Mepartricin long-term administration regulates steroid hormone and adrenergic receptor concentrations in the prostate of aged rats.

Mepartricin is a semi-synthetic macrolide antibiotic developed as a drug for the treatment of benign prostatic hyperplasia (BPH) in human patients. In the present study, aged rats are used as an experimental model to evaluate the effects of mepartricin on circulating hormone concentrations and prostate receptor concentrations, to compare these possible effects with clinical findings observed in long-term treated dogs. Fifty-six aged male rats were randomly divided into four experimental groups treated orally with 0 (group 1), 2 mg (group 2), 5 mg (group 3) and 20 mg (group 4) mepartricin/kg of body weight. for 28 days respectively. Serum oestradiol and testosterone concentrations were measured by radio-immune-assays methods. Binding assays were used to measure the prostate concentrations of oestrogen receptors (ER), androgen receptors (AnR), alpha(1)-adrenergic receptor (alpha(1)-AR), and beta-adrenerergic receptor (beta-AR) subtypes. Mepartricin induced a significant reduction of prostate weight and serum oestradiol concentrations. Serum testosterone concentrations were unaffected. The treatment induced a significant down-regulation of ER concentrations (P < 0.05) and a significant up-regulation of AnR (P < 0.05) in rat prostate. Mepartricin induced a significant (P < 0.05) dose-dependent up-regulation of alpha(1)-AR and beta(2)-AR. In contrast, the concentration of beta(3)-ARs was significantly decreased (P < 0.05) in treated animals. The increase in prostate beta(2)-AR concentrations observed in subjects treated with mepartricin may be a favourable element in the evolution of BPH, because of the role exerted by these receptors in the control of prostatic smooth muscle relaxation. Curiously, beta(3)-AR concentrations were significantly reduced in treated animals. Data collected suggest that the prostatic beta-AR expression might be strongly influenced by oestrogen deprivation (mepartricin treatment); therefore, the combination of oestrogen suppression (mepartricin) and adrenergic suppression (alpha(1)-AR blockers) may be proposed as a possible nonhormonal therapeutic strategy for the treatment of benign prostatic hyperplasia in dogs.

Effects of mepartricin, a polyene macrolide antibiotic, on estrogen-induced hyperplastic growth of the dorsolateral prostate and seminal vesicle in immature castrated rats.

OBJECTIVE: To investigate the effects of mepartricin, a polyene macrolide antibiotic, on estrogen-induced hyperplastic prostate and seminal vesicle (SV) growth in castrated rats. MATERIAL AND METHODS: Immature rats aged 3 weeks were castrated and left untreated for 1 week. Then, 17beta-estradiol benzoate (E(2)-BA) was subcutaneously injected at a dose of 10 microg/day twice weekly, and mepartricin was orally administered at doses of 2.5, 5 and 10 mg/kg once daily for 3 weeks. The weights and hydroxyproline contents of the prostate and SV, the activity of growth factors (GFs) in the dorsolateral prostate (DLP) and the serum estrogen level were measured. Histological examination of the prostate and SV was also performed. RESULTS: Mepartricin dose-dependently suppressed the increase in the serum estrogen level, the weights and hydroxyproline contents of the DLP and SV and the elevation of GF activity in the DLP induced by E(2)-BA treatment. Histological examination also revealed that treatment with mepartricin reduced collagen accumulation and thickening of the smooth muscle layer in the DLP and SV, and proliferation of the glandular epithelium in the DLP. CONCLUSIONS: These results suggest that mepartricin suppresses hyperplastic growth of the DLP and SV induced by estrogen in immature castrated rats, the underlying mechanism being a reduction in the serum estrogen level, thereby suppressing stromal cell proliferation and activation.

Role of mepartricin in category III chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized prospective placebo-controlled trial.

OBJECTIVES: To verify the efficacy of mepartricin versus placebo with regard to symptom improvement in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CPPS) and to verify a relation between hormonal levels and clinical improvement in these patients. METHODS: Twenty-six patients with CPPS were included in our study and randomized into two groups of 13 subjects each. Group 1 patients were treated with mepartricin (40 mg daily) and group 2 patients with placebo. All patients underwent treatment for 60 days. At the beginning and end of therapy, all patients underwent evaluation, including a standardized history, physical examination, luteinizing hormone, follicle-stimulating hormone, testosterone, and beta-estradiol measurements, and a National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire. RESULTS: We observed a decrease in the total NIH-CPSI score from 25.0 to 10.0 in group 1 and from 25.0 to 20.0 in group 2, revealing a 60% and 20% improvement in groups 1 and 2, respectively. A statistically significant decrease was observed with regard to pain (from 11.0 to 4.0 and from 10.0 to 8.0, respectively) and quality of life (from 10.0 to 5.0 and 10.0 to 9.0, respectively). No statistically significant difference was observed in urinary dysfunctions. The luteinizing hormone, follicle-stimulating hormone, and testosterone values were similar in both groups before and after treatment; the 17-beta-estradiol levels were significantly lower in group 1 compared with group 2 at the end of the study. CONCLUSIONS: Mepartricin provides significant symptomatic improvement in men with CPPS compared with placebo. The role of mepartricin in decreasing estrogen plasmatic levels and their concentration in the prostate may account for this clinical improvement.

