Comparison of the effects of muzolimine and a fixed combination of diuretics in essential hypertension.

The efficacy and tolerance of the loop diuretic muzolimine were compared with those of a fixed combination of hydrochlorothiazide and amiloride in patients with mild to moderate hypertension. After a placebo lead-in period, patients whose supine diastolic blood pressure was between 90 and 115 mm Hg were randomly allocated either to muzolimine, 20 mg/day, or to hydrochlorothiazide, 50 mg/day, and amiloride, 5 mg/day. The mean duration of follow-up was 4.7 months in both groups. Both muzolimine and the combination significantly decreased the mean blood pressure. The two treatments were similar in efficacy. The incidence of side effects during the trial was similar with both treatments, and no serious adverse reactions occurred. Eleven subjects in the muzolimine group were entered into an open long-term study. In all these subjects the blood pressure remained adequately controlled throughout the 4 to 6 months of additional follow-up and no side effects were reported. Muzolimine appears to be an effective and safe antihypertensive agent.

Long-term treatment of essential arterial hypertension with nitrendipine.

The efficacy and safety of long-term treatment with oral nitrendipine were evaluated in 34 patients with essential arterial hypertension. Nitrendipine alone significantly lowered systolic and diastolic blood pressure levels in 28 patients who completed the preliminary four-week dose-setting phase. Twenty-one patients completed the one-year treatment. Blood pressure control was maintained by nitrendipine alone in 11 patients. Ten patients not adequately controlled at the end of the dose-setting phase were successfully treated with nitrendipine combined with acebutolol or muzolimine. It is concluded that nitrendipine is a promising calcium antagonist for the treatment of arterial hypertension.

Pharmacokinetics and saluretic effect of muzolimine in severe cardiac failure.

Pharmacokinetics and effects on renal electrolyte excretion of a new diuretic drug, muzolimine (Bay g 2821), were investigated in 6 patients with severe congestive cardiac failure (New York Association classification Groups III and IV). After a single oral dose of 30 mg muzolimine, mean urinary excretion rate of sodium increased from 1.37 to 4.30 mmol/hour during the initial 24 hours, that of chloride from 0.86 to 3.97 mmol/hour, that of potassium from 1.23 to 1.63 mmol/hour, and that of water from 25.8 to 49.9 ml/hour. The saluretic effect lasted for 10 to 14 hours in 1 patient, 14 to 24 hours in 2, and more than 24 hours in 3 patients. Peak plasma concentrations of muzolimine occurred 1 to 7 hours after administration and averaged 487 ng/ml (range 268 to 868). Mean biological half-life of muzolimine in plasma was 14.3 hours (range 9.0 to 21.2 hours). The saluretic effect of muzolimine in congestive cardiac failure, thus, is of long duration, which may be explained by its long biological half-life.

Clinical trial with muzolimine in healthy and hypertensive subjects: new vistas on the drug action.

The mechanism of muzolimine (3-amino-1-[3,4-dichloro-alpha-methyl-benzyl]-2 pyrazolin-5-one) action is still not completely defined. The identified site of action is the Henle loop, similarly to furosemide which acts also by mediating renal prostaglandin synthesis. The aim of the present study was to evaluate the early effects of muzolimine (30 mg per os) on renal function and prostaglandin urinary excretion in healthy controls and hypertensive subjects. Urinary flow reached the peak values by the third hour after the drug and a diuretic effect not directly dependent on glomerular filtration was observed, especially in hypertensive patients. In these cases the diuresis increased also due to a low glomerular filtration rate and tubular phenomena were more evident than in controls: an increasing Na+ tubular excretion and a parallel decreasing % Na+ reabsorption. Blood pressure was not significantly influenced by muzolimine in healthy subjects, while it returned to normal values in the hypertensive group. A cyclooxigenase inhibitor, lysine acetylsalicylate (1 g i.m.) administered 10 minutes after muzolimine, was not able to modify the parameters under consideration. Therefore a mediation by prostaglandins on the diuretic and antihypertensive effects of the drug under study may probably be excluded.

Muzolimine in patients on chronic hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD).

