Monitorización terapéutica de escitalopram mediante el test de supresión con dexametasona / Therapeutic monitoring of escitalopram by dexamethasone suppression test

Introducción. La depresión está asociada a una disfunción de la regulación del eje hipotálamo-pituitario-adrenal, HPA, que se refleja en la alteración del test de supresión con Dexametasona, DST. Escitalopram y otros ISRS disminuyen la respuesta del eje HPA en el DST, siendo el objetivo del presente trabajo la validación del DST como marcador subrogado de la actividad serotoninergica central en los tratamientos con escitalopram y su aplicación al cálculo de sus regimenes nosológicos. Metodología. Estudio prospectivo observacional sobre 29pacientes, a los que se realizo el DST con 0,25 mg de Dexametasona y posterior análisis genético del CYP2C19 mediante test PHARMA chip de Progenika. Resultados. El rango de valores de cortisol plasmático post-DTS asociados a cada grupo fenotipico fueron: fenotipo PM=0,6-1,7 mcg/dl, fenotipo IM=1,2-3,5 mcg/dl y para el fenotipo EM=4,8-13,2 mcg/dl, realizándose el ajuste nosológico y correspondiéndoles, respectivamente, las siguiente dosis: 3-4 mg/día, 5-8 mg/día y 10-31 mg/día. Conclusiones. Se ha comprobado que el DST test puede utilizarse como marcador subrogado de la respuesta farmacológica al escitalopram y como instrumento para su ajuste nosológico, proporcionando datos significativos sobre distintos fenotipos metabolizadores del CYP2C19 (AU)

Introduction. Depression is associated with a dysfunction of regulation of the hypothalamic-pituitary-adrenal, HPA, which is reflected in the alteration of the dexamethasone suppression test, DST. Escitalopram and other SSRIs decrease the HPA axis response to the DST, beeing the aim of this study validate the DST as a surrogate marker of central serotonergic activity in the treatment with escitalopram and its application to the calculation of the dosage regimens. Methodology. Prospective observational study on 29patients, upon whom was performed the DST-test with0.25 mg of Dexamethasone and subsequent genetic analysis of CYP2C19 by Progenika PHARMA chip test. Results. The range of plasma cortisol levels post-DTS associated with each phenotypic group were: PM phenotype=0.6 to 1.7 mcg/dl, IM phenotype= 1.2 to 3.5 mcg/dl and EM phenotype = 4.8 to 13.2 mcg/dl, being carried out the dosetitration and corresponding, respectively, the following dose regimens: 3-4 mg/day, 5-8 mg/day and 10-31 mg/day. Conclusions. It has been shown that the DST test can be used as a surrogate marker of drug response to escitalopram and as a tool for dose adjustment, providing significant data on different phenotypes of CYP2C19 metabolizers (AU)

Purification of gonadotropin releasing hormone receptors using the avidin-biotin technique.

The avidin-biotin technique has been applied to the purification of gonadotropin releasing hormone (GnRH) receptors from other solubilized membrane proteins. The following steps were involved in this approach: (a) solubilization of rat pituitary GnRH receptor with the zwitterionic detergent CHAPS, 3-[(3-cholamidopropyl)-di-methylammonio]-1-propane sulfonate, (b) equilibration of the solubilized GnRH receptor with [biotinyl-D-Lys6]GnRH immobilized on avidin-agarose; and (c) elution of the receptors with high salt and GnRH analogues. Following two cycles of affinity chromatography the GnRH receptor was purified to homogeneity. The overall recovery of the purified receptor was 4-10% of the initial activity in the CHAPS extract and the calculated purification was approximately 10,000 to 15,000 fold. The development of a two step affinity chromatography for the purification of GnRH receptors can be used for detailed studies on the structure and function of the receptor. These studies will advance our understanding of the molecular basis of GnRH action.

Gonadotropin-releasing peptide from human follicular fluid: isolation, characterization, and chemical synthesis.

A gonadotropin-releasing peptide has been isolated from human follicular fluid. Its amino acid composition and sequence are completely different from the hypothalamic lutropin-releasing hormone. It is designated human follicular gonadotropin-releasing peptide and abbreviated as hF-GRP. The primary structure of this peptide (H-Thr-Asp-Thr-Ser-His-His-Asp-Gln-Asp-His-Pro-Thr-Phe-Asn-OH) has been confirmed by chemical synthesis. In the mouse pituitary incubation assay, the ED50 value for follitropin or lutropin release is estimated to be 1.2-1.6 nM.

New effective gonadotropin releasing hormone antagonists with minimal potency for histamine release in vitro.

In order to minimize the adverse effect of histamine release in the rat of some gonadotropin releasing hormone (GnRH) antagonists, such as [Ac-D2Nal1,D4FPhe2,DTrp3,DArg6]-GnRH, new structures with modifications at positions 1, 2, 3, 5, 6, 7, and 10 were synthesized and tested in several biological systems. In vitro: the affinity for the pituitary GnRH receptor was measured as was the ability of the analogues to inhibit GnRH-stimulated release of luteinizing hormone (LH) by dispersed anterior pituitary cells in culture and to release histamine from rat mast cells. In vivo: inhibition of ovulation in the cycling rat was determined after subcutaneous (sc) injection of the peptides at noon on the day of proestrus; the duration of action of the peptides was evaluated by measuring LH levels in the castrated male rat after sc injection of some selected analogues. [Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,D-4-p-methoxy benzoyl-2-aminobutyric acid6,DAla10]-GnRH was found to be one of the most potent analogues of this series, causing a 100% inhibition of ovulation at 5 micrograms/kg or less. Release of histamine was observed at doses 10-25 times that required for [Ac-D2Nal1,D4FPhe2,DTrp3,DArg6]-GnRH. Thus, introduction of arginine in position 5 with a hydrophobic amino acid in position 6 is compatible with high potency in several biological systems and results in compounds with lowered potency to release histamine compared to homologous peptides with tyrosine in position 5 and D-arginine in position 6.

