Log D versus HPLC derived hydrophobicity: The development of predictive tools to aid in the rational design of bioactive peptoids.

Hydrophobicity has proven to be an extremely useful parameter in small molecule drug discovery programmes given that it can be used as a predictive tool to enable rational design. For larger molecules, including peptoids, where folding is possible, the situation is more complicated and the average hydrophobicity (as determined by RP-HPLC retention time) may not always provide an effective predictive tool for rational design. Herein, we report the first ever application of partitioning experiments to determine the log D values for a series of peptoids. By comparing log D and average hydrophobicities we highlight the potential advantage of employing the former as a predictive tool in the rational design of biologically active peptoids.

Possible indices for the detection of the administration of dihydrotestosterone to athletes.

Dihydrotestosterone (DHT) can be used by an athlete as an anabolic steroid to evade the current International Olympic Committee approved drug tests. To investigate the possibility of a method for its detection, the heptanoate ester of DHT was administered to two male subjects (150 mg i.m.). Urine samples, collected before and after the injection, were subjected to enzymatic hydrolysis and the excretion rates of DHT, 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol) and testosterone (T) were determined by radioimmunoassay. Relative changes in the excretion of DHT, 3 alpha-diol, 5 alpha-androstane-3 beta,17 beta-diol (3 beta-diol), 5 beta-androstane-3 alpha, 17 beta-diol (5 beta-diol), T and epitestosterone (17 alpha hydroxyandrost-4-en-3-one; Epi-T) were determined by gas chromatography-mass spectrometry (GC-MS). Following administration of DHT, the urinary excretion rates of DHT, 3 alpha-diol and 3 beta-diol increased when compared to those of T, Epi-T, 5 beta-diol and luteinizing hormone (LH). Concentrations of DHT in the plasma increased whereas those of T, LH and follicle stimulating hormone decreased. The changes following such modest doses of DHT suggest that these ratios of urinary hormones may be used for the detection of doping with DHT.

Human chorionic gonadotrophin and sport.

Human chorionic gonadotrophin (hCG) is a glycoprotein hormone which is produced in large amounts during pregnancy and also by certain types of tumour. The biological action of hCG is identical to that of luteinizing hormone, although the former has a much longer plasma half-life. Some male athletes use pharmaceutical preparations of hCG to stimulate testosterone production before competition and/or to prevent testicular shutdown and atrophy during and after prolonged courses of androgen administration. Testosterone administration can be detected by measuring the ratio of concentrations of testosterone to epitestosterone (T/E). An athlete is often considered to have failed a drug test if the urinary T/E ratio is greater than 6. In contrast, hCG administration stimulates the endogenous production of both testosterone and epitestosterone without increasing the urinary T/E ratio above normal values. Although the administration of hCG was banned by the International Olympic Committee (IOC) in 1987, no definitive test for hCG has been approved by the IOC. Currently, the only way of measuring small concentrations of hCG is by immunoassay, and this does not have a discriminating power as great as gas-liquid chromatography with mass-spectrometry which is necessary to satisfy IOC requirements. Extraction procedures and chromatographic steps could be introduced before using a selected immunoassay for hCG to meet these requirements.

Criteria to indicate testosterone administration.

A detection method for testosterone administration was developed using radioimmunoassay to measure the urinary ratios of testosterone (T) to epitestosterone (E) and to luteinizing hormone (LH). A comparative study of the effect on these ratios of a single intramuscular injection of testosterone heptanoate followed by stimulation with human chorionic gonadotrophin (HCG) in three normal men was undertaken. To allow immediate investigation, a commercially supplied epitestosterone antiserum was used. This study showed that both T/E and T/LH ratios could be used to detect testosterone administration, the latter also being an indicator of HCG use due to cross-reactivity with the LH antiserum. Subsequently, an epitestosterone antiserum of superior specificity was raised and used in a study to demonstrate the insignificant effect of exercise on these ratios. Finally, an intramuscular injection of a combined preparation of testosterone/epitestosterone heptanoates resulted in raised ratios of T/LH but not of T/E. This demonstrated the importance of the T/LH ratio in circumstances where the T/E ratio can be easily circumvented.

A radioimmunoassay for the metabolites of the anabolic steroid nandrolone.

A new radioimmunoassay for the major metabolites of nandrolone was developed to overcome the interference of certain contraceptive steroids in the original assay of the parent steroid. The new assay gave greater screening capability by increasing retrospective detection and the signal-to-background ratio.

Androgens.

Testosterone is synthesised mainly if not entirely by the leydig cells and secreted episodically with a slight circadian variation. Only the free, nonprotein-bound fraction of the testosterone in the circulation is biologically active. This free testosterone passes into the target cells and is taken up by specific receptors in the muscle. In some other target tissues, testosterone is first reduced to 5alpha-dihydrotestosterone which is then taken up by specific receptors in the cytoplasm and transferred to the nucleus. Anti-androgens appear to act principally by inhibiting this uptake.

Interactions of benzodiazepines with warfarin.

Administration of nitrazepam (10 mg nightly), diazepam (15 mg/day), and chlordiazepoxide (15 and 30 mg/day) had no effect on steady-state plasma warfarin concentrations, the plasma half-life of warfarin, or anticoagulant control in patients and it appears safe to prescribe these agents to patients on long-term oral anticoagulants. Urinary excretion of 6 beta-hydroxycortisol, however, increased in two out of five patients given chlordiazepoxide. In rats pretreatment with chlordiazepoxide (40 mg/kg for four days) caused stimulation of liver microsomal enzyme activity but neither diazepam nor nitrazepam had this effect.