The radioprotective power of 2-isopropyl 5-methyl 1,3-thiazolane.

The adequate conditions of radioprotective treatment with 2-isopropyl 5-methyl 1,3-thiazolane were established for mice. Protection is maximum with a unique intraperitoneal injection of LD 50/2, 3 hours prior to the irradiation. The rate of radiation dose reduction is therefore 1.75. Survival rate of whole body irradiated mice with supralethal doses were determined for 11 months. The long term survival of the animals fully proved good prevention of radio-induced damages. In vitro pharmacological studies show the ability of the major metabolite of the compound to trap organic radicals.

Mice's brain radioprotection: comparative efficacy of a series of aminothiols and aminothiol precursors.

A serie of radioprotective aminothiols was checked upon irradiation of the mice's brain. Cysteamine protects efficiently the brain as soon as 15 minutes after its administration. Among the tested aminothiols, it was the most effective compound. 2-isopropyl 1,3-thiazolane, rapidly hydrolysed, delivers a large amount of cysteamine in the brain and was nearly as potent as exogenous cysteamine. The other thiazolanes which delivered only progressively cysteamine or 2-mercaptopropylamine during a long period of time showed lesser efficacy. WR 2721 which did not penetrate the brain exhibited only a feeble radioprotection. The imperviousness to straight active aminothiols may be compensated by the diffusion of their precursors across the blood brain barrier and by their speed of hydrolysis, yielding active aminothiols during a short period of time between their administration and the irradiation.

Mice's rectum radioprotection: comparative efficacy of a series of aminothiols and aminothiol precursors.

In mice, in a test of rectal gamma irradiation, cysteamine and cysteine are poor radioprotectors relative to thiazolanes or WR 2721. Among the tested prodrugs, 2-isopropyl 1,3-thiazolane was nearly as efficient as WR 2721 as soon as 15 minutes after its administration. The guarantee of radioprotection is the effective presence of the active aminothiols in the intracellular room during the irradiation. In this study, enterocytes of the rectal mucous membrane were not sufficiently permeable to exogenous cysteine or cysteamine. The cell imperviousness to these straight active aminothiols was compensated by the diffusion of their precursors across the membrane.

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in athletes. Blood sampling and doping control.

1. The pharmacokinetics of recombinant human erythropoietin (rHuEpo) were initially determined in two healthy volunteers after a single subcutaneous dose (50 u kg-1). Twenty subjects then received repeated subcutaneous administrations of high dose (200 u kg-1) rHuEpo and 10 subjects received placebo. An immunoradiometric assay was used to measure the concentrations of erythropoietin (Epo) in serum and urine. 2. Serum Epo concentration-time profiles were best described by a one-compartment open model with zero-order input. The mean elimination half-life (+/- s.d.) was 42.0 +/- 34.2 h. Clearance, uncorrected for bioavailability, was 0.05 +/- 0.011 h-1 kg-1. Erythropoietin concentrations returned to normal values in serum and urine, 7 and 4 days after the last administration, respectively. 3. The recombinant hormone was well tolerated. Significant changes in reticulocytes and red blood cells, haemoglobin concentrations and haematocrit were observed after administration of rHuEpo. In the control group, these parameters remained unchanged. 4. The change in reticulocytes was used as an index of the therapeutic effect of rHuEpo. The concentration-effect relationship was best described by an exponential model. 5. These data show the limitations of the measurement of Epo concentrations in blood and urine samples, collected in athletes during competition, for antidoping control. Epo doping can be detected only during or within 4 to 7 days of ending a course of rHuEpo.

Effects of benzodiazepine during a Wingate test: interaction with caffeine.

