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In chronic heart failure diuretic drugs improve central hemodynamic variables and cardiac pumping secondary to altered plasma and extracellular volumes; humoral markers of these changes include increased plasma renin and aldosterone levels. The latter increases are maximal over the first week but decline with chronic therapy. The plasma alpha-ANP levels show a reciprocal effect; these data are compatible with a rapid contraction of the plasma volume which is sustained during chronic therapy. The acute hemodynamic actions of diuretic agents reflect both immediate and direct vascular actions and also effects secondary to diuresis (volume redistribution). At rest substantial reductions in pulmonary "wedge" pressure (-29%), with a consequent fall in cardiac output (-10%), are described. Total systemic vascular resistance initially increases but "reverse autoregulation" over subsequent weeks returns this elevation gradually towards control values. Tolerance to these initial hemodynamic effects does not occur with maintained therapy; moreover, echocardiographic markers of contractility and exercise capacity may increase. The early venodilator effects of diuretic drugs can be attributed to prostaglandin release and the initial pressor actions to activation of the renin angiotensin system; these vascular actions may have limited relevance to long-term beneficial effects on hemodynamics. Direct pulmonary vasodilation and improved pulmonary compliance remain an interesting finding. Although most patients are both symptomatically and hemodynamically improved at rest, the actions during exercise are more varied. Some individuals with severely impaired left ventricular function show little hemodynamic improvement, whereas those with milder dysfunction usually benefit; in the main this is probably related to the latter being on a steeper cardiac function curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Muzolimine, the new sulphonamide-free loop-diuretic with both high ceiling and long-lasting activities, was tested in 21 adult patients with chronic renal failure (CRF) (creatinine clearance ranging from 30 to 5 ml/min) and acute fluid overload. Low-protein diet and individual drug therapy were unchanged throughout the study. All patients received a single oral dose of 240 mg of muzolimine for 4 or 6 consecutive days depending on individual response. Clinical status, diuresis, body weight, blood and urine chemistry were recorded daily. In 19 out of 21 patients muzolimine treatment induced reversal of edema and congestive heart failure and a satisfactory fluid balance was achieved. Only two patients did not respond to diuretic treatment and required dialysis to control fluid balance and azotemia. In responsive patients diuresis increased by 50-100% and no rebound antidiuresis was observed after drug withdrawal. Body weight decreased meanly by 9%. No significant change occurred in serum concentration of K throughout the study, even in the 11 patients on digoxin. Except for a slight decrease of serum Cl by the end of treatment, no significant change in serum electrolytes was recorded. No effect was observed on blood glucose, urea and creatinine clearance whereas a slight increase of serum uric acid was recorded. Urinary lysozyme and gamma-GT were similar before and after the trial. Apart from a single case of muscle cramps, no significant side-effects were recorded. In conclusion, the present results indicate that short-term, high-dose oral muzolimine treatment is effective and safe in most patients with advanced CRF and acute fluid retention.

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.

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.

Muzolimine, a new saliuretic, has been shown to combine high ceiling and long-acting effects in animal experiments. This study was designed to examine whether this desirable combination of effects, which up until the present time has not been incorporated into any substance also occurs during patient treatment. Fifty-three patients with mild essential hypertension (WHO groups I and II) in three medical centers were treated with either muzolimine or indapamide, which served as the reference preparation, in a randomised, double-blind study. After a two week run-in phase during which the patients received placebo, half of the patients received 20 mg muzolimine and the other half 2.5 mg indapamide once daily. Eight weeks of therapy were followed by a 2 week follow-up phase, during which placebo was dispensed. During the trial period a weekly clinical examination was performed including the measurement of blood pressure, pulse, hematocrit, electrolytes, uric acid, glucose, creatinine and lipid status. An electrocardiogram and Schellongtest were conducted every two weeks. Patients were instructed to keep a diary in which they were to note drug related complaints. Statistical analysis was carried out using the Pratt-Wilcoxon Pair Test. Differences were judged significant at the 5% level. Both muzolimine and indapamide were tolerated well with minimal side effects, which however, did not make it necessary to discontinue treatment. Both preparations induced mild blood pressure reductions of approximately 10 and 5 mmHg for the systolic and diastolic blood pressure, respectively. Two weeks after cessation of muzolimine treatment neither systolic nor diastolic blood pressure showed any significant difference to values achieved during the treatment phase.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.

