Relationship between metabolism and radioprotective activity of 2-phenylthiazolidine and its m-bromo derivative.

Molecular biotransformation of 2-phenylthiazolidine (1) and its m-bromo derivative (2) in the mouse is followed by autoradiographic studies and assessed by analysis of urinary metabolites. Cysteamine (4) is one of the metabolites of compounds 1 and 2. Radioprotective activity and efficacy over a period of time of 1, 2, and 4 correlate closely with distribution and metabolism.

[Radiocompetitive assay of sulfamido-3-chloro-4-benzoic acid with carbonic anhydrase as binding reagent (author's transl)]. / Dosage d'un sulfamide diurétique, l'Acide sulfamido-3-chloro-4-benzoique, par radiocompetition avec l'anhydrase carbonique.

The control of patients treated by diuretic sulfonamides can be carried out by a radiocompetitive assay using their binding properties to carbonic anhydrase (CA). In this paper we have studied the assay of sulfamido-3-chloro-4-benzoic acid (SD3) using dialysis equilibrium as separation procedure. With (CA) 2 X 10(-6) M and 14C-SD3 0.5 X 10(-6) M (specific activity: 2 muCi/mg), can be detected 0.5 X 10(-6) M of (SD3) in the assay medium. 6.5 mg protein present in serum lower the assay sensitivity twenty times, owing to an elevated value of the affinity constant, Ka, of albumin-(SD3) complex (10(3) mol-1). On the other hand, the molecules with sulfamidobenzoic group cannot be differentiated in this procedure.

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.

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.

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.

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.

Absorption and elimination of (14C) hesperidin methylchalcone in the rat.

Hesperidin methylchalcone resorption and excretion were studied in rats, using 14C-labelling. The level of radioactivity in the blood showed a peak 1-2 hours after oral administration of the labelled compound, at a dose of 10 mg/kg body weight. The blood kinetics pattern suggested an entero-hepatic cycle, which was demonstrated by i.v. administration of the compound at the same dose. The blood profiles for both administration routes, demonstrated that the bioavailability of the active principle was good. Urinary excretion was lower than faecal excretion after oral ingestion, and both were comparable after administration via the i.v. route. Moreover, excretion mainly occurred within the first 24 hours following administration. When hesperidin methylchalcone was given in a therapeutic, pharmaceutical formulation, its bioavailability was greatly improved. (This was not due to the alcoholic ingredient in the formula).

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.

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.

[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.