Effects of haemodialysis on the pharmacokinetics of muzolimine.

UNLABELLED: High ceiling diuretics allow a better control of fluid balance in dialysis patients with a minimum urine flow of 500 ml/day. The pharmacokinetics of the high ceiling, long acting diuretic muzolimine (M) was investigated in 6 patients on regular dialysis therapy. METHODS: Concentrations of unchanged M in plasma were determined by high performance thin-layer chromatography (HPTLC) after a single oral dose of 240 mg up to 26 h: A) during and after the performance of dialysis lasting for 3 h, B) 20 h after finishing haemodialysis therapy (non-blind randomized cross-over study). RESULTS: The M plasma levels and the M half-lives did not differ between the two treatment groups (half-life A: 5.1 +/- 0.24 h; B: 4.8 +/- 0.51 h). The M peak concentrations were between 2 and 5 micrograms/ml and were reached 2 h post administration or even earlier. The mean M plasma levels 24 h after administration were in the same range (A: 0.33 +/- 0.16 microgram/ml; B: 0.33 +/- 0.11 microgram/ml).

Pharmacodynamic and pharmacokinetic correlation of muzolimine with and without aluminium hydroxide.

The objective of the reported study was to investigate whether aluminium hydroxide administered in addition to muzolimine interferes with the pharmacodynamics or the pharmacokinetics of the drug. For this purpose a cross-over study in 6 healthy male volunteers was carried out in which each subject received muzolimine and after a wash-out period muzolimine together with Aludrox. To avoid interferences of a psychological nature a third period with placebo was added. The administrations were randomised. The excreted urinary volume was measured, and blood was taken at relevant times in order to follow the pharmacokinetic profile. These are the results: Urinary excretion after the oral administration of muzolimine was within normal limits compared with the literature. There was no change in elimination with respect to either extent or time characteristics after the combined administration of Aludrox. There was no change in the pharmacokinetic profile either.

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.

Pharmacokinetics of muzolimine after oral administration with and without aluminium hydroxide in healthy volunteers.

The pharmacokinetics of muzolimine administered with and without aluminium hydroxide was investigated in volunteers (randomized non-blind cross-over study). Six healthy male volunteers aged 20 to 28 years with a mean body weight of 68 +/- 8 kg received 40 mg muzolimine after a standardized breakfast without and with 1760 mg aluminium hydroxide (Aludrox) administered 10 min before breakfast. Muzolimine concentrations were determined in plasma and urine between 0.5 and 48 h post dosing. The data were analysed using a two- or three-compartment open model. The pharmacokinetic parameters of muzolimine, e.g. absorption half-life, peak concentration, time to reach peak concentration, AUC and mean time, obtained with both treatment regimens, did not show any significant difference (analysis of variance). As a conclusion, the pharmacokinetics of muzolimine is not altered by the ingestion of aluminium hydroxide, which might be important for patients with advanced renal failure.

The metabolism of muzolimine.

The metabolism of muzolimine, 3-amino-1-(3,4-dichloro-alpha-methyl-benzyl)-2-pyrazoline-5-one has been studied both in vivo and in vitro in various animal species. Using unlabelled muzolimine the major urinary metabolite in all species studied has been shown by chromatography and mass-spectrometry to have properties identical to synthetic N'-(1-aminoethylidene)-3,4-dichloro-acetophenone hydrazone. In addition, 3,4-dichloroacetophenone, 3,4-dichloromandelic and 3,4-dichlorobenzoic acids have been detected and quantified using GLC techniques. In vitro experiments using hepatic microsomal preparations from various species show that cleavage across the C-N1 bond occurs yielding 3,4-dichloroacetophenone and 3-amino-2-pyrazoline-5-one. The hydrazone was the major metabolite produced by these systems. Moreover, this compound also appears as the major metabolite in faecal extracts. Reverse-Phase High-Performance Liquid Chromatographic techniques have been employed for analysis of in vitro metabolism of muzolimine and confirmed the formation of the above metabolites.

Pharmacokinetics and pharmacodynamics of muzolimine in chronic heart failure.

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.

Influence of muzolimine on arterial wall elastin.

Muzolimine, 3-amino-1-(3,4-dichloro-alpha-methylbenzyl)-2- pyrazolin -5-one, an antihypertensive and diuretic drug, accumulates in the arterial tissue of rats and dogs after oral administration. Two weeks after the administration of 3 mg [14C]muzolimine, the aorta of rats contained 60-300 times more 14C-radioactivity/weight unit than the skin or tail tendon. The 14C-radioactivity was exclusively bound to the isolated aortic elastin and corresponded to 0.04% of the applied muzolimine dose. Up to ca 250 ng bound muzolimine/mg elastin was found in the aorta of dogs treated with non-labelled muzolimine for 52 weeks. The elastin-bound [14C]muzolimine was not extractable by organic solvents or by weak acids or bases but was released in a soluble form by pancreatic elastase and extracted from the elastase digest by dichloromethane. In the dichloromethane extract muzolimine was detected by HPLC and HPTLC, and was identified by mass spectrometry. Muzolimine pretreatment of rats for 2 months did not influence the elastin content of arterial tissue or [3H]glycine incorporation into aortic elastin under organ culture conditions, but after labelling the elastin with [4,5-3H]lysine, the [3H]desmosine and [3H]-isodesmosine isolated from the elastin of muzolimine-pretreated rats and incorporated under organ culture conditions was lower than that of control animals. In addition, aortic elastin of rats pretreated for 2 months with 800 ppm muzolimine in the diet was more resistant to elastase degradation. This effect might give some implications for muzolimine in the therapy of cardiovascular disorders with impaired arterial elastin metabolism.

[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.