RESUMEN
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different ovarian stimulation protocols: (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). During the ovarian stimulation regimen, the patients were submitted to hormonal (oestradiol and growth hormone), ultrasonographic (follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluations. Furthermore, the plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate.
Asunto(s)
Arginina/uso terapéutico , Fertilización In Vitro/métodos , Inducción de la Ovulación/métodos , Adulto , Arginina/administración & dosificación , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Gonadotropina Coriónica/administración & dosificación , Estradiol/sangre , Femenino , Fármacos para la Fertilidad Femenina/administración & dosificación , Hormona Folículo Estimulante/administración & dosificación , Hormona de Crecimiento Humana/sangre , Humanos , Infertilidad Femenina/tratamiento farmacológico , Infertilidad Femenina/fisiopatología , Infertilidad Femenina/terapia , Leuprolida/administración & dosificación , Ovario/irrigación sanguínea , Ovario/diagnóstico por imagen , Ovario/efectos de los fármacos , Embarazo , Estudios Prospectivos , UltrasonografíaRESUMEN
We have isolated a rat thyroid cDNA encoding a novel rat receptor-type tyrosine phosphatase protein. This gene, on the basis of its homology to another tyrosine phosphatase, the recently isolated human DEP-1/HPTPeta, has been named r-PTPeta. In rat thyroid cells the r-PTPeta gene acts as a differentiation marker. Indeed, the block of thyroid cell differentiation induced by viral and cellular oncogenes is associated with the inhibition or marked reduction of the expression of this gene, and its expression is positively regulated by thyrotropin, the physiological stimulator of thyroid cell growth.
Asunto(s)
Transformación Celular Neoplásica , Regulación Enzimológica de la Expresión Génica , Proteínas Tirosina Fosfatasas/biosíntesis , Proteínas Tirosina Fosfatasas/química , Glándula Tiroides/enzimología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Diferenciación Celular , Línea Celular , Codón , Cartilla de ADN , ADN Complementario , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Datos de Secuencia Molecular , Oncogenes , Especificidad de Órganos , Reacción en Cadena de la Polimerasa , Proteínas Tirosina Fosfatasas/aislamiento & purificación , Ratas , Ratas Endogámicas F344 , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores , Mapeo Restrictivo , Homología de Secuencia de Aminoácido , Glándula Tiroides/citología , Tirotropina/farmacología , Transcripción GenéticaRESUMEN
The extrinsic coagulation pathway is activated when tissue factor (TF) is exposed as a consequence of arterial damage. TF binds to factor VII (FVII) or activated FVII (FVIIa), generating a complex that activates both FX and FIX, ultimately leading to thrombin formation. To determine whether inhibition of FVII binding to TF would result in antithrombotic effects, active site-blocked FVIIa (FVIIai) was used in a rabbit model of intravascular thrombus formation. In addition, to study the interaction between extrinsic coagulation pathway activation and platelet aggregation, in the same model of intravascular thrombus formation, recombinant human FVIIa was administered in antiplatelet-treated rabbits. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were initiated by placing an external constrictor around the endothelially-injured rabbit carotid arteries (Folt's model). Carotid blood flow was measured continuously by a Doppler flow probe placed proximally to the constrictor. CFVs were induced in 29 New Zealand White rabbits. After CFVs were observed for 30 min, the animals were randomly divided in four groups: 5 animals received via a small catheter (26G) placed proximally to the stenosis, an intra-arterial infusion of human recombinant FVIIai (0.1 mg/kg/min for 10 min); 9 animals received AP-1, a monoclonal antibody against rabbit TF (0.1 mg/kg i.v. bolus); 7 animals received ridogrel, a dual thromboxane A2 synthetase inhibitor and thromboxane A2 receptor antagonist (10 mg/kg i.v. bolus); finally, 8 rabbits received aurintrycarboxilic acid (ATA), an inhibitor of platelet glycoprotein Ib/von Willebrand factor interaction (10 mg/kg i.v. bolus). FVIIai abolished CFVs in 5 of 5 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 106 +/- 9% of the baseline values; NS vs baseline). AP-1 abolished CFVs in 7 of 9 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 58 +/- 35% of the baseline values; NS vs baseline). Finally, in all the animals receiving ridogrel or ATA CFVs were abolished (CFV frequency 0 cycles/hour; p < 0.05 in both groups; carotid blood flow velocity, respectively 62 +/- 32 and 66 +/- 40% of the baseline values; NS vs baseline in both groups). Thirty minutes following inhibition of CFVs, in the FVIIai treated rabbits, human recombinant FVIIa was infused, via the small catheter placed proximally to the stenosis, at the dose of 0.1 mg/kg/min for 10 min. In the other three groups, FVIIa, at the same dose, was infused i.v. Infusion of FVIIa restored CFVs in all FVIIai treated animals and in 6 of 7 AP-1 treated animals, thus indicating that AP-1 and FVIIai bindings to TF was competitive and was replaced by FVIIa. Infusion of FVIIa failed to restore CFVs in ridogrel e ATA treated rabbits (1 of 7 and 0 of 8 rabbits, respectively), showing that activation of extrinsic coagulation by FVIIa was overcome by inhibition of platelet function. Activated partial thromboplastin time, and ex vivo platelet aggregation in response to ADP and thrombin, were not different after FVIIai infusion, while prothrombin time was slightly but significantly prolonged as compared to baseline values. Thus, FVII-VIIa plays an important role in initiating thrombus formation in vivo. Administration of FVIIai exerts a potent antithrombotic effects in this model without affecting systemic coagulation. In addition, in this model platelets exert an important role in arterial thrombosis, since in the presence of inhibition of platelet function, activation of the extrinsic coagulation pathway failed to restore thrombus formation.
