Biomedical subjects
M Motta
Publications and source records attributed to M Motta.
Selective inhibition of the 5 alpha-reductase of the rat epididymis.
The effect of several synthetic steroids belonging either to the 4-aza-3-oxo-steroid family or to androstene and androstane derivatives was investigated "in vitro" on the epididymal as well as prostatic 5 alpha-reductase activity. For this purpose rat caput epididymis and prostate were incubated with the different steroidal compounds at molar concentrations of 10(-7), 10(-6), and 10(-5) in the presence of labelled testosterone as substrate. The steroids 4-MA (17 beta, N,N-diethyl-carbamoyl-4-aza-5 alpha-androstan-3-one) and 4-OH-A (4-hydroxy-androstenedione), already known to be effective 5 alpha-reductase inhibitors at the level of the prostate, have been used as reference molecules. The 5 alpha-reductase activity was evaluated by measuring pg of dihydrotestosterone (DHT) formed in 2 h of incubation by mg of tissue. The steroids A, B, C, F, G and I inhibit the formation of DHT in the rat epididymis although to different extents; they are also equally effective on the formation of DHT in the rat prostate. The steroids D, E, H and L are devoid of any inhibitory property on the formation of DHT in both the rat epididymis and prostate. The most interesting results were obtained with compound M which exhibits a dose-dependent and significant inhibitory effect on the formation of DHT in the epididymis, but it is inactive at the level of the prostate. These findings suggest that it is possible (a) to selectively interfere with the 5 alpha-reductase of the epididymis without affecting that present in the prostate, and (b) consequently to envisage new ways to regulate male fertility.
Treatment of pre-menopausal advanced breast cancer with goserelin--a long-acting luteinizing hormone releasing hormone agonist.
Twenty-two pre-menopausal evaluable patients with advanced breast cancer (median age 39 years; ER positive 19, unknown three; prior adjuvant chemotherapy 16) were treated with the LHRH agonist goserelin depot (Zoladex). Serum levels of 17 beta-estradiol and progesterone were suppressed by goserelin within 3-4 weeks of therapy, while serum leuteinizing hormone and follicle stimulating hormone titers remained in the low level of the normal range. Complete or partial response was documented in seven of 22 cases (32%) and occurred in all major sites of disease. Tumor response was documented in women regularly menstruating at the start of therapy. Median time to disease progression was 23 weeks; median duration of response was 64 weeks; overall survival was 141 weeks. Zoladex was well tolerated: only hot flushes in 82% and reversible cutaneous pigmentation in the site of injection in 45% of the patients were observed. In our experience the activity of Zoladex was comparable to that of oophorectomy, without the psychological trauma and the morbidity related to surgical castration.
Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP.
Highly potent LH-releasing hormone (LHRH) agonists have been recently introduced in therapy for the treatment of the carcinoma of the prostate, an androgen-dependent pathology. These peptides are believed to act mainly by inhibiting the pituitary-testicular axis and, consequently, by reducing testosterone levels. The recent observation that binding sites for LHRH analogs are present on prostatic tumor tissue suggests that these drugs could also act directly on the tumor. To verify this hypothesis, the effects of two potent LHRH agonists [Zoladex (Z) and Buserelin (B)] have been studied on the proliferation of the human prostatic cancer cell line LNCaP (lymph node carcinoma of the prostate). LNCaP cells were treated for 9 days with different doses of either Z or B (concentrations from 10(-12)-10(-6) M). Both analogs significantly inhibited cell proliferation at doses between 10(-9)-10(-6) M. The antiproliferative action of the two LHRH agonists was shown to be dose dependent, with IC50 values of 0.82 and 1.79 nM for Z and B, respectively. A similar treatment with B was without any significant effect on the proliferation of a mouse embryo fibroblast cell line (Swiss 3T3), which was used as a nontumoral control. The inhibitory action of both LHRH agonists (10(-8) M) on LNCaP cell proliferation was completely antagonized by the simultaneous treatment of the cells with a potent LHRH antagonist (Nal-Arg-LHRH; 10(-8) M); when given alone at the dose selected, the antagonist did not affect cell growth. These results clearly suggest that the antiproliferative effect of LHRH agonists on LNCaP cells may be mediated by specific receptors. The presence of binding sites for [125I]B was consequently demonstrated on the membranes of LNCaP cells cultured in a medium containing charcoal-stripped fetal calf serum, i.e. in the absence of steroids. The affinity of these binding sites for the ligand was lower than that observed for the same receptors on rat pituitary membranes. To clarify the mechanism of the antiproliferative action of the LHRH agonists, the effects of both Z and B on the incorporation of [3H]thymidine and [14C]methionine into LNCaP cells were investigated. During a short incubation period (3 h), the two LHRH agonists rapidly inhibited [3H]thymidine incorporation into the cells. The same treatment did not affect the incorporation of [14C]methionine into proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
[Retrospective survey of pharmacologic tolerance in the prevention of neoplastic recurrence of superficial urothelioma].
