An impairment of the survival of mice subjected to whole-body gamma-irradiation with a lethal dose of 10 Gy and treated with a repeated postirradiation administration of prostaglandin synthesis inhibitors (PGSls), indomcthacin or diclofenac, was observed. Morphological examination of the gastrointestinal tract and the estimation of blood loss into its lumen in animals treated with diclofenac did not show serious damage such as haemorrhages or perforation, but revealed structural injury to the intestinal mucosa indicating inflammatory processes. The lesions found arc supposed to be connected with increased intestinal permeability which leads to endotoxin escape from the gut and a subsequent increased mortality rate of irradiated animals. It may be concluded that PGSls are not suitable for the management of radiation sickness after an exposure to lethal doses of ionizing radiation
The effects of diclofenac, an inhibitor of prostaglandin synthesis, were studied on the acute radiation syndrome elicited in mice by fractional irradiation. Several haematological parameters were evaluated in mice irradiated with 5x2 Gy and 3x, 4x, or 5x3 Gy (intervals between fractions 24 h) from a 60Co gamma-ray source. The animals were treated with diclofenac either before each fraction or only once before the last fraction. The survival of mice was recorded after the irradiation regimen of 5x3 Gy followed by a "top-up" dose of 3.5 Gy given 24 h after the last radiation fraction. Statistically significant enhancement of the endogenous spleen colony formation and of leukopoiesis was found in mice treated with diclofenac repeatedly, as compared with both saline-treated irradiated controls and animals administered a single diclofenac dose, if a sublethal total radiation dose had been accumulated. However, following accumulation of a lethal total radiation dose, slightly impaired survival was observed in mice given diclofenac. It follows from the results that diclofenac is a suitable drug for enhancing leukopoiesis impaired by sublethal fractionated irradiation. Nevertheless, undesirable side effects of this drug negatively influence the survival of experimental animals following a lethal accumulated radiation dose.
We have recently demonstrated that the combined administration of dipyridamole and adenosine monophospate to mice induces radioprotective effects in terms of postirradiation haemopoietic recovery in animals irradiated with a single dose. The aim of the present experiments was to investigate the radioprotective ability of the drug combination under conditions of fractionated radiation treatment. It has been shown that administration of drugs either 15 or 60 min before each of the five daily 3-Gy doses of gamma-radiation enhances haemopoietic recovery and survival of mice exposed to an additional "top-up" dose of 3.5 Gy. Furthermore, it has been ascertained that the regimen using administration of the drugs 60 min prior to irradiation is more effective than administration of the drugs 15 min prior to irradiation. Due to the evidence that administration of the drugs 15 min prior to irradiation protects the organism mainly via mechanisms of systemic hypoxia while the pretreatment 60 min before irradiation avoids the role of hypoxia and mainly induces cell proliferation effects, our results suggest a more effective protective role of mechanisms stimulating haemopoiesis under conditions of fractionated radiation. The data may provide a basis for more rational use of radioprotection in fractionated radiation regimens.