Ovulation and gonadotropin-releasing activity of [p-LEU-6, DES-GLY NH2-10, pro-ethylamide-9] -GNRH.

The ovulation-inducing and gonadotropin-releasing activities of [d-Leu-6, des-Gly NH2-10, Pro-ethylamide-9]-GnRH (II), were evaluated in rats, rabbits, and sheep. A sc dose of 3.4 ng/100 g body wt of the analog was equal to 160 ng/100 g body wt of GnRH in causing ovulation in the diestrous rat. At these dose levels, the integrated LH release was 1.9 times greater for the analog. Both the time of increase and maximum serum concentrations of LH were delayed after injection of the analog. Oral administration of II and GnRH to the proestrous rat resulted in an ED50 for ovulation of 0.92 and 54 mug/100 g body wt,respectively. Serum levels of LH and FSH were highly variable for the various treatment groups when both releasing substances were administered orally. The intense ovulating activity of II was also evident in the estrous rabbit as indicated by an activity 31 times greater than that of GnRH. Additionally, the analog was at least 50 times more active than GnRH in releasing LH in both the mid-luteal and anestrous ewe. From our experiments with the cycling rat it appears that the intense ovulation-inducing activity of II can be accounted for by the intrinsic LH-releasing activity of the nonapeptide, rather than by a prolonged release stimulus.

PIP: Ovulation and gonadotropin-releasing activity of D-Leu6, des-Gly NH2 10, Pro-ethylamide 9 -GnRH (38715) (2) were investigated in rats, rabbits and sheep. When given to the diestrous or proestrous rat, 2 was 47 and 59 times, respectively, more effective than pGlu-His-Trp-Ser-Tyr-Gly -Leu-Arg-Pro-Gly-NG2 (GnRH) in causing ovulation. The analog increased the number of ova shed at the higher dose levels in the diestrous rat (p less than .05) but neither peptide affected the number of ova recovered from proestrus rats. Generally, serum luteinizing hormone and follicle stimulating levels were related to the dose of the peptide. The integrated luteinizing hormone (LH) release was 1.9 times greater for the analog and the time of increase and maximum serum concentrations of LH were delayed after injection of the analog. The analog was at least 50 times more active than GnRH in releasing LH in both the midluteal and anestrous ewe. It appears that the intense ovulation-inducing activity of 2 can be accounted for by the intrinsic LH-releasing activity of the nonapeptide rather than by a prolonged release stimulus.

Use of synthetic luteinizing hormone-releasing hormone in treatment of oligospermic men: a preliminary report.

Synthetic luteinizing hormone-releasing hormone (LH-RH) was administered to four normogonadotropic, oligospermic men (24 to 39 years of age) who had no endocrinologic, urologic, or associated vascular disease, to assess its possible therapeutic value in male infertility. Previous testicular biopsies of these subjects indicated alteration of spermiogenesis only. LH-RH (mean dose, 500 mug/day) was administered intramuscularly for 100 to 135 days. Each patient had at least two sperm count before starting therapy and had one every 20 to 30 days during and for two to five months after treatment. The sperm count, semen volume, sperm motility and morphology, and seminal plasma concentrations of fructose and citric acid were studied in each semen sample. In three of the four patients, urinary LH and FSH excretion and plasma testosterone levels were also measured. The sperm count increased clearly in two subjects 30 to 80 days after therapy started; the response was small in the third subject and negative in the fourth. The remaining parameters followed variable courses. Libido increased in all subjects. In the post-treatment period, the two patients who had shown the best response during treatment experienced a new and abrupt increase in the sperm count which remained well above initial values at the end of follow-up. LH-RH appears to be of value in the treatment of certain types of oligospermia, but several issues remain unsettled.

Response of luteinizing hormone and follicle-stimulating hormone to different doses of synthetic luteinizing hormone-releasing hormone by intramuscular administration in normal and oligospermic men: preliminary report.

The response of LH and FSH levels to intramuscularly administered synthetic LH-RH was studied in two healthy volunteers and three oligospermic patients. Four tests with 50, 100, 250, and 500 mug of LH-RH, respectively, were carried out on each subject at 8 am; the interval between tests was one week. The serum levels of LH and FSH were determined by radioimmunoassay (double-antibody method) before each injection, and 60, 120, 180, and 240 minutes after each injection. No differences in the basal values of either hormone were observed. In both oligospermic and normal men, maximal responses were obtained with doses between 100 and 250 mug. With 500 mug, levels decreased rather than increased. Maximal peaks occurred between 60 and 180 minutes after injection. In the two normal subjects, the responses of LH and FSH were similar. Two of the three oligospermic patients showed discordant responses. From the results, we can assume that LH-RH doses between 100 and 250 mug should be used as a basis for chronic treatment.