Quantitative evaluation of virilizing activity of steroids by measuring morphological changes in uro-genital region of rats.
A new technique to measure the uro-genital parameters such as the lengths of urovaginal septum, corpora cavernosa and anogenital distance on the sagittal sections of the pelvic region of female fetus of rat under microscope equipped with a micrometer was developed. In the examination of 180 normal female fetuses on the 21st day of gestation, relationships were observed between the fetal body weight and the length of urovaginal septum as well as anogenital distance, but not on the length of corpora cavernosa. Following maternal subcutaneous administration of various doses of 17alpha-methyltestosterone between the 17th and 20th day of gestation, dose-dependent abridgment in urovaginal septum length and extensions in corpora cavernosa length and anogenital distance were observed in female fetus on the 21st day's examination. When these three parametars were calculated on the relative value to the fetal body weight, however, linear relationships against log-dose were observed in all parameters. Among these three parameters the abridgment in urovaginal septum was shown to be the most sensitive. A quantitative assay of virilizing activity of steroids in female fetuses was examined on rats treated subcutaneously with 17alpha-methyltestosterone and norethandrolone. Linear regressions against the log-doses of both steroids were demonstrated in urovaginal septum length, and parallelism was noted between both regression lines. The relative potency of norethandrolone to 17alpha-methyltestosterone calculated on urovaginal septum length was 0.354 with fiducial limits of 0.293-0.44l, and it was suggested that the virilizing activities of steroids can be evaluated quantitatively. (+info
Catecholamine reuptake inhibition causes weight loss by increasing locomotor activity and thermogenesis.
Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA+NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA+NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA+NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA+NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA+NE reuptake (with GBR+NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity. (+info
Rate-dependent effects of monoamine releasers on intracranial self-stimulation in rats: implications for abuse liability assessment.
Effects of norethandrolone on the transport and peripheral metabolism of thyroxine in patients lacking thyroxine-binding globulin. Observations on the physiological role of thyroxine-binding prealbumin.
Studies of the effect of norethandrolone on the transport and peripheral metabolism of thyroxine were carried out in four patients lacking thyroxine-binding globulin. Before norethandrolone administration, values for serum protein-bound iodine (PBI) were decreased (1.8 +/-0.5 mug/100 ml) and the proportion of free thyroxine increased (0.036 +/-0.008%). As a result, values for the absolute concentration of free thyroxine iodine were at the lower end of the normal range (0.63 +/-0.12 mmug/100 ml). During the control thyroxine-turnover study, the thyroxine distribution space was strikingly increased (18.2 +/-7.9 liters) and the fractional rate of thyroxine turnover moderately increased (17.1 +/-11.3%/day), as compared to the expected mean values for normal subjects. Therefore, calculated values for the daily rate of thyroxine clearance were increased even more, ranging between 255 and 500% of normal values. However, owing to the low PBI in these patients, the daily disposal of thyroxine iodine was similar to that expected in normals on the basis of age and weight. During the administration of norethandrolone, the thyroxine-binding capacity of the thyroxine-binding prealbumin increased strikingly in all patients, values averaging 162% of those found during the control period. This increase was associated with a highly significant increase in PBI (133% of control values) and a small but significant decrease in the proportion of free thyroxine, resulting in no significant change in the absolute concentration of free thyroxine iodine. In all four patients, administration of norethandrolone was associated with a pronounced decrease in the thyroxine distribution space to values which averaged 69% of those found during the control period. Values for the fractional rate of thyroxine turnover increased slightly. As a result, thyroxine-clearance rate decreased in all patients. Owing to the reciprocal changes in clearance rate and PBI, no significant change in total daily thyroxine disposal was observed. The present studies reveal that when the thyroxine-binding prealbumin is increased in patients lacking thyroxine-binding globulin, several indices of peripheral thyroxine transport and metabolism are altered. However, these changes were small, even in the absence of thyroxine-binding globulin. It is suggested, therefore, that the effect of changes in thyroxine-binding prealbumin would be even smaller in individuals in whom thyroxine-binding globulin is present. (+info
Chronic cholangitides: aetiology, diagnosis, and treatment.
A number of different chronic diseases affect the intrahepatic bile radicles or cholangioles. They include primary and secondary sclerosing cholangitis, primary biliary cirrhosis, chronic cholestatic drug jaundice, atresia, and carcinoma. Aetiological factors include infection, immunological changes, hormones, and congenital defects.Patients with chronic cholestasis have decreased bile salts in the intestinal contents and suffer from a bile salt deficiency syndrome. Failure to absorb dietary fat is managed by a low-fat diet and by medium-chain trigly-cerides which are absorbed in the absence of intestinal bile salts. Fat-soluble vitamin deficiencies are prevented by parenteral vitamins A, D, and K(1). Calcium absorption is defective, and improvement may follow intramuscular vitamin D, medium-chain triglycerides, a low-fat diet, and oral calcium supplements.In partial intestinal bile salt deficiency the anionic bile-salt-chelating resin cholestyramine controls pruritus though steatorrhoea increases. Pruritus associated with total lack of intestinal bile salts is managed by methyl-testosterone or norethandrolone, though the jaundice increases. (+info
Evidence for microfilament involvement in norethandrolone-induced intrahepatic cholestasis.
An experimental study of norethandrolone (NED)-induced intrahepatic cholestasis was made. NED was infused via a portal vein catheter into rat liver in vivo, and measurements were made of bile flow. Liver specimens were taken at intervals for light microscopy and for transmission and scanning electron microscopy. Bile-canalicular-rich membrane fractions were prepared. The effects of NED were also examined in isolated hepatocytes in suspension culture. NED infusion induced total cholestasis by 3 hours. Canalicular alterations commonly associated with cholestasis were found in in vivo infused liver and in isolated hepatocytes. Pericanalicular microfilament changes were also noted in both, with loss of filament structure and replacement by a granular zone. In isolated canalicular membrane fractions prepared from NED-treated animals, the normal investment of pericanalicular filaments was no longer present. Loss of the bile canalicular ruthenium red surface coat was also noted. In view of the identical findings in isolated hepatocytes and in in vivo liver, obstruction and mechanical factors can be excluded as possible causes. The results raise the possibility that the mechanism of NED-induced cholestasis may be related to disaggregation and/or detachment of microfilaments from the canalicular membranes. (+info
International cooperation in analytical chemistry: experience of antidoping control at the XI Pan American Games.
We describe the experience of the international cooperation carried out for antidoping control at the XI Pan American Games. A temporary accreditation was granted by the International Olympic Committee to the accredited laboratory of Barcelona (Spain) to set up a Doping Control Laboratory in Havana. Two other laboratories from Mexico and Cuba contributed personnel, materials, and instrumentation. The main issues associated with the preparation and organization of the project are described. During 16 days, 741 urine samples were tested for stimulants, narcotics, anabolic steroids, beta-blockers, diuretics, cannabinoids, local anesthetics, and human chorionic gonadotropin by gas-liquid chromatography, gas chromatography/mass spectrometry, high-performance liquid chromatography, and immunoassay techniques. Analytical methodologies, quality-control strategies, and the main results are reported. (+info