Effect of long-term treatment with insulin and/or acarbose on glomerular basement membrane thickening in alloxan-diabetic rats

Acarbose is a competitive inhibitor of the intestinal alpha-glycosidases, that can delay absorption of intestinal carbohydrates causing their malabsorption. In the present paper we studied the effects of insulin, acarbose and their association on glomerular basement membrane thickening in alloxan-diabetic rats. Twenty-five male and female Wistar rats, approximately 3 months old at the beginning of the experiment, were assigned randomly to each of five experimental groups: normal control rats, alloxan-diabetic control rats, alloxan-diabetic rats treated with acarbose, alloxan-diabetic rats treated with insulin, and aloxan-diabetic rats treated with insulin plus acarbose. Alloxan was administered in a single iv dose of 42 mg/kg body weight. Insulin was given subcutaneously at doses of 18 to 30 IU/kg corrected daily on the basis of glycosuria and ketonuria. Acarbose was given mixed with rat chow in a dose of 50 mg/100 g chow. Body weight, water and food intake and diuresis, as well as blood and urine glucose were determined after 1, 3, 6, 9, and 12 months of treatment. Glomerular basement membrane (GBM) thickening was determined by electron microscopy at the same times. Clear clinical and laboratory signs of severe diabetes, with blood glucose levels above 200 mg/dl and urine glucose above 3000 mg/dl, were observed in all alloxan-diabetic control rats, in all periods of follow-up, whereas administration of insulin or acarbose reduced the blood glucose levels of treated groups. The most satisfactory control of blood and urine glucose was observed in animals treated with both insulin and acarbose. However, diarrhea was observed in diabetic rats treated with acarbose associated or not with insulin, GBM thickening was correlated with age in all groups. Beginning at six months after diabetes induction, the GBM of untreated diabetic rats was significantly thicker (mean + 4.446 + 0.45 mm) than that of normal rats (2.977 + 0.63 mm). Both insulin and acarbose prevented GBM thickening and their combination induced thickening similar to the age-dependent thickening observed for normal rats of the same age. We conclude that acarbose when combined with insulin may be a good option in the control of diabetes and its renal complications.

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.

Platelet cytosolic free calcium concentration in hypertension associated with early stage kidney disease.

Chronic hypertension accompanying early stage kidney disease is characterized by increased vascular resistance, but the underlying processes responsible for the enhanced vascular tone are unclear. We studied free calcium levels in blood platelets with the fluorescent dye quin-2. Platelets have many features in common with vascular smooth muscle cells. The cytosolic calcium concentration in platelets was elevated in 27 renal hypertensive patients, who were compared with 12 normotensive subjects (P less than 0.001). There was a close correlation between the free calcium level and mean blood pressure (r = 0.88, P less than 0.001). Short-term antihypertensive treatment with a calcium entry blocker or a diuretic resulted in a significant reduction in cytosolic calcium (P less than 0.05), and this correlated with the fall in blood pressure (r = 0.95, P less than 0.001). These data suggest an integrative contributory role of calcium in the pathophysiology of hypertension accompanying early stage kidney disease.

[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.

Effects of muzolimine and of a combination of hydrochlorothiazide/triamterene in healthy subjects and in nephrotic patients.

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.

Short-term, high-dose muzolimine treatment in patients with chronic renal failure and acute fluid retention.

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.

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.

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.

Dose finding study in chronic congestive heart failure patients. Results of a short- and long-term study.

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)

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)

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.