The importance of the urine volume and the residual functional capacity of the kidneys has been emphasized by several authors in connection with preservation of the quality of life of patients having to undergo chronic dialysis therapy. Since it has been found that muzolimine can increase diuresis even in patients with extremely high uraemia (GFR values less than 5 ml/min), a group of 16 patients (10 haemodialysis patients, HD, and 6 peritoneal dialysis patients, CAPD) was treated daily with 90 mg for a period of one year, commencing with the start of dialysis therapy. The aim of the study was to monitor the diuresis and to evaluate any changes in the quality of life. The latter were assessed on the basis of clinical criteria by the scheme of Ravid et al. The results were compared with the results obtained from another group of 16 patients (10 HD and 6 CAPD) who had likewise been on dialysis for a year but without receiving diuretic therapy. The two groups were homogeneous in age, sex, aetiology of the kidney disease, and renal function. Even though diuresis, like the residual renal function, normally deteriorates in the course of time owing to the underlying kidney disease, the administration of muzolimine showed that the compound is able to induce statistically significantly higher diuresis in the treated patients in the first year of dialysis compared with the untreated patients. In addition it was possible to preserve the residual kidney function established at the start of the dialysis therapy, which corresponds to a significantly improved quality of life.

[Pharmacodynamic and pharmacokinetic studies of muzolimine in patients with hepatogeneous ascites (author's transl)]. / Klinisch-pharmakologische und pharmakokinetische Untersuchungen zur Wirkung von Muzolimin bei Patienten mit hepatogenem Aszites.

A clinical pharmacological study was carried out with 11 patients suffering from hepatogeneous ascites. After pretreatment with spironolactone (twice daily 100 mg), 80 mg of a new loop diuretic, muzolimine, were administered orally in addition to 100 mg of spironolactone. The diuretic effect started rapidly, reached its maximum about 6 h after administration and declined slowly until 24 h. The electrolyte profile showed a pronounced excretion of sodium and chloride, whereas potassium excretion was distinctly lower. Sodium/potassium ratio was 5.9 during the first 8 hours, and the mean ratio was 5.2 during 24 hours. Urinary volume and sodium excretion were significantly correlated with plasma levels of muzolimine. Mean plasma half-life of muzolimine in these patients with liver cirrhosis was 7.9 h and was thus longer than in healthy volunteers.

Muzolimine in the treatment of essential arterial hypertension not controlled with other antihypertensive drugs.

Fifty-three adult patients suffering from various degrees of essential arterial hypertension, which was not controlled with other antihypertensive drugs, participated in this study with the intention: To demonstrate the effectiveness of a 20 mg or 40 mg daily muzolimine dose as complementary treatment. To determine whether the effective dose obtained can be maintained for a long-term administration. To verify its tolerance. Therefore, muzolimine was administered in addition to the basic treatment, which went on unmodified during this study. A laboratory set of examinations, three controls of systolic and diastolic blood pressures and heart rate--each in supine and standing position--were performed before starting the treatment. At the end of the two initial weeks of treatment with administrations of 20 mg daily muzolimine doses, the diastolic blood pressure normalized at values below 90 mmHg in sixteen patients. These patients continued the muzolimine treatment taking the same dose for seven days, being submitted to two more controls during this time. As the normalization was confirmed, laboratory controls were repeated. Thirteen patients of this group continued the same treatment for three months. The remaining thirty-seven patients, who did not normalize their diastolic blood pressure, immediately started a second treatment period of two weeks, receiving a 40 mg daily muzolimine dose. At the end of this period, diastolic blood pressure normalized in twenty-four patients, decreased significantly in six, moderately in five, and remained unchanged in two. At the end of this second period, laboratory tests were repeated. Nineteen patients of this group continued the same treatment for three months.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of diuretics in varying degrees of renal impairment: an overview.

Administration of diuretics during acute renal failure in animals has been demonstrated to be of value with mannitol and/or loop-blocking diuretics, furosemide or ethacrynic acid. There is evidence that if these drugs are given very early in the controlled experimental environment that there will be some beneficial effect in maintaining renal function. However, in man the temporal relationship between the acute onset and the successful response to the administration of the drugs is, at best, coincidental and the use of diuretics in acute renal failure may not produce the same results as seen in the laboratory. One of the best guides to the underlying disease when there is acute decompensation in renal function is the utility of the renal failure index which utilizes urine and plasma sodium and urine and plasma creatinine ratios. Large doses of loop-blocking diuretics can be of benefit in patients with mild to moderate chronic renal insufficiency and fluid retention and/or hypertension. When renal insufficiency is severe in the pre-dialysis setting, furosemide, bumetanide or muzolimine may be of some benefit; however, as renal failure worsens the response of the kidney is sluggish and it is wise to begin to dialyze when glomerular filtration deteriorates below 5 ml per minute.

[Clinical and hemodynamic effects of medium-term treatment with muzolimine in subjects with essential arterial hypertension]. / Effetti clinici ed emodinamici del trattamento a medio termine con muzolimina in soggetti con ipertensione arteriosa essenziale.

The antihypertensive effects and haemodynamic changes after administration of 30 mg/die of muzolimine for 30 days in a group of patients with mild or moderate essential hypertension have been evaluated. Our findings showed a significant reduction of body weight, arterial blood pressure, systemic vascular resistance, plasma volume and small but significant increase of left ventricular ejection fraction. No relevant side effect have been observed.

