Steady-state pharmacokinetics and pharmacodynamics of cilazapril in the presence and absence of cyclopenthiazide.

Twenty-two patients with essential hypertension received a single dose of 2.5 mg cilazapril and were then randomised into a double-blind parallel group study to receive either placebo, 1.25 mg cilazapril + 0.5 mg cyclopenthiazide (CPTZ), 2.5 mg cilazapril + 0.5 mg CPTZ, or 2.5 mg cilazapril alone for 1 month. After oral administration of a single dose of 2.5 mg cilazapril, the active diacid cilazaprilat appeared rapidly in the plasma (Tmax 2.0 +/- 0.2 h). With the radioinhibitor assay used in this study, a single elimination phase of cilazaprilat was evident, with a half-life (t1/2) of 2-3 h. At steady state, the pharmacokinetics of cilazaprilat were similar to single-dose administration and were not altered by CPTZ. The Cmax and area under the curve (AUC) of cilazaprilat were directly proportional to dose. Cilazapril administration in the dose range of 1.25-2.5 mg produced a dose-proportional inhibition of angiotensin-converting enzyme (ACE) activity that was maximum 2 h after drug administration. The degree of ACE inhibition correlated with the plasma concentration-time profile of cilazaprilat and the maximum decrease in blood pressure (BP). The EC50 for ACE inhibition by cilazaprilat was 7.7 ng/ml after acute treatment and was not significantly altered during chronic administration or by concomitant administration of CPTZ. There was no evidence of a dose-related antihypertensive effect of cilazapril at steady state and, with the small numbers of subjects used in this study, there was no evidence of 24-h BP control with monotherapy.

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)

An open, parallel group study comparing a frusemide/amiloride diuretic and a diuretic containing cyclopenthiazide with sustained release potassium in the treatment of congestive cardiac failure--a multicentre general practice study.

A total of 71 patients with cardiac failure requiring diuretic treatment were randomly allocated to receive either 20 mg frusemide/2.5 mg amiloride or 0.25 mg cyclopenthiazide/8.1 mmol sustained release potassium once daily for 12 weeks. Of the 35 patients treated with cyclopenthiazide/potassium, in 47% of patients the daily dose was doubled compared with in only 30% of the 36 patients treated with frusemide/amiloride. Both treatments significantly improved crepitations, oedema, orthopnoea and patient self-assessments of dyspnoea on effort; there were no significant differences between the two treatments. Plasma potassium concentrations were unaffected by either treatment and there were no clinically significant changes in laboratory data. Of the five patients receiving frusemide/amiloride and of the eight receiving cyclopenthiazide/potassium who withdrew from the trial, three and four, respectively, were due to possible drug-related effects. It is concluded that frusemide/amiloride is efficacious and acceptable for the treatment of congestive heart failure.

Low and conventional dose cyclopenthiazide on glucose and lipid metabolism in mild hypertension.

In a double-blind, placebo controlled, randomised parallel study we investigated the antihypertensive activity and metabolic adverse effects of three doses of cyclopenthiazide in 53 patients with mild hypertension. After a 4 week placebo washout period, patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to receive 50 micrograms, 125 micrograms and 500 micrograms of cyclopenthiazide or matching placebo, over an 8 week active treatment period. Blood pressure was recorded at 2 weekly intervals during the trial. Venous samples were taken for evaluation of drug effect on indices of carbohydrate and lipid metabolism just prior to, and on completion of, the active treatment period. Systolic and diastolic blood pressure decreased significantly (P less than 0.05) with the 125 micrograms and 500 micrograms doses of cyclopenthiazide. No change was apparent in any index of glucose and lipid metabolism over time. Low and conventional doses of cyclopenthiazide lower blood pressure without alteration to the metabolic profile in the short term.

Drugs, including alcohol, that act as risk factors for cataract, and possible protection against cataract by aspirin-like analgesics and cyclopenthiazide.

A case-control study of cataract in Oxfordshire explored the risks and benefits associated with a variety of drugs. Steroids including the diuretic spironolactone, nifedipine, heavy smoking, and beer drinking were associated with a raised risk. On the other hand aspirin-like analgesics (paracetamol, ibuprofen, aspirin, etc. appeared to protect against cataract. Cyclopenthiazide appeared to provide a similar protection.

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 breast pain clinic: a rational approach to classification and treatment of breast pain.

Three hundred and fifty women complaining of breast pain symptoms of sufficient severity to interfere with their normal lifestyle were reviewed in a special breast pain clinic over a 5 year period. Seventy-two patients (21%) had spontaneous resolution of breast pain and they required reassurance only before discharge. Of the remaining 278 patients, accurate classification of breast pain syndromes was achieved in 89%, the commonest syndrome being cyclical breast pain which accounted for 54% of the women followed up. The remaining womens' breast pain was classified as trigger zone (14%), continuous (8%), Tietze's disease (5%), spinal root (4%), duct ectasia (4%) and psychological depression (2%). In the remaining 25 patients (9%) the breast pain could not be classified. The experience from this clinic is that a majority of women complaining of severe breast pain symptoms can be accurately classified and appropriate therapy instituted.

Antihypertensive therapy with indoramin: risk-benefit profile in clinical practice.