Asunto(s)
Trombosis de las Arterias Carótidas/tratamiento farmacológico , Modelos Animales de Enfermedad , Factor VII/antagonistas & inhibidores , Factor VIIa/uso terapéutico , Fibrinolíticos/uso terapéutico , Enfermedad Aguda , Animales , Coagulación Sanguínea/efectos de los fármacos , Trombosis de las Arterias Carótidas/sangre , Arteria Carótida Común , Evaluación Preclínica de Medicamentos , Factor VIIa/antagonistas & inhibidores , Femenino , Humanos , Masculino , Conejos , Distribución Aleatoria , Proteínas Recombinantes/uso terapéutico , RecurrenciaRESUMEN
Because endogenous opioids have been considered to be deeply involved as a causal factor of hypothalamic amenorrhoea, this study was designed to evaluate the efficacy of the administration of naltrexone, an antagonist of opioid receptors, on luteinizing hormone (LH) secretion in patients with hypothalamic amenorrhoea. A total of 30 patients with hypothalamic amenorrhoea were studied. Patients were divided into two groups: group A, hypogonadotrophic (n = 15), and group B, normogonadotrophic (n = 15). All patients were administered naltrexone at a dose of 50 mg/ day per os for 6 months. A third group of 10 amenorrhoeic patients was treated with placebo per os with the same schedule. All patients were evaluated for LH spontaneous pulsatile release in baseline conditions and after 3 and 6 months of treatment. Plasma gonadal steroid concentrations increased significantly in all patients after 3 months of naltrexone therapy, but only hypogonadotrophic patients showed a sharp increase in both LH plasma concentrations and LH pulse amplitude within the first 3 months of treatment which remained unchanged until the sixth month of treatment. Plasma follicle stimulating hormone concentrations did not change significantly in any patient. Menstrual bleeding occurred within 90 days of the beginning of treatment in 24 out of the 30 patients. Patients treated with placebo did not show a significant change in gonadotrophin and gonadal steroid plasma concentrations. The results of our study support the efficacy of naltrexone administration on neuroendocrine pathways controlling LH secretion in patients with hypothalamic amenorrhoea.
Asunto(s)
Amenorrea/tratamiento farmacológico , Amenorrea/fisiopatología , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiopatología , Hormona Luteinizante/metabolismo , Naltrexona/uso terapéutico , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/fisiopatología , Femenino , Hormona Folículo Estimulante/metabolismo , Humanos , Naltrexona/administración & dosificación , Antagonistas de NarcóticosRESUMEN
It is well known that pregnancy is a condition in which plasma magnesium falls because of accumulation of the ion in the placenta and fetus. Magnesium (Mg) is therefore widely given as a supplement during pregnancy, particularly in cases of preterm labour. In our experience, the combination of oral Mg (magnesium pyrrolidone carboxylic acid) at a dose of 360 mg/day with conventional ritodrine treatment allows a reduction in ritodrine dosage, accompanied by a significant reduction in side effects. We therefore evaluated changes in fetal blood flow, using pulsed Doppler, in women submitted to combined magnesium and ritodrine treatment compared to those treated with ritodrine plus placebo. The Mg-treated group showed a decrease in vessel resistance both in the umbilical artery and in the fetal middle cerebral artery, indicating that fetal vasculature is sensitive to exogenous Mg. Measurement of plasma and mononuclear cell Mg showed an intracellular increase in the cation of about 10 per cent. We conclude that oral magnesium supplementation in pregnancy is safe and that it has a positive effect on the fetal circulation.