To assess the effects of benzodiazepine alone and associated with caffeine on performance and substrate responses during supramaximal exercise, seven healthy volunteers performed the Wingate test after ingestion of placebo (Pla), benzodiazepine alone, i.e., 1 mg of lorazepam (Bz), and benzodiazepine followed by 250 mg of caffeine (Bz-Caf). Peak power (PP), mean power (MP), and percentage of power decrease (%PD) were determined, and substrate responses were estimated by blood lactate and catecholamine concentrations. Four hours after Bz ingestion, there was a significant decrease in PP (PPBz: 626 +/- 72 vs PPPla: 669 +/- 78 W), maximal blood lactate (La max) (La maxBz: 9.5 +/- 1.5 vs La maxPla: 12.4 +/- 1.8 mmol.l-1), and end-exercise epinephrine (E) (EBz: 339 +/- 113 vs EPla: 672 +/- 247 ng.l-1). No other changes were noted. Caffeine ingestion 1 h before the test (Bz-Caf) corrected the decrease in La max (La maxBz-Caf: 11.5 +/- 1.4 mmol.l-1) and E (EBz-Caf: 573 +/- 190 ng.l-1) but was unable to prevent the impairment of performance (PPBz-Caf: 625 +/- 68 W vs PPPla). Moderate benzodiazepine intake significantly altered performance and substrate responses during supramaximal exercise. Moderate caffeine intake antagonized the metabolic but not the performance effects of 1 mg of lorazepam.

Determination of urinary testosterone and epitestosterone during pubertal development: a cross-sectional study in 141 normal male subjects.

OBJECTIVES: Exogenous testosterone administration is classically detected by measuring the ratio of testosterone to epitestosterone in urine. Athletes are considered to be positive for drug abuse if the urinary testosterone to epitestosterone ratio is greater than 6. We aimed at investigating the urinary excretion of testosterone and epitestosterone during pubertal development. DESIGN: We performed a cross-sectional study of 141 normal male subjects between ages 8 and 26 years. PATIENTS: We studied 141 subjects: 32 at stage 1 of Tanner, 27 at stage 2, 30 at stage 3, 25 at stage 4 and 27 at stage 5. MEASUREMENTS: Subjects performed a 24-hour urine collection. Urinary testosterone and epitestosterone were measured by gas chromatography-mass spectrometry with selected ion monitoring. RESULTS: Urinary testosterone was 20.5 +/- 1.7 nmol/24 h (mean +/- SEM) at stage 1, 49 +/- 2.9 at stage 2, 98.8 +/- 3.4 at stage 3, 371.8 +/- 21.8 at stage 4 and 403.4 +/- 16.1 nmol/24h at stage 5. Urinary epitestosterone was 13.1 +/- 1.5 nmol/24h at stage 1, 29.1 +/- 3.3 at stage 2, 48.3 +/- 3.7 at stage 3, 156.3 +/- 14.8 at stage 4 and 221.1 +/- 18.6 nmol/24h at stage 5. The urinary excretions of both steroids increased significantly during puberty and were highly correlated with chronological age (P < 0.001). Comparison of the correlation slopes (P < 0.001) showed that the urinary profiles of testosterone and epitestosterone are not parallel during pubertal development. Two subjects presented a testosterone to epitestosterone ratio above 6, corresponding to a low urinary concentration of epitestosterone, without pathological explanation. CONCLUSION: Testosterone and epitestosterone do not present the same urinary profiles throughout puberty. Marked increases of the testosterone to epitestosterone ratio can be observed at this period and may interfere with doping tests.

[Study of urinary excretion of testosterone and epitestosterone glucuronides in children and adolescents]. / Etude de l'excrétion urinaire des glucuronides de testostérone et d'épitestostérone chez l'enfant et l'adolescent.

Urinary testosterone to epitestosterone ratio (T/E) is used as a marker for illegal exogenous testosterone use. Mean value in healthy adults is 1.13 and 6 is the upper limit of the accepted range. Urinary excretion of these two steroids were studied in 57 children and teenagers at different pubertal stages, using gas chromatography coupled with mass spectrometry with selective ion detection. Urinary excretion of testosterone and epitestosterone increased significantly during puberty. Mean T/E ratio remained fairly constant but interindividual variations were marked and in one subject the T/E ratio exceeded 6. These data suggest that this test may yield false-positive results in adolescents.

Effects of caffeine ingestion on performance and anaerobic metabolism during the Wingate Test.