As from June 1989 all superficial bladder tumours (regardless whether treated by surgery or endoscopy) have been included in 5 different chemo, immuno or chemoimmunoprophylactic protocols of therapy against neoplastic recurrence. The protocols considered: mitomycin alone and in association with alpha 2a IFN; epirubicin alone and in association with alpha 2b IFN; immunomodulating alpha 2a IFN. The administration procedures adhered to those set down in the literature and late treatment modalities were used for the associations. The aim of the study was to perform a retrospective evaluation of the intravesical therapies regarding local and systemic tolerability to various drugs and disregarding any evaluation of drug efficacy, i.e. the percentage of patients free from recurrence. We evaluated 92 patients and a total of 1028 instillations carried out prior to June 1991. The number of patients in each protocol was: 31 on IFN; 13 on mitomycin; 24 on epirubicin; 14 on the immunomodulator plus with mitomycin; 10 on the immunomodulator associated with epirubicin. Treatment was suspended in 11/92 patients (11.9%). The highest percentage of interruptions (21.4%) was observed in the mitomycin plus IFN protocol, while the lowest (6.4%) was seen in the IFN monoprotocol. The percentage of patients who presented no side effects during prophylaxis was similar in all protocols studied (50% of patients on the two associations and 54.8% on IFN alone) with the exception of the epirubicin protocol patients who showed lower tolerance (41.6%). The number of "irritable" instillations in each protocol group was analyzed. The lowest number (9/162 = 5.5%) was conserved in the epirubicin plus IFN protocol, while the highest (19/108 17.5%) was seen in the mitomycin group.(ABSTRACT TRUNCATED AT 250 WORDS)
Evaluation of the biological activity of unmodified synthetic eel calcitonin rectal capsules. Comparison with intramuscular administration and placebo.
Biological activity of eel calcitonin 100 IU administered by the rectal route was evaluated in healthy volunteers by measuring plasmatic variations of cyclic adenosine monophosphate (cAMP) after a single dose and during a 21-day treatment. This formulation appears to allow a bioavailability of the drug which is half of the same dose administered intramuscularly, and to cause a prompt and significant increase of plasma cAMP, with minimal variations of calcaemia. Repeated administration shows the persistence in time of this effect. The overall conclusion is that the amount of calcitonin absorbed through the rectal mucosa seems sufficient to induce a typical biological response related to the interaction of the hormone with its specific receptors in bone.
Extracorporeal shock wave lithotripsy for urinary stone disease: our experience.
The authors report results of an 18 month study on ESWL treatment for calculosis of different tracts of the urinary apparatus. Average success rate is 80%, even if it varies depending on the site and size of the calculus. Surgery and PCN are required only in cases of unsuccessful treatment or particular forms of lithiasis. ESWL has determined advanced in the treatment of renoureteral stones in the last decade. However some significant generalized complications observed in our patients at follow-up raise doubts concerning possible, unforeseable long term effects of ESWL treatment.
Intertubular capillary changes in kidney allografts: a morphologic investigation on 61 renal specimens.
A total of 61 kidney allograft specimens (51 biopsies and 10 nephrectomies) from 44 patients were investigated. Transplant glomerulopathy (TGP) was found in 38 specimens. Electron microscopy disclosed peculiar intertubular capillary changes (ITCC) in 47 specimens (all those showing TGP and nine without TGP). They were characterized by splitting and multilayering of the basement membranes. TGP and ITCC were graded and found mild (in 23 and 22 specimens), moderate (in 11 and 16 specimens), and severe (in four and nine specimens). Both worsened with time lapse from transplantation. When both were compared in single specimens, their grading was similar or, with a few exceptions, more severe for ITCC. TGP and ITCC were more frequent in biopsies with morphologic evidence of rejection and less frequent in patients treated with Cyclosporine A. Repeated biopsies and nephrectomies were studied in 10 patients and a somewhat more precocious appearance of ITCC than of TGP was found. Earlier and more severe ITCC were found in two patients who had had two transplants as compared to those with one. Morphologic similarities between TGP and ITCC suggest a common pathogenetic mechanism related to endothelial damage. The association to the histological evidence of rejection as well as the apparently protective activity of Cyclosporine A could support the involvement of an immune-mediated mechanism in agreement with what is reported in literature. The constant association of ITCC and TGP and its possible more precocious appearance enforce the diagnostic value of the former, which allows to infer the presence or the subsequent development of TGP even in biopsies where glomeruli are lacking.
