RESUMO
The efficacy of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in the medical management of uterine leiomyomas (fibromas) was evaluated. Cetrorelix was administered to 18 pre-menopausal women with myomas with a mean age of 33.3 years, who had been candidates for hysterectomy. The initial dose of Cetrorelix was 5 mg twice daily s.c. for the first 2 days and thereafter 0.8 mg was given twice daily s.c. for at least 3 months. The mean duration of the treatment was 4.4 months. Before the therapy with Cetrorelix, the mean uterine volume, measured by ultrasonography, was 395.4 +/- 69.2 ml (range 89-1166). Sixteen patients showed a progressive reduction in uterine volume from 410.4 +/- 77.1 to a mean of 230.8 +/- 52.6 ml at 3 months. All patients became amenorrhoeic and had hot flushes. After treatment with Cetrorelix, a surgical myomectomy was performed in 12 women. One of the patients subjected to myomectomy after therapy with Cetrorelix became pregnant. These patients have been followed for up to 25 months and only in one case has the uterine volume increased after therapy. Three patients had good responses to therapy with Cetrorelix and it was decided to follow them only by observation. One patient became pregnant 2 months later. In the other patient, the uterine volume remained unchanged for the duration of the follow-up of 2 years and the third patient showed an increase after 21 months. In three patients, it was necessary to perform total hysterectomy. In 14 patients, serum concentrations of luteinizing hormone, follicle stimulating hormone and oestradiol decreased after the administration of the first dose of Cetrorelix and continued at subnormal values throughout therapy. In 15 patients who were not subjected to total hysterectomy, menstrual function returned at 1 month after cessation of treatment. Overall results support the use of Cetrorelix for the management of uterine leiomyomas.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/uso terapêutico , Leiomioma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Feminino , Fase Folicular , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Histerectomia , Leiomioma/diagnóstico por imagem , Leiomioma/cirurgia , Fase Luteal , Pessoa de Meia-Idade , Gravidez , Ultrassonografia , Hemorragia Uterina , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/cirurgia , Útero/diagnóstico por imagemRESUMO
OBJECTIVES: To assess the clinical response to luteinizing hormone-releasing hormone (LH-RH) antagonist cetrorelix (SB-75) in patients with advanced carcinoma of the prostate and paraplegia due to metastatic invasion of spinal cord. METHODS: Cetrorelix was given at two different dose regimens to 5 patients with prostatic cancer Stage D2 and paraplegia. Urologic and neurologic examinations, laboratory studies, radiography (myelography), and prostate ultrasonography were carried out. Prostate-specific antigen (PSA) and free testosterone were also measured. RESULTS: In all patients, the neurologic symptoms regressed. The recovery of the thermic and vibratory sensation and motility of the toes was observed. The neurologic improvement continued during the treatment and at 3 months all the patients were able to walk with the aid of a cane. In 1 patient, the myelography showed that the spinal cord compression had disappeared and prostate volume assessed by ultrasonography showed a significant decrease. The bladder function greatly improved in all 5 patients during the treatment with cetrorelix. Baseline levels of luteinizing hormone fell from 9.28 to 1.0 IU/L and those of follicle-stimulating hormone (FSH) fell from 18.28 to 12 IU/L (P < 0.05) after the first day of therapy with cetrorelix. Mean levels of free testosterone were reduced from 52.4 to 14.7 pmol/L (P < 0.005) at 12 hours and to 13.1 pmol/L (P < 0.005) 3 days after the first injection of cetrorelix. A persistent inhibition of gonadotropins and testosterone was maintained during the subsequent 3 months of therapy. The high levels of PSA gradually decreased. CONCLUSIONS: Our results show that LH-RH antagonist cetrorelix causes an immediate lowering of the serum testosterone levels in patients with prostate cancer and metastases in the spinal cord, in whom the LH-RH agonists cannot be used as single drugs because of the possibility of flare-up and appears to be appropriate for long-term therapy.
