Radioprotection, pharmacokinetic and behavioural studies in mouse implanted with biodegradable drug (amifostine) pellets.

PURPOSE: We evaluated the use of a subcutaneously (s.c.) implantable, biodegradable pellet as a drug delivery system for the radioprotector amifostine. MATERIALS AND METHODS: Mice were implanted s.c. with either the custom-made biodegradable amifostine drug pellet or the placebo pellet without amifostine, exposed to cobalt-60 gamma-radiation (bilateral, 1 Gy min(-1), 7-16 Gy), and the 30-day survival rate was monitored. The non-irradiated mouse was used for pharmacokinetic and behavioural tests. RESULTS: Significant radioprotection (85-95% survival) at 10 Gy was observed in the three-amifostine pellet implanted group 3-5 h after implantation. LD50/30 was 7.97, 8.74 and 16.64 Gy for the control, three-placebo pellet (dose reduction factor, DRF=1.10, p<0.01), and three-amifostine pellet (DRF=1.79, p<0.01) groups respectively in mouse exposed to radiation 2h after implantation. Radioprotection at 12 Gy was observed up to 4h after s.c. amifostine administration and up to 3h after implantation. Pharmacokinetic data revealed that the three-amifostine pellet group had sustained blood WR-1065 levels at 2 h after implantation, in contrast to the reported sharp peak at 30 min for s.c. administration. Although locomotor activity was significantly reduced (p<0.01) in the amifostine pellet group, the onset of the locomotor decrement was delayed as compared with groups that received 400 and 750 mg kg(-1) s.c. amifostine. CONCLUSIONS: Amifostine in biodegradable implant was effective. The radioprotection observed was comparable between conventional s.c. administration of the drug and implantation. Pharmacokinetic data and locomotor activity suggest that the implantation was beneficial though radioprotection data warrants formulation improvements in implants.

Chromatographic and mass spectral analysis of the radioprotector and chemoprotector S-3-(3-methylaminopropylamino)propanethiol (WR-151326) and its symmetrical disulfide (WR-25595501).

Metabolically active forms of the radioprotective and chemoprotective drug S-3-(3-methylaminopropylamino)propylphosphorothioic acid (WR-151327) are S-3-(3-methylaminopropylamino)propanethiol (WR-151326) and its symmetrical disulfide (WR-25595501). This paper describes applications of sensitive and specific procedures such as capillary column gas chromatography with flame ionization detection, electron impact mass spectrometry and liquid chromatography with electrochemical detection for structural characterization and analysis of the active forms of WR-151327. These chromatographic procedures provide reproducible linear calibration graphs for a relatively wide range of concentrations of the active forms of WR-151327. The described procedures will further facilitate in vivo and in vitro investigations of chemoprotective and radioprotective properties of WR-151327 and its active metabolites.

Ontogeny of ovarian glutathione and sensitivity to primordial oocyte destruction by cyclophosphamide.

Ovarian reduced glutathione concentration (microgram/mg wet ovarian weight) develops from levels of less than 0.2 microgram/mg in newborn Osborn Mendel rats to plateau at 0.7 microgram/mg between the ages of 3-7 weeks of age, finally reaching mature levels of approximately 1.0 microgram/mg between 7-8 weeks of age. Ovarian reduced glutathione concentration matures somewhat faster in Sprague Dawley rats, reaching mature levels of 1.0 microgram/mg between 4-6 weeks of age. The development of ovarian glutathione from immature (less than 0.2 microgram/mg) to mature levels (1.0 microgram/mg) was also observed over similar developmental time spans in DBA/2N and C57BL/6N mice. The sensitivity of primordial oocytes to destruction by cyclophosphamide in C57BL/6N mice was considerably different at 4 and 6 weeks of age. The ED50 for primordial oocyte destruction at 4 weeks of age in C57BL/6N mice was 140 mg/kg while at 6 weeks of age the ED50 was 260 mg/kg. The increase in ovarian reduced glutathione with age and the increasing resistance to primordial oocyte destruction over the same time period are consistent with the hypothesis that glutathione plays a major role in the modulation of primordial oocyte destruction.

Occupational Health/Safety Program Accreditation Commission.

This presents a brief history of programs for accrediting occupational health activities with discussion of weaknesses and strengths. The relatively short life of the Occupational Health/Safety Program Accreditation Commission is reviewed with emphasis on its charge, goals and accomplishments. The mechanisms for accreditating Occupational Health and Safety Programs is described and some reasons for seeking accreditation are given.