Medical castration with zoladex: a conservative approach to premenopausal breast cancer.
For almost a century surgical castration represented the initial standard therapy for metastatic breast cancer in premenopausal women with hormone dependent tumors. Today the suppression of ovarian function can also be obtained by the administration of supraphysiologic doses of luteinizing hormone releasing hormone (LHRH) agonists. From April 1987 to February 1989, 23 premenopausal patients with advanced breast cancer (median age 39 years, range 28-52, ER positive 20, unknown 3; prior chemotherapy 17) were treated with the LHRH agonist goserelin depot (Zoladex) at the dose of 3.6 mg. every 4 weeks. Twenty-two patients were evaluable. Serum levels of 17 beta estradiol, progesterone, FSH and LH were suppressed by goserelin and fell to postmenopausal values within 8 weeks of therapy in 77% of cases. Complete response (CR) plus partial response (PR) was documented in 7 of 22 (32%) and occurred in all major sites of disease. Five patients achieved CR (soft tissue 3, viscera 2). Response rate was higher in patients not previously treated with chemotherapy (4/6). In the present series, all responses were seen in women greater than 35 years old, regularly menstruating at the start of treatment. Time to progression for the entire case series was 22 weeks and for responders 64 weeks. Oophorectomy was performed after disease progression in four patients without success. Goserelin was well tolerated. Local cutaneous dyschromia occurred in 45% and hot flushes in 82%. Treatment efficacy of goserelin is comparable to that of oophorectomy, without the psychological trauma and the morbidity related to surgical castration.
Androgen metabolism in different target tissues.
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[Aspects of the clinical and experimental pharmacology of analogs of LHRH].
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Effect of unilateral vagotomy on serum gonadotropin concentration in rats with two testes and in hemicastrates.
The effect of right- or left-sided vagotomy on serum gonadotropin secretion was studied in rats with two testes and in hemicastrates. Right-sided vagotomy in animals with two testes in situ induced a very marked rise in serum LH levels. Left-sided vagotomy was also accompanied with a slight increase in LH secretion. The difference in serum LH levels between right-and left-sided vagotomized animals was significant. FSH levels were unaffected by either right- or left-sided vagotomy. Removal of the right or of the left testis resulted in a significant increase in serum gonadotropin levels. Unilateral vagotomy in hemicastrates did not alter the hemicastration-induced changes in serum gonadotropin hormone levels. These data indicate that the vagus nerve might have a modulatory role in the control of LH secretion in rats with two testes but not in hemicastrates. The different response in LH levels after right-sided and left-sided vagotomy suggests a functional asymmetry of the vagus nerve in the regulation of LH secretion.
Substance P-like immunoreactive nerve fibers of the human laryngeal mucosa--preliminary report.
Substance P (SP) is considered a primary sensory transmitter and is widely distributed within the autonomic nervous system. This study is concerned with the distribution of SP-like immunoreactive nerve fibers in the human larynx. Individual SP-like immunoreactive nerve fibers were detected in the subepithelial connective tissue of the laryngeal mucosa, in the ventricular and subglottic glandular regions and in a few nervous ganglia in the deep connective tissue. No intraepithelial SP-like immunoreactive fibers were present in our material.
[Evaluation of the risk of hepatitis delta virus (HDV) infection in a population of hemodialyzed patients: significance of the determination of anti-delta antibodies in the blood].