In order to determine the effects of caffeine ingestion on performance and metabolic responses during supramaximal exercise, six healthy volunteers performed the Wingate Anaerobic Test twice. Sixty min before each trial, while in a fasting state, they took capsules containing either caffeine (5 mg/kg) or a placebo, according to a single blind and randomized procedure. Caffeine administration did not significantly change either maximal anaerobic capacity (AC) or power (AP) and power decrease (PD). It did, however, induce significant (p less than 0.05) increases in both catecholamine and blood lactate levels as compared to values obtained after placebo administration. Moreover, maximal blood lactate occurred earlier (p less than 0.05), and lactate output seemed to be greater with caffeine (p less than 0.01). There was a strong correlation, both with and without caffeine, between epinephrine and lactate levels (r = 0.81) and between both AP and AC and lactate levels. These data suggest that caffeine, essentially via epinephrine, modifies glycolytic metabolism but fails to improve performance during the Wingate Anaerobic Test in nonspecifically trained subjects.

[Influence of brief high intensity exercise on plasma adrenaline and noradrenaline levels]. / Influence d'un exercise bref et intense sur les concentrations plasmatiques d'adrénaline et de noradrénaline.

This study was conducted to determine catecholamine response to maximal intensity exercise of a few seconds' duration. To do this, epinephrine (E) and norepinephrine (NE) levels were measured during Force-Velocity Test. Blood samples were taken at the end of each sprint. Compared to rest (E0 = 77.4 +/- 3.8 pg/ml), the E concentration significantly increased after the first sprint (E2 = 109.8 +/- 14.7 pg/ml) and after the last one (E8 = 126.9 +/- 19.4 pg/ml) which correspond to the exhaustion state of our subjects. NE concentration doubled after the first sprint (NE2 = 589.1 +/- 94.7 pg/ml) and remained at this level until the end of the test. E2 seems to have been a stress reaction to an unfamiliar test. E8 may represent the "exercise plus exhaustion" stimulus on the stimulation of the adrenal gland (AG). This would suggest that stimulus intensity plays a role even when duration is very brief, although the time factor seems to limit the response of AG. The evolution of NE suggest that the brief duration of the sprints may limit the adatation response of NE to energy demands.

Effects of moderate exercise on the pharmacokinetics of caffeine.

The effect of moderate exercise on the kinetics of caffeine in 12 healthy volunteers-6 heavy coffee drinkers (HD) and 6 light coffee drinkers (LD) has been studied. Kinetics at Rest was measured first (R): the subjects remained at rest for 8 h after a single 250 mg dose of caffeine. One week later, the Exercise Kinetics (E) was measured under the same conditions, but with the subjects performing moderate exercise (30% of VO2 max) during the first hour of the study. Exercise raised the maximal plasma caffeine concentrations (R: 7.28: E: 10.45) and reduced both the half-life (R 3.99 h: E 2.29 h) and the volume of distribution (R 37 l: E 20.9 l). Both during exercise and at rest. HD had a greater half-life elimination and volume of distribution than LD. The results suggest potentiation of the effects of caffeine during exercise and an increase in its distribution due to regular heavy coffee intake.

[Effect of acute or chronic administration of caffeine on performance and on catecholamines during maximal cycle ergometer exercise]. / Influence de la prise aiguë ou chronique de caféine sur la performance et les catécholamines au cours d'un exercice maximal.

Seven men were studied during maximal cycle ergometer exercise, to assess the effects of a single or continuous caffeine ingestion on performance and catecholamine secretion. A single blind and randomised procedure was followed with three trials at 100 +/- 5% VO2 max until exhaustion. The first trial was performed after a single administration of 250 mg of caffeine (a). The second and third trials were performed after a treatment of 5 days with 250 mg caffeine per day (continuous = c) and after placebo (p). a and c caffeine administration, 60 min prior to exercise, did not significantly change the time to exhaustion, but increased the plasma levels of both epinephrine (E) and norepinephrine (NE) at exhaustion (p less than 0.05). Single ingestion of caffeine accelerated the elimination of E and NE and increased the maximal blood lactic acid. These data suggest that both single and continuous administration of caffeine do not enhance performance during maximal cycle ergometer exercise, but do increase the exercise response of catecholamine. Only a single administration modifies the blood lactate accumulation.

Comparison of the metabolism and pharmacokinetics of metbufen and itanoxone and their analogues in rats.