Muzolimine was administered by mouth to 24 patients with creatinine clearances ranging from 4 to 28 ml/min to treat oedema or hypertension, or both. In four of these 24 patients muzolimine was given after intravenous high-dose frusemide had been unsuccessful. Muzolimine significantly increased urine volume and excretions of sodium, chloride, and potassium ions. Its diuretic efficacy was further shown by a mean reduction in body-weight of 8% and by the disappearance of oedema in all affected patients, even those refractory to intravenous frusemide. No rebound phenomenon was observed after the drug was stopped. Mean blood pressure was reduced in all hypertensive patients. Blood pressure was restored to normal in five out of seven patients treated with muzolimine alone and 10 out of 11 in whom muzolimine had been added to previously unsatisfactory antihypertensive treatment. Muzolimine was well tolerated by all patients. Muzolimine appears to be the diuretic of choice when treating patients with advanced renal disease.

The authors have compared the clinical and metabolic effects of two high ceiling diuretics, muzolimine (M) and furosemide (F), by i.v. and oral routes in 40 patients classified in four groups with different degrees of renal failure. The study demonstrated a more pronounced effectiveness of M than F by oral administration, while it appeared equal to F when given i.v. The urine volume and Na+ excretion were significantly increased during M treatment compared to oral F in each group. Calcium urinary excretion was reduced with M while P was increased compared with F. BUN, creatinine and uric acid were temporarily increased in the 3rd and 4th groups, probably due to extracellular fluid volume contraction, associated also with transient change in GFR. M at a lower dosage than F has demonstrated an effective diuretic response irrespective the degree of renal impairment. From its pharmacological properties, M appears a safe and active diuretic agent, particularly at a high dosage in patients with severe renal failure, and is notable for its lack of important side effects.

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.

Thirty patients with moderate to severe hypertension (diastolic blood pressure greater than or equal to 115 mmHg), after a run-in wash out period of 15 days, were treated with muzolimine at a dosage of 20 mg once daily, given at 1 p.m., for three weeks. At the end of this period of treatment the patients with diastolic blood pressure greater than or equal to 100 mmHg started a double blind randomized study of comparison of nitrendipine, a vasodilator calcium antagonist agent, and captopril, an inhibitor of converting enzyme. The dosage was 10 mg twice daily for nitrendipine and 25 mg twice daily for captopril, the duration of each treatment being four weeks. At the end of 28 days of double blind treatment, the patients with diastolic blood pressure greater than or equal to 100 mmHg were treated with a triple combination: muzolimine plus nitrendipine plus captopril at the same dosage for a further four weeks. At the end of run-in and of each period of treatment blood pressure and heart rate were recorded in supine and erect positions and after a treadmill exercise test. At these times laboratory tests, including PRA and aldosterone, were performed. After the run-in period supine blood pressure was 189.6 +/- 13.9/123.1 +/- 7.7 mmHg. At the end of muzolimine treatment, supine blood pressure was 176.5 +/- 10.8/117.8 +/- 5.6 mmHg (p less than 0.001); at this time 4 patients had their diastolic blood pressure normalized and left the study. Thus 26 patients were randomized for comparative study.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

This is an interim report of haemodynamic studies with oral muzolimine in male patients under 70 yr with haemodynamically confirmed left ventricular failure complicating acute myocardial infarction. All were in sinus rhythm and without hypotension (SBP 100 mmHg) and were studied by conventional intravascular haemodynamic methods within 18 hr of onset of symptoms of acute myocardial infarction. A preliminary dose-finding study in four patients indicated that both 60 and 120 mg oral muzolimine induced substantial diuresis but only the latter dose was associated with an appreciable reduction in left heart filling pressure within 2 hr. The aims of the main study are to determine the haemodynamic effects of oral muzolimine 120 mg given once daily for 10 days in these high risk patients. Thereafter patients are randomised to continued oral muzolimine or placebo for a period of three months. The effects of such treatment on their haemodynamic profile at rest and during dynamic exercise are being measured by comparison with the 10 day measurements. In the first six patients entered into the main study, 120 mg oral muzolimine resulted in a progressive reduction in the elevated left heart filling pressure without tachycardia or any other major haemodynamic change over 8 hr on both Day 1 and Day 2. These potentially advantageous haemodynamic effects await confirmation from further results in this on-going study.

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.

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 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.