Effects of mepartricin on estradiol and testosterone serum levels and on prostatic estrogen, androgen and adrenergic receptor concentrations in adult rats.

The effects induced by oral administration of 0, 5 and 20 mg of meparticin kg(-1)of body weight for 28 days (group 1, 2 and 3, respectively) upon prostatic estrogen, androgen, alpha(1)- and beta-adrenergic receptor concentrations and on estradiol and testosterone serum levels in adult male rats were studied. The effects produced by mepartricin treatments on the weight and dimension of the gland were investigated. Both mepartricin dosages induced significant decreases (P< 0.05) of the absolute and relative weights and of the dimensions of the prostate. A significant dose-dependent decrease (P< 0.05) in estradiol serum levels was observed in treated rats, whereas no significant modifications were found in testosterone serum levels. As far as prostatic steroid receptor concentrations were concerned, a significant (P< 0.05) decrease in estrogen receptor number was observed in both treated groups, whilst a significant increase (P< 0.05) of androgen receptor concentrations was recorded only in rats treated with 20 mg mepartricin kg(-1). Conversely, a dose-dependent up-regulation of both prostatic alpha(1)- and beta-AR was found. Data obtained suggest that the prostatic alpha(1)-AR expression may be strongly influenced by estrogen deprivation (mepartricin treatment), therefore the combination of estrogen suppression (mepartricin) and adrenergic suppression (alpha(1)-AR blockers) may be suggested as a possible pharmacotherapeutic strategy for the treatment of benign prostatic hyperplasia.

Effects of mepartricin, a polyene macrolide agent, on fecal excretion and serum concentration of estrogen and number of prostatic estrogen receptors in immature rats.

BACKGROUND: Mepartricin, an antifungal agent, was investigated for effects on fecal excretion and serum concentration of sex steroids and the number of sex steroid prostatic receptors in immature rats. METHODS: Mepartricin was orally administered at 2.5, 5, and 10 mg/kg once daily for 2 weeks. Fecal estrogen and testosterone excretions, serum estrogen, testosterone and luteinizing hormone concentrations, and numbers of prostatic estrogen and androgen receptors were assayed. Prostate weight was also monitored. RESULTS: Fecal estrogen excretion showed a dose-dependent increase, which was significant for the two higher dosages. Conversely, the serum estrogen concentration and prostatic estrogen receptors were significantly decreased. No significant changes in fecal testosterone excretion, serum testosterone and luteinizing hormone concentrations, and prostatic androgen receptors were observed. Prostate weight was significantly reduced at 5 mg/kg, but we did not observe dose-dependency. CONCLUSIONS: Mepartricin increases fecal excretion of estrogen by binding with it in the intestinal tract, which results in reducing the serum estrogen concentration and number of prostatic estrogen receptors.

[Effects of mepartricin on the growth of hypertrophic prostatic tissue in primary culture. Creation of the experimental model and preliminary results]. / Gli effetti della mepartricina sulla crescita del tessuto prostatico ipertrofico in coltura primaria. Creazione del modello sperimentale e risultati preliminari.

The aim of this study was to standardise a method for the in vitro culture of hypertrophic prostatic tissue, to assay the morphological type of isolated cells, to evaluate the degree of proliferation and to identify their differentiated iter. In addition, the effects of mepartricina on growth was also studied obtaining preliminary results. Of a total of 40 biopsies used in this experiment, 30 were placed directly in culture using Freshney's method, whereas the remaining 10 were used in a method involving the primary culture of the dispersed cells obtained from enzymatically disaggregated tissue. In vitro proliferation was analysed using optic microscopy, histological and histochemical techniques, and a scanning electron microscope. Cellular kinetics were also studied by bromodeoxyuridine marking. Using these tests it was found that it is possible to obtain the development and growth in this form of culture of fibroblastic-type colonies of epithelial origin characterised by different morphologies and growth curves. In addition, cells from the epithelioid colonies are characterised by a high level of proliferative activity and a low degree of differentiation. Mepartricina appears, on the other hand, to inhibit the in vitro growth of hypertrophic prostatic tissue.

