trial. The most common symptom or sign occurring during treatment was headache, the next most common being heartburn. No patient developed angina while on the regimen. Three patients discontinued the study owing to unwanted effects. This study represents a total of 28237 patient-days of treatment. In part II of the trial we studied the effects of a similar regiment in 67 patients for 1 year preceded by a 2-week wash-out period. Forty-six of the patients completed a full year's treatment. Statistically significant reductions in blood pressures and pulse rates occurred after commencement of active treatment and were maintained throughout the study period. Four patients withdrew from the study owing to adverse effects, 1 patient died of an acute myocardial infarction, and 1 patient was considered a treatment failure. This study represents 19858 patient-days of treatment.

An open comparison between free and a fixed combination of diuretic and beta-blocker in the management of essential hypertension.

A total of 1,117 patients with inadequately controlled hypertension in spite of treatment with a combination of diuretic and beta-adrenergic blocker were studied. Treatment was changed to one or two tablets daily of Trasidrex (160 mg oxprenolol hydrochloride in a sustained release formulation and 0.25 mg cyclopenthiazide) with a subsequent improvement, 4 weeks later, in blood pressure control. Side-effects of treatment were uncommon and treatment was approved by the majority of patients. The majority of doctors participating thought a fixed combination would improve patient compliance with therapy.

A multicentre study examining the substitution of Trasidrex for the free combination of Slow-Trasicor and Navidrex-K.

A multicentre, open study of general practice patients with essential hypertension who were currently being treated with oxprenolol and cyclopenthiazide was undertaken in which the patients were transferred to Trasidrex for 12 weeks. Weight, blood pressure, heart rate and side-effects were assessed pre-trial and at 4-week intervals. A global assessment was also made at the same time intervals. The mean serum potassium remained virtually unchanged after 12 weeks treatment with Trasidrex. Blood pressure control was marginally improved during the study and it is thought possible that better patient compliance might explain this. Trasidrex was tolerated equally as well as the free combination.

Oxprenolol slow-release with cyclopenthiazide-KCl compared with methyldopa in the treatment of essential hypertension. A multicentre general practice trial.

Two hundred and thirty-eight patients with essential hypertension from 39 general practice centres were treated in a double-blind trial with either oxprenolol 160 mg in a slow-release (SR) formulation with cyclopenthiazide 0,25 mg and potassium chloride 600 mg given once daily, or methyldopa 250 mg 3 times daily. After a 2-week placebo washout period, each patient was treated for 10 weeks. Both treatments significantly reduced blood pressure. Oxprenolol SR plus cyclopenthiazide-KCl was shown to possess significantly superior antihypertensive activity to methyldopa. Pulse rate, as expected, was significantly decreased by the beta-blocker and virtually unaffected by methyldopa. The overall incidence of side-effects was low. The incidence of sleepiness and dry mouth was significantly higher in the methyldopa group, and erythema in the oxprenolol group. The principle of general practitioners conducting multi-centre double-blind trials for research purposes, on drugs which are predominantly given to ambulatory patients, has been established for the first time in South Africa. Virtually no difficulty was encountered in getting patients' consent in the general practice milieu.