The aim of the present study was to investigate muzolimine pharmacokinetics and pharmacodynamics in chronic heart failure. We report preliminary results from 6 patients, aged 64.2 years (range 54-73), in chronic heart failure (NYHA class III). All patients had lowered ejection fraction determined by echocardiography, and increased heart volume determined by cardiac X-ray. They were under treatment with long-term digitoxin with serum digitoxin concentrations within or below the therapeutic range. We investigated muzolimine pharmacokinetics on day 1 of treatment and after 28 days. Heart rate and rhythm were monitored with 24 hours ECG recording and analyzed on an Avionics Arrhythmia Analyzer. Heart rate, cardiac volume, ejection fraction and laboratory findings were not significantly changed between day 1 and day 28 of treatment. The time for peak absorption ranged between 1.5 and 6 hours on day 1 and 1.0 and 3 hours on day 28. The peak concentration was significantly higher on day 28. No significant difference was found in the areas under the concentration curves, serum elimination half-lives and renal clearances after acute and chronic administration. In the first 4 patients studied, we found ventricular and supraventricular arrhythmias before treatment and after 28 days on muzolimine. These preliminary data indicate a change in the pharmacokinetics of muzolimine on chronic dosing with more rapid absorption, higher peak concentrations, and increased area under the other plasma concentration curves.

There is a very high prevalence of hypertension in diabetic subjects, which makes it necessary to use an antihypertensive drug with the least possible metabolic interference. For example, in the early phase of hypertension, diuretics usually worsen the metabolic equilibrium. According to recent reports, a new diuretic, muzolimine (MZ), which acts on the loop of Henle, seems to present a minor effect on carbohydrate metabolic balance. In order to determine whether this assumption was correct or not, we carried out a clinical trial on 26 type II (non-insulin-dependent) diabetics, in fairly good metabolic control and with moderate hypertension (orthostatic diastolic pressure from 100 to 115 mmHg), comparing the effect of MZ with those of chlorthalidone (CL). According to a randomized, single-blind cross-over design, the patients were treated with MZ (20 mg/day) or CL (50 mg/day) for the duration of 4 weeks. After the treatment period with the first drug, there was a 2 week wash-out period on placebo (PL) before the second drug was given. During the study, a set of metabolic and non-metabolic parameters was monitored, as were the clinostatic and orthostatic blood pressure values. The results show that the antihypertensive effect of the two drugs was the same (both caused a more than 10% decrease in systolic and diastolic blood pressure). No significant changes in plasma electrolyte levels occurred. There was a significant (p less than 0.05) increase in urinary aldosterone excretion after CL (20.7 +/- 11 micrograms/24 hours vs. 13.3 +/- 8.5 after PL, and 14.5 +/- 7.2 after MZ) (mean values +/- standard deviations).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of muzolimine (initial dose 60 mg followed by 30 mg/day for 14 days) on 15 patients with aortic and mitral incompetence and chronic cardiac failure, functional class 3, was analyzed on the basis of repeated clinical observations, metabolic studies as well as mono and bidimensional echo changes 2, 24 hours and 15 days after the initial dose. An important variation was a reduction in body weight by 3-4% after the first day and by a further 1-2% after 2 weeks. No significant variations were observed regarding heart rate and blood pressure at rest. Plasma level of electrolytes as well as other important biochemical parameters in the serum (BUN, glucose and creatinine) were uninfluenced. A small increase was observed in both the plasma level of chloride and in the red cell count. Urine volume increased by two to threefold after the first day; this increase was still present after 2 weeks. Changes in the left ventricular end-diastolic and end-systolic volumes were not significant after the first day; however a slight but significant reduction was observed after 2 weeks and was in parallel with the improvement of the functional class of the patients. Data, in particular the possible mode of action of muzolimine after acute administration and after short-term therapy, are discussed.

Ten male cirrhotic patients with ascites and reduced renal function were randomly given equivalent doses of furosemide and muzolimine by the oral route, through a single blind cross-over protocol. Renal function, electrolyte plasma concentrations and urinary excretions and renin-angiotensin-aldosterone system components were evaluated under basal conditions and after drug administration. The diuretic and saluretic effects being equal, the response to muzolimine was initially weaker but more prolonged than to furosemide, without rebound phenomena. The furosemide-induced natriuresis was in part related to the filtered sodium load, whereas muzolimine natriuresis was only correlated to the inhibition of tubular sodium reabsorption. No potassium wasting effect was seen after muzolimine administration. Transient plasma potassium concentration reduction observed during muzolimine suggests an ion shift within the intracellular compartment. Therefore, a possible interaction of the drug with cellular sodium active transport systems can be hypothesized. A significant increase of plasma renin activity was observed after furosemide. No significant changes were seen after muzolimine administration.

