Glutathione uptake after intraperitoneal administration and glutathione radiopharmacology after rectal administration, in mice.

Glutathione is a biologic aminothiol radioprotector. Hydrolysis of exogenous glutathione takes place in the extracellular compartment and leads to two metabolites: gamma-glutamylcysteine and glycine. In healthy mice, after an intraperitoneal administration of glutathione, all organs absorb the gamma-glutamylcysteine and the glycine with variable kinetics according to their enzymatic equipment. The rectal administration of glutathione in mice previously irradiated at the pelvic region, increases the availability of glutathione in the rectum and in other organs at a distant from the irradiation site. This contribution could be used to protect the rectum and the uterus during therapeutic irradiation.

2-Mercapto-propylamine: radiopharmacology in mice, pharmacokinetic studies in mice and in rats, mutagenicity and differential distribution between tissues and EMT6 tumour in mice.

Radiopharmacological studies conducted with 2-mercapto-propylamine (2MPA), a methylated derivative of cysteamine, indicated a good efficiency in whole body irradiated mice as observed over a period of 9 months. Its efficacy was also checked for supralethal irradiations of restricted body parts: in the brain and the rectum. The diffusion of 14C-labelled 2MPA was assessed by an autoradiographic study and measurement of its distribution in the main organs in mice. 2MPA penetrated the blood brain barrier but concentrated preferentially in the liver, kidney and skin. Fixation on plasmatic proteins was much lower in rats than in mice but urinary and faecal eliminations were of the same order for the two species. An important biliary excretion of 2MPA or its metabolites in rats combined with their lack in the faeces underlies an entero-hepatic cycle. A differential diffusion of 2MPA between normal tissues in mice and EMT6 tumours was clearly revealed by autoradiographic observations. The ability of 2MPA to trap 2,2'-diphenyl 1-picryl hydrazyl, an organic free radical, was checked by in vitro studies. Its performance indicated that 2MPA acted at least as a free radical scavenger. Ames test demonstrated that 2MPA whatever the dose employed was not a mutagenic agent. Pharmacological and pharmacokinetical observations provided a better understanding of the activity of this drug.

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.

[Radioprotective agents derived from benzonitrile]. / Agents radioprotecteurs dérivés du benzonitrile.

Benzonitriles have been evaluated as potential antiradiation agents in mice. They have an interesting radioprotective activity, in particular 3,5-dinitrobenzonitrile, one of the non-sulfur-containing radioprotective compounds which presents a consistent DRF (DRF = 1.35).

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.