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Paraplegia/etiologia , Neoplasias da Próstata/tratamento farmacológico , Compressão da Medula Espinal/etiologia , Neoplasias da Medula Espinal/tratamento farmacológico , Neoplasias da Medula Espinal/secundário , Idoso , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Medula Espinal/complicações , Testosterona/sangueRESUMO
Cetrorelix (SB-75; [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10] luteinizing hormone-releasing hormone (LHRH)) is a new highly potent antagonist analog of LHRH containing the D-ureidoalkyl amino acid D-citrulline at position 6 and is free of allergenic effects. This study shows the inhibition of LH and follicle-stimulating hormone (FSH) release in normal men, postmenopausal women and patients with gonadal dysgenesis, using different doses and i.m., s.c. and i.v. routes of administration of SB-75. The mean serum levels of LH and FSH in normal men who received one single dose of 300 micrograms of SB-75 sc started to decline rapidly 1 h after its administration; the LH suppression was sustained for 14 h and that of FSH up to 24 h or longer as the samples were obtained only up to this time. The nadir for LH was reached at 14 h and that for FSH at 24 h or later after administration of the antagonist (p < 0.05). Serum levels of total and free testosterone decreased after the first hour and this inhibition was maintained for up to 14 h. The nadir for total testosterone was at 6 h and that for free testosterone was at 8 h (p < 0.001), corresponding to 56% and 60% of inhibition, respectively. In postmenopausal women, inhibition of the elevated basal serum LH and FSH levels occurred after a single injection of the antagonist analog SB-75 in doses of 75, 150, 300, 600 and 1200 micrograms using im, sc and iv routes of administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hormônio Foliculoestimulante/sangue , Hormônios Esteroides Gonadais/sangue , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Luteinizante/sangue , Adulto , Feminino , Hormônio Foliculoestimulante/antagonistas & inibidores , Disgenesia Gonadal/sangue , Hormônios Esteroides Gonadais/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/efeitos adversos , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Hormônio Luteinizante/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Pós-Menopausa , Valores de ReferênciaRESUMO
Among new highly potent antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH), containing neutral hydrophilic D-ureidoalkyl amino acids such as D-Cit and D-Hci at position 6 and free of edematogenic and anaphylactoid reactions, Ac-D-Nal(2)1, D-Ph(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10 (LH-RH) (SB-75; Cetrorelix) was shown to be one of the most powerful. In this trial, we evaluated the response to 500 micrograms SB-75 given every 12 hr subcutaneously (sc) for 4 weeks in 11 patients with benign prostatic hyperplasia (BPH), and 6 weeks in 6 prostatic cancer patients (2 stage C, 4 stage D2). In patients with BPH presenting with prostatism and urinary outflow obstruction, there was a noticeable clinical improvement after the first week of SB-75 administration. This improvement continued during the course of treatment. Before therapy with SB-75, the serum levels of prostate-specific antigen (PSA) (6.73 +/- 1.46 ng/ml), acid phosphatases, total (12.67 +/- 1.15 U/l), and prostatic (2.27 +/- 0.34 U/l), were mildly elevated, but declined to normal values at 4 weeks: (2.13 +/- 0.59 ng/ml; P < 0.01), (7.68 +/- 0.89 U/l; P < 0.01), and (1.39 +/- 0.18 U/l; P < 0.01), respectively. Mean prostatic volume assessed by ultrasonography showed a significant decrease in all patients from 67.84 +/- 8.86 to 37.92 +/- 8.52 cm3; P < 0.01, which represents a reduction of 44%. In patients with prostate cancer, after the first week of therapy with SB-75, we observed a significant decrease in bone pain, relief in urinary outflow obstruction, and reversal of the signs of prostatism. Subjective improvement continued during the following weeks of treatment, so that the patients no longer needed analgesics. PSA, acid, and alkaline phosphatases gradually fell, achieving nearly normal values at 6 weeks. Initial serum testosterone levels in BPH and prostatic cancer patients were within normal limits, but during treatment with the antagonistic analog SB-75, fell to castration values. A major fall in free testosterone levels was observed after the first dose; the maximal inhibition was seen after 6-12 hr, with a simultaneous decrease in levels of both gonadotropins. Our results show that antagonist SB-75 can be safely administered for prolonged periods of time. The rapid shrinkage of the prostate and concomitant improvement in obstructive symptoms of prostatism obtained with antagonistic analog SB-75 in patients with BPH may decrease the morbidity of prostatic surgery and offer a therapeutic alternative in men who are considered poor surgical risks.