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.

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.

27 patients with creatinine clearances ranging from 20 to 2 ml/min were treated daily with 6.9 mg/kg of muzolimine, for 10 to 25 days. The hyperhydration state with oedema decreased gradually in all patients without hypotensive phenomena. Muzolimine benefited hypertension in patients with expansion of the extracellular space and it also strengthened the effect of clonidine or minoxidil. Important diuretic and natriuretic effects were obtained. Metabolic acidosis improved. No subjective adverse reactions to the drug or side effects were noted. High-dose muzolimine appears to be efficacious and safe for short-term treatment in patients with severe chronic renal failure.

A multi-center open trial was carried out with 103 patients with chronic congestive heart failure (CHF) of diverse etiologies with oedemas, 25 with hepatomegalia, placed in classes II or III of NYHA functional capacity, with increasing doses of 30, 60 and 90 mg of muzolimine qd to ascertain (1) the effective dose for the elimination of oedemas and hepatomegalia and (2) whether such a dose keeps its efficacy throughout a long administration period. After a wash-out period of 3-7 days, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) in supine and standing positions, body weight (BW) and 24 hour diuresis were controlled and laboratory tests were performed. Muzolimine was administered and an assessment of the therapeutic effect was carried out every week. When the clinical results were ineffective, the dose was increased weekly up to 90 mg. When the results were partial, the same dose was given for another week and when it was effective the search for the dose was concluded. Out of the 103 patients, 67 needed only 30 mg of muzolimine for an effective elimination of oedemas and hepatomegalia, 32 needed 60 mg and only 4 had to have the dose increased to 90 mg to obtain efficacy. The SBP and DBP diminished by 6.3% and 7.2% respectively, and HR was reduced, though not significantly. BW diminished an average of 2.4 Kg and the diuresis increased significantly from a mean value of 1.043 ml/24 h to 1.714 ml/24 h. Sixty-two patients with effective results agreed to undergo chronic treatment for 24 weeks and be controlled every 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy of muzolimine (BAY g 2821) in doses of 30 or 60 mg/day was studied over an observation period of 4 weeks in 48 patients with mild to moderate heart failure (NYHA stage 2 or 3) in a biometrically planned, multicentre study. Eleven of these patients were excluded from the evaluation of efficacy for various reasons. All 37 patients who remained (23 men and 14 women; mean age 59.6 years, mean body weight 73.8 kg) were treated throughout with one tablet per day (30 mg). A marked improvement of the symptoms of cardiac insufficiency was observed in these 37 evaluated cases in the course of the treatment period. At the end of the study body weight was reduced by 1.8 kg, heart rate fell from 84 to 75 beats/min and blood pressure decreased from 154/88 to 145/85 mm Hg on average. The laboratory parameters tested failed to show any clinically abnormal alterations. Twelve of 48 patients complained of side effects (dizziness, headaches, vomiting, nausea), these developing largely in the first 2 weeks and being transient in character. To summarize, it can be stated that patients with chronic heart failure (NYHA 2 and 3) can be effectively treated by muzolimine monotherapy.

The authors have compared during 4 weeks of study the effects of furosemide (F) by oral route or i.v. and muzolimine (M)/os in 10 patients with nephrotic syndrome (NS) and normal renal function. A satisfactory diuretic response was observed with i.v. F (100 mg) and M/os (30-60 mg) with respect to the basal condition (P less than 0.001), while F/os (100 mg) was ineffective in these patients. This behaviour may be explained by the different pharmacological properties of M vs. F, by gut alterations due to the oedema of mucosa or loss of some "carrier(s)" operating for intestinal absorption of these two high ceiling diuretics.

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.

The diuretic effects of 30 mg muzolimine and 25 mg hydrochlorothiazide/50 mg triamterene were comparable in healthy subjects and nephrotic patients (serum albumin less than 32 g/l, creatinine clearance greater than 50 ml/min/1.73 m2). A single daily dose of 30 mg muzolimine or 25 mg hydrochlorothiazide/50 mg triamterene was sufficient in the majority of the investigated nephrotic patients. The different diuretic effects which were observed in nephrotic patients were not related to the severity of hypalbuminemia, but rather to differences in preceding diuretic treatment. Plasma levels and urinary excretion of unchanged muzolimine were comparable in healthy subjects and nephrotic patients after one day of diuretic treatment; after seven days of treatment plasma levels of muzolimine were significantly lower and urinary excretion significantly higher in nephrotic patients than in control subjects.