Comparison of the effects of muzolimine and furosemide in patients with end-stage renal failure on chronic dialysis.

The pharmacodynamic effects of muzolimine and furosemide were compared in a single dose cross-over study in 8 patients on regular dialysis treatment, who had a residual diuresis of more than 300 ml/day. The study periods comprised two dialysis-free intervals of 3 days. On the second dialysis-free day either muzolimine 240 mg or furosemide 240 mg was administered orally. Urine was collected in 12-h periods on the pre-treatment, treatment and post-treatment days, and the excretion of sodium, potassium, urea and creatinine were measured. After administration of muzolimine 240 mg urine volume rose to twice that of the previous day, and sodium excretion increased approximately threefold. In contrast, the effect of furosemide 240 mg was not a pronounced; the diuresis was only 1.6 times that on the previous day and natriuresis was only 2.2 times as large. Excretion of potassium and creatinine was only slightly increased by either substance. The elimination of urea was increased by both substances to the same degree as the corresponding increase in diuresis.

Serum lipoproteins in patients with mild renal disease treated with the diuretic muzolimine.

Patients with renal functional impairment are prone to develop hypertension and hyperlipidemia, and both abnormalities tend to occur already at an early stage of kidney disease. In 18 patients with mild renal disease (glomerular filtration rate 65 +/- 5 ml/min) and hypertension (mean blood pressure 126 +/- 4 mm Hg), the effect of six weeks of treatment with the loop-diuretic muzolimine on serum lipoproteins was assessed. Compared to placebo values, the diuretic significantly increased serum low-density lipoprotein cholesterol (LDL-C) and apoprotein B (+ 18 and 11%, respectively, P less than 0.005) in 13 men or postmenopausal women, but not in 5 premenopausal women. Serum high-density lipoprotein cholesterol (HDL-C), and total triglycerides or lipoprotein triglyceride fractions were not consistently changed in both subgroups. Thus, the ratio LDL-C/HDL-C was increased from 3.2 +/- 0.3 to 3.9 +/- 0.3 (P less than 0.05) in the men or postmenopausal women, while no such tendency occurred in the premenopausal women (4.1 +/- 0.6 to 3.7 +/- 0.6). Changes in serum LDL-C were not associated with hemoconcentration or alterations in carbohydrate metabolism and were not related to variations in serum potassium or blood pressure. Increased serum levels of the atherogenic LDL-C fraction during diuretic treatment in men or postmenopausal women with renal disease may represent a potentially undesirable effect, particularly since such patients may tend to have hyperlipidemia in the untreated state.

Effects of a new loop diuretic (muzolimine) in cirrhosis with ascites: comparison with furosemide.

Muzolimine is a loop diuretic with both the dose-dependent increasing effectiveness of loop diuretics and the long-lasting effect of thiazides. This is a potential advantage in the treatment of ascites in advanced cirrhosis since these patients have a low tolerance to sudden reductions of blood volume. Equivalent single, oral doses of furosemide (40 mg) and muzolimine (30 mg) were given to 10 cirrhotic patients with ascites and reduced renal perfusion (glomerular filtration rate = 30 to 75 ml per min). The study was preceded by 4 days of equilibration (dietary sodium 40 mmoles per day), and the drugs were alternated via a single-blind, cross-over protocol after a wash-out period of 3 days. Renal function was monitored under basal conditions and after diuretic administration through 4-hr clearance periods for 24 hr. The renin-aldosterone axis was evaluated before diuretic administration and after 8 and 24 hr. Muzolimine led to a 12-hr cumulative diuresis [AUC0-12 = 2.52 +/- 0.42 (S.E.) ml per min] and natriuresis (5.14 +/- 1.05 mmoles per hr), which were comparable to those of furosemide (2.85 +/- 0.29 ml per min and 6.75 +/- 1.63 mmoles per hr). Its effect, however, was distributed over a longer period (8 hr) than furosemide (4 hr). Muzolimine activity mainly differed from furosemide because of: significantly lower 12-hr potassium excretion (AUC0-12 = 0.28 +/- 0.82 vs. 2.69 +/- 0.46 mmoles per hr; p less than 0.005); greater sodium/chloride excretion ratio (0.45 +/- 0.08 vs. 0.26 +/- 0.06; p less than 0.025), and absence of rebound phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effect of muzolimine in postischemic acute renal failure in rats.