In vitro activity of antibiotics against Ureaplasma urealyticum and Chlamydia trachomatis strains from patients with nongonococcal urethritis.

The activity of minocycline, doxycycline, tetracycline, erythromycin, mepartricin and lincomycin against 35 freshly isolated Ureaplasma urealyticum strains was tested. Doxycycline was the most active. Twelve strains were resistant to minocycline and four of these were sensitive to erythromycin. Mepartricin showed no activity against the organisms at a concentration of 10 micrograms/ml. The susceptibility of 30 low-laboratory-passage Chlamydia trachomatis strains against tetracycline and erythromycin was tested. A variable degree of sensitivity to tetracycline and erythromycin was found, the median MIC values being 0.13 micrograms/ml and 0.025 micrograms/ml respectively. No resistant Chlamydia trachomatis strain was found.

In-vitro activity of antifungal agents in combination with four quinolones.

The antifungal activity of amphotericin B (AMB), mepartricin (MEPA), 5-fluorocytosine (5FC) and three imidazoles was tested in combination with each of four quinolones against 60 clinical yeast isolates. The inhibitory activity of AMB and MEPA was marginally enhanced by the azaquinolones, nalidixic acid (NAL) and enoxacin (ENO), but there was antagonism when combined with the fluorinated quinolones ciprofloxacin (CIP) and norfloxacin (NOR). All quinolones except NAL partially antagonised 5FC. Miconazole (MCZ), ketoconazole (KTZ) and itraconazole (ITZ) were each found to be synergistic with low concentrations of the quinolones, and also with high concentrations of NAL and ENO, but were strongly antagonised by high concentrations of CIP and NOR.

A comparison of the activity of mepartricin and amphotericin B against yeasts.

An in-vitro comparison was made of the activity of mepartricin and amphotericin B against yeasts both in the presence and absence of pooled human plasma. The methods used included minimum inhibitory concentrations (MICs), liquid cultures and scanning electron microscopy (SEM). Mepartricin was found to be consistently more active than amphotericin B and to exhibit a partial inhibitory action over a wider range of concentrations below the MIC. In the presence of plasma, amphotericin B had increased activity but there was a slight reduction for mepartricin. By electron microscopy both drugs exhibited a rapid effect on Candida albicans and the cell membrane was found to be their primary target. Mepartricin was found to have the additional effect of causing a delayed separation of dividing cells and damage on both sides of the septum between mother and daughter cells. This suggests interference with the enzymatic mechanism of septum formation or chitin synthesis.

In vitro and in vivo antifungal activity of the combination methylpartricin-5-fluorocytosine.

In vitro studies on the antifungal activity exerted by the combinations SPA-S-222 (a hydrosoluble derivative of the polyene antibiotic methylpartricin) and 5-fluorocytosine evidence a favourable interaction against the formation of germ-tube in Candida albicans; against Cryptococcus neoformans and 5FC induced-resistant strains of Candida albicans. In the experimental infections with Candida albicans and Cryptococcus neoformans a significantly favourable interaction was exerted by polyene-5FC combinations.

[Clinico-experimental correlation of the hypolipemic effects of mepartricin]. / Correlazione clinico-sperimentale degli effetti ipolipemizzanti della mepartricina.

Mepartricin (SPA-S-160) fat-lowering effect was evaluated in several groups of rats, normal or with experimental hyperlipidemia. The substance had a normalizing action on the lipid levels, and in particular on the cholesterol component. These findings, compared to those obtained in preliminary clinical studies, confirm a mechanism of action, common to some other polyenes, selecting as molecular target the interaction with the cholesterol component.

In vitro antimycoplasmal activity of mepartricin.

The in vitro antimycoplasmal activity of mepartricin was evaluated on several mycoplasma strains. The results demonstrate that this polyene antibiotic possesses a high efficacy against these microorganisms.

The effects of the polyene antibiotic mepartricin on polymorphonuclear leucocyte function: an in-vitro study.

Mepartricin, a polyene antibiotic with candidacidal and trichomonicidal activity, was found to be without toxic effects for human polymorphonuclear leucocytes; the drug seems to be unable to enter the human cells. Some synergism between the antifungal activities of mepartricin and of human leucocytes is seen if Candida cells are pre-incubated with sub-lethal concentrations of the drug.