Metbufen, II, itanoxone, I, and two other derivatives of gamma-aryl-gamma-keto-substituted butyric acids labelled with 14C in their carbonyl group were synthesized for a metabolic investigation in rats. Profound changes in pharmacokinetic parameters, most specifically in the distribution, elimination, and metabolic pathways, were induced by substitution in the aromatic nucleus or changes in saturation of the aliphatic chain. The metabolites isolated from plasma and urine were identified by gas chromatography and mass spectrometry, by comparison with chemical controls, revealing the processes of metabolism of these structural analogues. This difference in metabolism further understanding of the diversity of biological effects inherent in these compounds.

Brain penetration of orally administered sodium pyroglutamate.

The absorption and brain penetration of [3H]pyroglutamate was determined after oral administration to rats. Gas-liquid chromatography of the methylated derivatives followed by mass fragmentometry was used to analyse the plasma and brain levels of pyroglutamate. [3H]Pyroglutamate was separated from other labelled compounds by thin layer chromatography. The administration of 500 mg kg-1 [3H]pyroglutamate resulted in a 30-fold increase in plasma levels and a doubling in the brain levels. Over 60% of the cerebral radioactivity was present as [3H]pyroglutamate demonstrating that pyroglutamate is not only well absorbed but also penetrates in significant amounts into the brain.

Pharmacokinetic and metabolic study of itanoxone in the crab Pachygrapsus marmoratus (Decapoda, Brachyura): comparative study with clofibric acid.

The LD50 of itanoxone injected i.v. in the crab Pachygrapsus marmoratus is 144 mg/kg. Hypolipidemic drug distribution is distinct according to organ and sex. The fixation power of muscle is comparatively low. Ovary radioactivity is higher than in the testicles. Itanoxone storage is large in the hepatopancreas. Metabolism, increasing over time, is not noticeably different according to sex. Two metabolites, chlorobiphenylcarboxylic acid and chlorobiphenylacetic acid, found in crab, are also identified in rat and man. The pharmacokinetic and metabolic study of itanoxone and clofibric acid in the crab shows a difference between the two drugs. Itanoxone metabolism and fixation is higher than clofibric acid.

Toxicokinetic and metabolic study of dimethylnitrosamine and diethylnitrosamine in crayfish Austropotamobius pallipes.

The acute toxicities of dimethylnitrosamine and diethylnitrosamine have been evaluated in adult male crayfish Austropotamobius pallipes; LD50 values are 2250 mg/kg and 230 mg/kg, respectively. Toxicokinetic studies of 14C-dimethylnitrosamine and 14C-diethylnitrosamine in crayfish, administered by i.v. injection, show high concentrations of 14C in abdominal muscle and hepatopancreas. Excretion is greater with dimethylnitrosamine, and retention in the tissues, especially the hepatopancreas, is greater with diethylnitrosamine. Metabolites identified in excreta include monomethylnitrosamine from dimethylnitrosamine, and hydroxyethyl-ethyl-, bishydroxyethyl- and carboxyethyl-ethylnitrosamine from diethylnitrosamine.

Involvement of the N4-oxide group in the phototoxicity of chlordiazepoxide in the rat.

To verify whether or not N4-oxide function is involved in the phototoxicity of chlordiazepoxide (CDZ, Librium), photopharmacology of reduced chlordiazepoxide (RCDZ) lacking the N4-oxide group was carried out and compared to that of CDZ. From the distribution of the 2 compounds in the skin and their UV-spectra in the wavelength region of the UV lamp, doses were calculated to allow the comparison of the photopharmacological effects. Contrary to what has been described for CDZ, no difference was found for RCDZ between irradiated and non-irradiated rats. The discussion leads to the conclusion that the N4-oxide group is responsible for systemic effects reported for phototoxic CDZ.

Percutaneous absorption of 5-iodo-2' deoxycytidine in the hairless rat and in man.

A study of percutaneous absorption of the anti-herpetic agent 5-iodo-2' deoxycytidine (IDC) was performed in vitro on the rat and on man and in vivo on the rat, using samples of normal skin and skin stripped of its stratum corneum. With normal skin, absorption was 1.84 cm.h1 10(-4) for the rat and 0.33 cm.h1 10(-4) for human skin; when the stratum corneum was absent, absorption was approximately 15 times higher. The results are discussed in terms of efficacy and toxicity of the drug.