Evidence has been presented in the past that muzolimine might act at a localization differently to sulfamoyl-type diuretics and/or with a different or additional mechanism. This is further supported by the fact that at the maximum of the dose-response curves for muzolimine and furosemide in rats, a combination of maximal oral doses still results in significantly higher sodium excretion. To further substantiate that this aspect of muzolimine is of relevance, e. g. for the therapy of acute renal failure, muzolimine treatment by food or implanted osmotic minipumps was employed in an obstructive model of severe renal ischemia in rats. Acute renal ischemia was induced in Wistar rats by clamping the left renal pedicle for 60 minutes with a microsurgery clamp. The right kidney had been removed four days before ischemia. Clearance data were obtained on the first, third and on the ninth to fourteenth days after ischemia in the surviving animals. Renal ischemia resulted in anuria, increased mortality and impaired renal function with histopathologically apparent tubular obstruction in the untreated controls. Treatment with muzolimine by food (in a concentration of 800 ppm for four days) and additional oral gavage one hour prior to ischemia prevented the sequelae of ischemia to a great extent. Similar beneficial effects could be obtained by therapeutic implantation of osmotic minipumps ensuring administration of 0.44 micrograms muzolimine/h per animal. These results in rats further support the suggestion that muzolimine might act differently to sulfamoyl-diuretics. Furthermore, they strongly implicate muzolimine as the diuretic of choice in acute renal failure.

Muzolimine therapy in patients with congestive heart failure in comparison with furosemide pretreatment. Effect on digoxin plasma concentration.

Eight patients suffering from congestive heart failure (NYHA III-IV) and pretreated with digoxin received muzolimine over 14 days in an open clinical study. The muzolimine dose was adjusted to 3/4 of the daily furosemide dose necessary to keep the body weight constant at least three days prior to the onset of muzolimine treatment. Plasma concentrations of epinephrine, norepinephrine, aldosterone, renin and digoxin were determined on the last day of the furosemide treatment period and on the last day of the muzolimine period. No significant changes were observed in plasma concentrations of epinephrine, aldosterone, renin, creatinine, and potassium. After muzolimine treatment, however, body weight and sonographically determined liver size decreased further and plasma norepinephrine concentrations were significantly lower. The digoxin concentrations did not change after muzolimine treatment. The results demonstrate the beneficial effect of muzolimine in heart failure patients. Since plasma concentration of digoxin does not change despite marked diuretic effects of muzolimine no relevant interaction between both substances has to be expected.

Comparison of muzolimine and furosemide in heart failure.

Comparative and randomized evaluation of 30 mg muzolimine and 40 mg furosemide was assessed in 18 patients with CHF. Muzolimine is slightly more effective than furosemide with regard to total 24-hour urine excretion, and a significant difference was found in the time-response curve. In fact the maximum rate of diuresis occurred at the second hour with muzolimine and at fourth hour with furosemide. Both drugs were well tolerated and no side-effects were observed.

Treatment of mild to moderate essential hypertension with muzolimine. Two years of follow-up.

This study was carried out in association with medical practitioners who were responsible for observing the patients. In a first phase, 58 subjects younger than 70 years with moderate essential hypertension were allotted at random to treatment with either indapamide (2.5 mg per day) or muzolimine (20 mg per day). The double blind-double dummy study lasted for six months and demonstrated that the two drugs were similar in efficacy and tolerance. At the end of this phase 42 patients whose supine diastolic blood pressure fell to below 100 mmHg were selected to continue the trial with 20 mg per day muzolimine in an open long-term study. The survey comprised two periods: the first lasted for six months, the patients being examined every two months, and the second lasted for one year and patients were seen quarterly. However, 8 subjects entered directly into the second period. At each examination standing and supine blood pressure, heart rate and body weight were noted; blood was sampled to allow measurements of serum plasma parameters. Thus 15 patients were treated with muzolimine over two years and 15 over 18 months. Clinically the fall in blood pressure observed initially was maintained throughout the rest of the trial; but 3 patients needed another drug, i.e. central hypotensor (2 cases) and beta-blocker (1 case). Two subjects complained of transitory cramps, but 3 other complications not imputable to the treatment were observed: one myocardial infarction and 2 strokes. Biologically there was no change in mean plasma potassium level, but 3 patients received a potassium supplement.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of muzolimine after acute and chronic dosing in hypertensive patients with mild renal insufficiency.

Pharmacokinetics and clinical effects of muzolimine were investigated in 6 hypertensive patients with incipient renal insufficiency. Muzolimine plasma levels were determined after the first dose and after 8 weeks of treatment with muzolimine (20 mg o.d.). The area under the curve of muzolimine plasma levels was greater after 8 weeks than after the first dose. Also, peak plasma concentrations were higher after 8 weeks; however, muzolimine half-lives in the beta-phase were unchanged. Blood pressure and body weight decreased with time. Muzolimine was well tolerated.