Ninety-four patients on digitalis treatment for chronic congestive heart failure (NYHA class II-III) were enrolled for a 12 month trial in a random, double-blind, placebo-controlled study. After a placebo run-in period, patients were assigned to placebo or captopril 25 mg t.i.d. Digitalis was continued while diuretics were withdrawn. Clinical status, exercise capacity, cardiac dimensions and performance were evaluated with a full physical examination, 12 lead ECG, chest X-ray, 24 hour Holter monitoring, bicycle effort capacity, M-mode echocardiography and radionuclide ventriculography at 1, 2 and 3 weeks and 1, 2, 3, 6 and 12 months. There were no significant differences in the trend of survival curves after six months follow-up between the captopril or placebo treatment groups. Patients treated with captopril, without the addition of diuretics, had an improvement in NYHA class (P less than 0.01), an increase in exercise capacity (P less than 0.025), a decrease in cardiothoracic ratio (P less than 0.025) and an increase of echocardiographic left ventricular contractility (P less than 0.005). Only four patients treated with captopril were withdrawn from the follow-up for allergic side effects. Preliminary results at 6 months prove that captopril, compared to placebo, is useful in mild to moderate heart failure.

Thiazide therapy is a widely used first line treatment for arterial hypertension. Its useful value, particularly in mild or moderate hypertension, is sometimes reduced by metabolic side-effects, as hypokalaemia and hyperuricaemia. In the present study the antihypertensive efficacy of a new, non-sulphonamide diuretic Bay g 2821 (muzolimine) was evaluated in comparison with the combination of hydrochlorothiazide-amiloride over a period of 4 weeks. A highly significant decrease in systolic and diastolic blood pressures was produced by both treatments. No decrease in serum potassium nor an increase in cholesterol, triglycerides, uric acid or glucose was detected during the 4 week treatment period. Subjective side-effects, such as headache and dizziness, were very rarely observed during Bay g 2821 treatment. The new diuretic appears, therefore, to be effective in the treatment of arterial hypertension without untoward side-effects.

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.

Previous short-term studies of muzolimine (a diuretic with frusemide-like activity) had shown that it did not induce a significant change in the serum potassium concentration. In the present study sodium and potassium handling and other metabolic variables have been compared during 16 weeks of therapy with muzolimine and chlorthalidone, a thiazide-like diuretic. During muzolimine treatment, plasma and red cell potassium concentrations remained unchanged, while a significant fall in potassium occurred with chlorthalidone. Neither drug affected the activity of sodium-potassium cotransport or sodium-lithium countertransport in red cells in vitro. Muzolimine and chlorthalidone had similar effects on arterial pressure and on the other metabolic variables tested.

Muzolimine (240 mg) was administered orally to 24 patients with chronic renal failure. In five patients with creatinine clearance ranging between 10 and 30 ml/min and five others with creatinine clearance lower than 10 ml/min, urinary output was measured in periods of 24 hours before, and 0 to 4, 4 to 10, 10 to 24, 24 to 48, 48 to 72 hours after administration of the drug. The amounts of sodium, chloride, potassium and urea excreted in each sample were determined. Our results show that the diuretic activity of muzolimine 240 mg in these patients is excellent, especially in the first four hours after its administration. Pharmacokinetic data observed in advanced renal failure (creatinine clearance between 10 and 30 ml/min) are similar to those observed in healthy subjects or patients with normal renal function. However, attention should be paid to possible accumulation of the drug in terminal renal failure (creatinine clearance lower than 10 ml/min) because a significant increase of the terminal half-life of the drug is observed in these patients. Dialysibility of the drug in haemodialysis and during chronic ambulatory peritoneal dialysis is poor.

