Muzolimine-induced severe neuromyeloencephalopathy: report of seven cases.

We report on 7 patients (2 women, 5 men) with chronic renal failure, who developed under a high dosage of the new diuretic muzolimine (range 240 to 1440 mg per day) fatal neuromyeloencephalopathy. Clinical neurophysiological and neuroradiological findings and finally neuropathological studies in 2 patients resembled those found in vitamin-B12-deficiency-syndrome with a predominant affection of the spinal posterior column and the corticospinal tracts. The first neurological symptoms like paraesthesia, severe hyperpathia of the legs and mild to heavy spinal ataxia occurred after an average time of treatment of 78 days and a mean dosage of 52 g. The most progressive neurological deficits like severe tetraspastic paresis, were seen only in the nondialytic renal insufficient group (3 patients), while the others had a more benign course of the disease. This lead to the hypothesis of a partially dialysable toxic metabolite of muzolimine. After a follow-up of more than 2 1/2 years no significant recovery was seen in these cases.

[Neuromyeloencephalopathy caused by high-dose muzolimine medication in patients with renal failure]. / Neuromyeloenzephalopathie (NME) unter hochdosierter Muzolimin-Medikation bei niereninsuffizienten Patienten.

We report on 7 patients suffering from chronic renal failure (2 females, 5 males; aged 35-75 (phi 53.5) years) who showed severe neuromyeloencephalopathy (NME) after high doses of a new Henle's loop diuretic, Muzolimine. The temporal and phenomenological development of these systems was strikingly parallel. The neurological deficit was revealed on neurophysiological, neuroradiological and in 2 cases on neuropathological tests (gross demyelinisation of the posterior column, mainly of the fasciculus gracilis, less in the lateral corticospinal tract and in some spinal roots). The critical drug dose for first neurological impairment was 52 g on average; at this point the patients had been treated for 78 days. The maximal daily dose was 1.440 mg. Dominant clinical features were pallhypaesthesia, ataxia, signs of peripheral neuropathy in combination with hyperreflexia and progressive para- to tetraspastic paresis. Constellation of symptoms, course of disease and findings of additional investigations, especially those of neuropathology, very much resemble Vitamin B12 deficiency and SMON-(Subacute Myelo Optic Neuropathy) syndrome. The rare entity of Muzolimine-NME is discussed in respect to other endogenous and exotoxic neuromyelopathies. We present the hypothesis of a toxic, partially dialysable metabolite of Muzolimine.

[Neurotoxic action of muzolimine at high doses in uremic patients. Observation of a group of 29 subjects]. / Azione neurotossica della muzolimina ad alte dosi in pazienti uremici. Osservazione su un gruppo di 29 soggetti.

We report the results of a study on 29 patients affected by renal chronic insufficiency and treated with high doses of muzolimine. From our data it results that to the muzolimine is probable due a neurological syndrome very similar to combined sclerosis. Up today, it is not possible to know how and where the muzolimine develops its neurotoxic effect.

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.

Comparative study of muzolimine and acebutolol in the treatment of moderate hypertension.

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.

Interference on metabolism induced by muzolimine and chlorthalidone in type II hypertensive diabetics.

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)

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).

Muzolimine in advanced chronic renal failure.

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.

Muzolimine in chronic renal failure: a study in 16 patients.

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)

Muzolimine as monotherapy in the treatment of patients with congestive cardiac failure.

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.

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.

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)

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)

Efficacy of two different doses of muzolimine in the treatment of mild hypertension.

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.

Clinical evaluation of muzolimine and indapamide during treatment for essential 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)

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)

Muzolimine and nitrendipine in the treatment of arterial hypertension.

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)