In a multicenter, prospective study of step II antihypertensive therapy with indoramin, 1,847 hypertensive patients (773 men and 1,074 women) between the ages of 18 and 70 years were treated by 148 general practitioners. Patients whose blood pressure was inadequately controlled after 4 weeks of therapy with cyclopenthiazide (0.25 to 1.0 mg/day) had indoramin (25 to 200 mg/day) added to their treatment regimen. During cyclopenthiazide treatment, mean (+/- SD) blood pressure decreased from 176/105 +/- 20/7 mm Hg at baseline to 164/98 +/- 21/9 mm Hg (p less than 0.001), and only 447 (24%) patients obtained satisfactory blood pressure control. The addition of indoramin produced a further reduction in mean blood pressure from 169/102 +/- 18/6 to 152/89 +/- 18/8 mm Hg during the first 3 months of treatment (p less than 0.001); this response was maintained for up to 2 years. Satisfactory blood pressure reduction was achieved in 79% of the patients who received indoramin (mean dose, 68 mg/day) plus cyclopenthiazide. Only 25 patients (2%) discontinued indoramin treatment because of nonresponse, and 156 (12%) withdrew because of adverse effects, the most common being sedation, dizziness/giddiness, and headache. These results indicate that indoramin provides safe and effective blood pressure control when used as step II treatment for hypertensive patients who fail to respond to single-agent diuretic therapy.

The effects of oxprenolol on ambulatory intra-arterial blood pressure in essential hypertension.

Continuous intra-arterial blood pressure recording using the "Oxford" technique has been used to study the antihypertensive effects of oxprenolol taken three times daily in fully ambulatory patients with essential hypertension, outside hospital. During the first 24 h of treatment there was a reduction in daytime heart rate and a small reduction in daytime blood pressure. After 10 weeks treatment there was a more substantial fall in daytime blood pressure from the hour of waking, but no effect on sleeping nighttime blood pressure or heart rate. Twenty-four hour variation, as assessed by the amplitude of a fitted regression curve, showed a reduction in heart rate but not blood pressure variation. In 4 patients restudied after 11 weeks treatment with oxprenolol (tid) and cyclopenthiazide at 9 a.m. there was some evidence of an antihypertensive effect occurring during both the daytime and nighttime.

Xipamide and cyclopenthiazide in essential hypertension--comparative effects on blood pressure and plasma potassium.

1 The blood pressure lowering effect of xipamide, a non-thiazide diuretic given for 6 weeks was compared in a randomised cross-over trial with that of cyclopenthiazide in 14 patients with essential hypertension. 2 Xipamide 10 or 20 mg given once daily was as effective in lowering supine blood pressure as daily cyclopenthiazide 0.5 mg. There was no difference in the blood pressure lowering effect of 10 mg xipamide daily for 2 weeks compared to 20 mg daily given for a further 4 weeks. 3 Plasma potassium was reduced by both drugs, but markedly more after both 10 mg and 20 mg xipamide than after cyclopenthiazide 0.5 mg. By the sixth week of treatment 13 of 14 patients on xipamide but only 6 of 14 on cyclopenthiazide has plasma potassium concentrations of, or less than, 3.5 mmol/l. The fall in plasma potassium was significantly greater and the final plasma potassium concentration was significantly lower after either dose of xipamide than after cyclopenthiazide. 4 These results suggest that 10 mg or 20 mg of xipamide daily is effective in lowering blood pressure in hypertensive patients but is associated with hypokalaemia. In view of recent evidence linking diuretic-induced hypokalaemia with cardiac dysrhythmias in patients with essential hypertension we would suggest that thiazide diuretics be used in preference to xipamide for the routine management of essential hypertension. Our results also suggest that the currently recommended dose of xipamide (20 mg) for the treatment of hypertension is excessive, and lower amounts than 10 mg per day might possibly be as effective in lowering blood pressure with less adverse metabolic consequences.

Comparison of the antihypertensive effects of indapamide and cyclopenthiazide.

The antihypertensive effects of indapamide, 2.5 mg, and cyclopenthiazide, 0.5 mg daily were compared over a two week period. The falls in both diastolic and systolic blood pressure were greater with indapamide than with cyclopenthiazide reaching statistical significance for the supine diastolic values. This difference was still seen when matching patient groups of similar age, sex or severity of blood pressure were compared.

The treatment of hypertension in older patients: a double-blind, between-patient study, in previously treated patients comparing a diuretic, a beta-receptor antagonist, and their fixed combination.

Six hundred and forty-eight previously treated hypertensive patients, with a mean age of 64 years, were studied. In spite of treatment over a mean period of 18 months, their blood pressure was inadequately controlled, with an initial mean level of 180/108 mm Hg. Previous treatment which had consisted of either a diuretic alone, a beta-receptor antagonist alone or these two drugs in combination was discontinued and patients were randomly allocated, in double-blind manner, to a 6-week treatment course of cyclopenthiazide (Navidrex) or sustained release oxprenolol (Slow-Trasicor) or a fixed combination of these two compounds (Trasidrex) with the aim of lowering the diastolic pressure to less than 100 mm Hg. Blood pressure was substantially reduced in each treatment group, with the lowest final pressures in the group treated with the fixed combination, where 87% of the patients completing the study reached the target level of a diastolic pressure of less than 100 mm Hg. Very few side-effects of treatment were reported with any of these compounds. The results from this study suggest that these compounds in their standard dosage range are useful and safe antihypertensive agents in older patients. In those patients where blood pressure control with a single agent was proving difficult, the transfer to one or two tablets daily of the fixed combination (Trasidrex) produced a very satisfactory outcome in the large majority of cases.

A study comparing indapamide with cyclopenthiazide in geriatric patients.

The efficacy of indapamide was compared with cyclopenthiazide in geriatric hypertensive patients. On admission to the study patients were randomly allocated following a placebo run-in period before therapy commenced. Indapamide produced a greater fall in blood pressure which was well maintained in contrast to cyclopenthiazide. Both drugs were well tolerated.