Muzolimine is a diuretic with chemical features different from all other known diuretics, and its use seem to be particularly interesting in patients with chronic renal failure. In fact, similarly to furosemide, muzolimine presents a strong action on Henle's loop but with a slower and more lasting effect, as experimentally demonstrated in both animals and man. We used high doses muzolimine (240, 480, 720 mg/die) in 16 patients with chronic renal failure (creatinine clearance less than 20 ml/min) and clinical pattern of important hydrosaline retention (6 primitive glomerulonephritis, 3 interstitial nephrites, 1 vascular nephropathy, 1 diabetic nephropathy, 1 lupus nephritis, 1 amyloidosis, 1 polycystic nephropathy and 2 nephropathies of unknown diagnosis). Muzolimine diuretic action was compared with furosemide 500 mg/die. The schedule employed was: furosemide 500 mg/die for 5 days followed by 6 days of muzolimine treatment at increasing doses (240 mg on 1st and 2nd day, 480 mg on 3rd and 4th, 720 mg on 5th and 6th). In all patients (undergoing a diet constant in water, sodium, potassium and protein content) body weight, blood pressure, heart rate, serum and urinary electrolyte concentration, serum and urinary uric acid, BUN, creatinine clearance, glycaemia, hematocrit and hemoglobin were daily controlled. A clinical and laboratory investigation of the possible side effects was also assessed; in particular liver enzymes, bilirubin and total serum proteins were considered. In our study muzolimine increased the renal excretion of water, sodium and chloride in all cases. This effect is more evident during the treatment with the highest dose (720 mg/die) but already appears with the 480 mg/die dose and is higher than that obtained with comparable doses of furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: A report is given on the effects of oral therapy with muzolimine (M) in patients with mild hypertension., Subjects and Method: 21 untreated patients, aged 35 to 69 (mean 53.1 yrs) with orthostatic diastolic BP between 100 and 115 mmHg were randomly assigned to either group A (10 mg M/day) or group B (20 mg M/day) in a single blind study for a period of two weeks. Clinostatic and orthostatic systolic and diastolic BP and heart rate were recorded at weekly intervals. PRA, aldosteronemia, ECG and blood chemistry were analyzed at the beginning and at the end of the study. Student's t-test was used for the statistical evaluation and p values below 0.05 were considered significant., Results: Both clinostatic and orthostatic diastolic BP were significantly reduced in group A whereas only orthostatic diastolic BP was decreased in group B (Fig. 1). PRA and aldosteronemia values and blood chemistry showed no statistically significant changes. No side effects were noted. We conclude that 10 mg/day of muzolimine is more effective than 20 mg/day in reducing orthostatic diastolic BP (A vs. B p less than 0.02). Although these results are only preliminary data and further investigations are required, they suggest that muzolimine may be safely used, in combination with other antihypertensive agents, particularly in cases of renal failure.

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)

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)

Unlabelled: The aim of this study was to test the efficiency of muzolimine in patients with acute renal failure (ARF)., Methods: 6 patients, all males, 46 to 78 years old (mean 67.3 +/- 12.5) suffering from acute renal failure as a complication of a surgical procedure (4 cases) or a medical disease (2 cases) were selected. Creatinine clearance rates were below 20 ml/min for all subjects except one (mean: 14.4 ml/min range 4-34), blood urea levels from 21 to 65 mmol/l (mean = 36.4); mean urinary output, during the 24 hours preceding the study (D-1) was 100.4 +/- 57 ml/h (range 36-208) without any diuretic treatment. No patient was on dialysis. On the treatment day a single oral dose of muzolimine (240 mg) was administered in the morning. During the treatment day (D0) and the post treatment day (D + 1), pharmacodynamics and pharmacokinetics were evaluated. Mean urinary output increased from 1.67 +/- 0.95 ml/min, at D-1 to 3.24 +/- 2 ml/min at D0 (NS), with great differences between patients. The main effect was noted between 0 and 6 hours after the ingestion of muzolimine. The mean electrolyte output increased from D0 to D1 for Na+ (0.1 mmol/min +/- 0.08----0.25 +/- 0.1-NS), K+ (0.05 mmol/min +/- 0.02----0.08 +/- 0.07-NS), Cl- (0.07 +/- 0.07 mmol/min----0.30 +/- 0.12 p less than 0.05) and Ca++ (1.89 +/- 1.89 meq/24 h----4.1 +/- 2 NS), with large individual variations. Mean urea output increased slightly in only 3 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

In a controlled double-blind study the effect of muzolimine (20 mg o.d.) and acebutolol (400 mg o.d.) were investigated in outpatients suffering from moderate essential hypertension. After a three week placebo run-in period, 49 patients were recruited and followed by a cooperative group of general practitioners over a period of 3 months. Blood pressure decreased to the same extent in both groups. With regard to clinical and biological tolerance, no differences appeared between the two drugs.