Hepatitis delta virus (HDV) is a defective virus which requires the helper function of hepatitis B virus (HBV) for replication. HDV infection occurs only during or after HDV infection. Viral infection spreads parenterally in both cases. However, it has been reported that the risk of HDV infection is limited to hemodialysed patients, unlike the risk of HBV infection. In order to verify these findings the Authors studied 108 patients undergoing periodical hemodialytic treatment in order to study the delta antibodies present in their blood. Sixty-one of these subjects had received previous blood transfusions, 15 were HBsAg positive and 7 positive for other serological markers of the hepatitis B virus. None of the subjects examined was positive for anti HDV. Our results agreed with the literature reporting an incidence of positive HDV serological markers limited to hemodialyzed patients. The Authors observed that the behaviour of the HDV serological markers can vary from patient to patient and that it is impossible to furnish diagnosis of HDV infection after HBV and HDV clearance. Since these factors can lead to underestimation of the real incidence of HDV infection in hemodialyzed patients, the Authors underline the need to perform long term epidemiological studies and to investigate all the HDV serological markers.
Venous and systemic gas embolism.
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[Cutaneous tuberculosis with multifocal visceral involvement].
The case of a young Senegalese man who developed a form of cutaneous tuberculosis associated with a disseminated disease, successfully treated with appropriate antitubercular chemotherapy is reported. We found Mycobacterium Microti in the cutaneous ulcers, the only organism isolated after many cultural and microscopical examinations of different exudates and tissues. This mycobacterium was considered up to now to be pathogenic to rodents, but not man. Its possible pathogenicity to man (under certain situations) is also suggested, and it is expected that this possibility will be supported by other reports in the near future. In addition, stress is laid on the problems of diagnosis and classification of the cutaneous tuberculosis, so uncommon in the Western Hemisphere, and its possible association with leprosy.
Antihormonal activities of 5 alpha-reductase and aromatase inhibitors.
The problem of developing androgen antagonists has been tackled so far only by synthesizing steroids able to displace testosterone and other androgens from their specific receptor sites. The observation that testosterone has to be converted intracellularly either to 5 alpha-reduced metabolites (DHT, 3 alpha-diol, etc.) or to estrogens, in order to become fully active on androgen-dependent structures (both central and peripheral), has opened the possibility of creating molecules which prevent these conversions, and which could then block the actions of testosterone. The availability of these new compounds has allowed a better understanding of the selective physiological role of each of the metabolites of testosterone, and to provide the basis for the development of new hormone antagonists to be used in those clinical conditions for which an inhibition of the actions of testosterone is foreseen. The usefulness of these enzyme inhibitors is underlined by some examples described in this paper. The results obtained may permit the formulation of the following conclusions: (1) The conversion of testosterone to its 5 alpha-reduced metabolites occurring in the neuroendocrine structures may represent an essential step for the appearance of the inhibitory feedback effect testosterone exerts on LH secretion; (2) Testosterone exhibits its negative feedback effect on FSH secretion as such and not following the local aromatization to estrogens; (3) Testosterone exerts its effect on the intrahypothalamic stores of LHRH acting as such and not following its local conversion either to 5 alpha-reduced metabolites or to estrogenic molecules; (4) Some of the new enzyme inhibitors (e.g. 4-OH-A) may represent an interesting tool for the treatment and/or the prevention of BPH and possibly of other androgen-dependent diseases (prostate carcinoma, acne etc.), as shown by their ability to prevent the in vitro conversion of testosterone to its 5 alpha-reduced metabolites both in the normal prostate of the rat and in the human BPH tissue.
Testosterone and the control of hypothalamic GnRH.
The aim of the present study was to test the hypothesis that the restoring effect of testosterone on hypothalamic GnRH stores in orchidectomized rats might be linked to the intrahypothalamic transformation of the hormone into estrogenic metabolites. To this purpose, advantage has been taken of the availability of the potent antiestrogen, tamoxifen (TMX). Different groups of adult male rats castrated since 4 weeks were submitted to a 6-day treatment with testosterone propionate (TP, 2 mg/rat daily); TMX (50 or 200 micrograms/rat daily); or TP (2 mg/rat daily) plus TMX (50 or 200 micrograms/rat daily). The animals were sacrificed 24 h after the last injection, and hypothalamic GnRH content was measured by radioimmunoassay. The results have confirmed the ability of TP to counteract the decreasing effect of orchidectomy on hypothalamic GnRH stores, and have shown that TMX does not have any intrinsic activity on this parameter. Furthermore, TMX at either dose used in the present experiments, was found not to be able to abolish the restoring effect of TP on MBH-GnRH stores. It is concluded that the action of testosterone on hypothalamic GnRH does not require the conversion of the hormone into estrogens.