Effect of biphosphonates on abnormal mandibular growth of rats intoxicated with uranium.

Intoxication with uranium induces severe alterations in kidneys and in acute intoxications inhibits bone formation and bone growth. Administered at high doses, uranium leads to death, an event that can be prevented by the administration of ethane-1-hydroxy-1,1 biphosphonate (EHBP), which would presumably exert its effect via its chelating properties. Based on this information, the aim of the present study was to determine the best therapeutic method for treatment using biphosphonates to prevent mandibular growth alterations in animals that survive uranyl nitrate poisoning. Seven groups of Wistar rats weighing 14 g were used as follows: I, untreated control; II, one intraperitoneal injection (IPI) of 2 mg Kg(-1) of body weight of uranyl nitrate (238U). In groups III to VII animals were intoxicated as in Group II and in addition were given a single injection of 10 mg Kg(-1) of ethane-1-hydroxy-1, 1-biphosphonate (EHBP), or 3-amine-1, 1-hydroxypropylene-1, 1 biphosphonate (APD) as follows; Group III, IPI of EHBP given immediately after poisoning (0 h); IV, IPI of EHBP given at 24 h; V, subcutaneous injection (SCI) of EHBP at 0 h; VI, SCI of EHBP at 48 h; VII SCI of APD at 0 h. Survivors were killed on the sixtieth day. Body weight increase, survival rate, and biometric parameters of mandibular growth (Eratalay's method) were studied. Student's "t" test was used for statistical analysis. On day 60 there was only one survivor in Group II and none in Group IV. All animals in the other groups survived. Mandibular growth parameters showed the worst results in Group VII and the best in Group V for which no difference with the controls was observed. These results show that a single subcutaneous injection of EHBP given immediately after uranium poisoning, apart from preventing death, is capable of preventing undesirable alterations in mandibular growth.

Influence of bisphosphonate on the negative erythropoietic effects of uranyl nitrate.

Uranium salts, such as uranyl nitrate, induce severe renal dysfunction and tubular necrosis and a significant impairment of both oxygen dependent erythropoietin production and response to recombinant human erythropoietin. All effects are transient and reach maximal severity on the 7th day post injection. We investigated the effects of ethane 1-hydroxy-1, 1-bisphosphonate, which counteracts the inhibitory effect of uranyl nitrate on bone formation, on the negative erythropoietic effects of uranyl nitrate. Adult female Wistar rats received 1 mg/kg body weight of uranyl acetate by the i.v. route. Ethane 1-hydroxy-1,1-bisphosphonate was injected simultaneously at a dose of 7.5 mg/kg by the same route. Seven days after drug injections, plasma erythropoietin was estimated after hypobaric hypoxemia or cobalt chloride administration. The response to exogenous erythropoietin was also measured in uranyl nitrate- and/or ethane 1-hydroxy-1,1-bisphosphonate-injected rats made polycythemic by transfusion. The erythroid response was quantitated in terms of red blood cell 59iron uptake. Ethane 1-hydroxy-1, 1-bisphosphonate counteracted the effect of uranyl nitrate on oxygen-dependent and cobalt-dependent erythropoietin production, but did not correct the right shift of the dose-response relationship for exogenous erythropoietin induced by uranyl nitrate in the polycythemic rat.