Food and muzolimine interaction.

The influence of food on the bioavailability of muzolimine was investigated in a non-controlled cross-over study. Six healthy volunteers received 40 mg muzolimine directly after a standardized American breakfast (non-fasting volunteers) and, one week later, after an overnight fast with breakfast 90 min after drug intake (fasting volunteers). The concentrations of muzolimine in plasma and urine were determined between 0 and 48 h after administration. Results (means +/- SEM): in the fasting volunteers, the areas under the muzolimine plasma level curves (0-32 h) were higher than in the non-fasting volunteers (3002 +/- 390 vs. 2038 +/- 344 ng X h/ml, p less than 0.001), the peak concentrations were higher (332 +/- 36 vs. 176 +/- 38 ng/ml, p less than 0.05) and appeared earlier (1.8 +/- 0.2 h vs. 4.0 +/- 0.5 h, p less than 0.01). Also, the urinary volumes and sodium excretion were higher in the fasting volunteers than in the non-fasting volunteers. Hence, the bioavailability of muzolimine is reduced if administered after a meal which should be considered in the treatment schedule.

The effect of muzolimine on the tubuloglomerular feedback mechanism in the rat kidney.

Inhibition of tubuloglomerular feedback (TGF) by loop diuretics can enhance the diuretic response by attenuating the fall in GFR to be expected with the diuretic-induced rise in distal salt delivery. To establish whether such a mechanism contributes to muzolimine (M)-induced diuresis, TGF activity was tested in male Wistar rats by measuring early proximal flow rate in nephrons, the loops of Henle of which were perfused with M at various concentrations in the presence or absence of M systemically. Since M inhibited TGF only at concentrations far in excess of those adequate to produce substantial diuresis, it is concluded that TGF inhibition by M plays no significant role in the diuretic response to this agent.

Haemodynamic studies with muzolimine in left ventricular failure complicating acute myocardial infarction.

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.

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.

Diuretic effect and pharmacokinetic data observed at different stages of chronic renal failure with 240 mg of muzolimine.

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.

Clinical study of muzolimine in acute renal failure, pharmacodynamics and pharmacokinetics.

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)

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.