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hiperplasia Prostática/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Fosfatase Ácida/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Infusões Intravenosas , Estudos Longitudinais , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/sangue , Neoplasias da Próstata/sangue , Testosterona/sangue , Ultrassonografia , Micção/efeitos dos fármacosRESUMO
For the past 6 years we used daily injection of luteinizing hormone-releasing hormone (LH-RH) agonists to treat patients with advanced prostate carcinoma. In this study we determined the hormonal response of the pituitary-testicular axis over a 2-month period and evaluated the safety and tolerance of the single intramuscular administration of sustained-release formulations of D-Trp-6-LH-RH microcapsules designed to release 50, 100, or 200 micrograms/day for over 1 month. Serum levels of LH, testosterone, and D-Trp-6-LH-RH were measured by RIA for up to 60 days in 10 patients with advanced prostatic carcinoma who had not received any previous drug therapy. After the administration of the microcapsules there was a biphasic increase in D-Trp-6-LH-RH serum levels. The maximal peak was obtained between 1 and 3 hr, and a second peak occurred between weeks 4 and 6. LH levels increased initially, with a maximal peak at 60 min, and elevated serum LH values persisted for more than 24 hr. LH levels began to fall on the second day, reaching subnormal values after 1 week. Serum testosterone rose during the first week and fell subsequently to less than 100 ng/dl. A rebound in LH and testosterone was seen about the 50th day after the microcapsule administration. Following the first week of therapy, we observed in all patients a significant decrease in bone pain, improvement in urinary flow obstruction, and a reversal of the signs of prostatism. No side effects were observed, and acceptance of the microcapsules was very good. Our results show that a single dose of D-Trp-6-LH-RH microcapsules suppresses of the pituitary-testicular axis for at least 50 days. D-Trp-6-LH-RH microcapsules facilitate the treatment and should lead to an improvement in the therapeutic response.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Hormônio Liberador de Gonadotropina/análogos & derivados , Hipófise/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Testículo/efeitos dos fármacos , Fosfatase Ácida/sangue , Idoso , Antineoplásicos/sangue , Cápsulas , Preparações de Ação Retardada , Avaliação de Medicamentos , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/sangue , Humanos , Injeções Intramusculares , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Testosterona/sangue , Pamoato de TriptorrelinaRESUMO
Carcinoma of the exocrine pancreas seems to be sex-hormone sensitive. Administration of agonistic analogs of luteinizing hormone--releasing hormone (LH-RH) creates a state of sex-hormone deficiency. Therapy with D-Trp-6-LH-RH was evaluated in 17 patients with unresectable and biopsy-proven adenocarcinoma of the pancreas (stage IV). Nine patients were male and 8 female, and the median age at diagnosis was 60 years. The majority of patients underwent a gastro-intestinal and biliary bypass. The therapy with D-Trp-6-LH-RH was started 3-31 days after bypass surgery. The analog was given at the dose of 1 mg/day subcutaneously for the first 7 days. Subsequently, the dose was reduced to 100 micrograms/day. One month after the start of the therapy the gonadotropin levels were in subnormal range. This therapy led to clinical improvement, better quality of life and an increase in survival time. The median survival time for all the groups was 7.2 months (men 7.4 months and women 6.9 months). LH-RH agonists appear to decrease pancreatic cancer growth by eliminating the stimulatory effect of sex steroids, and by direct effects on tumors. Further improvement in the clinical response in patients with inoperable pancreatic carcinoma might be possibly obtained by the combination of LH--RH agonists with modern somatostatin analogs.