Efficacy of trimedoxime in mice poisoned with dichlorvos, heptenophos or monocrotophos.

The aim of the study was to examine antidotal potency of trimedoxime in mice poisoned with three direct dimethoxy-substituted organophosphorus inhibitors. In order to assess the protective efficacy of trimedoxime against dichlorvos, heptenophos or monocrotophos, median effective doses and efficacy half-times were calculated. Trimedoxime (24 mg/kg intravenously) was injected 5 min. before 1.3 LD50 intravenously of poisons. Activities of brain, diaphragmal and erythrocyte acetylcholinesterase, as well as of plasma carboxylesterases were determined at different time intervals (10, 40 and 60 min.) after administration of the antidotes. Protective effect of trimedoxime decreased according to the following order: monocrotophos > heptenophos > dichlorvos. Administration of the oxime produced a significant reactivation of central and peripheral acetylcholinesterase inhibited with dichlorvos and heptenophos, with the exception of erythrocyte acetylcholinesterase inhibited by heptenophos. Surprisingly, trimedoxime did not induce reactivation of monocrotophos-inhibited acetylcholinesterase in any of the tissues tested. These organophosphorus compounds produced a significant inhibition of plasma carboxylesterase activity, while administration of trimedoxime led to regeneration of the enzyme activity. The same dose of trimedoxime assured survival of experimental animals poisoned by all three organophosphorus compounds, although the biochemical findings were quite different.

[The role of the blockade of separate subtypes of muscarinic receptors in realizing the antidotal effect of m-cholinolytics in dimethyl dichlorovinyl phosphate poisoning]. / Rol' blokady otdel'nykh podstipov muskarinovykh retseptorov v osushchestvlenii antidotnogo éffekta m-kholinolitikov pri otravlenii dimetildikhklorvinilfosfatom.

On comparison of the values of receptor selectivity of a series of m-cholinoblockers in vitro with those of the selectivity of their effect in in vivo experiments, pharmacological tests characterizing the interaction of ligands with m1, m2, and m3-subtypes of muscarine receptors were determined. Analysis of the protective effect of m-cholinoblockers in poisoning with organophosphorus compounds (OPC) depending on their activity in the determined tests showed that blocking of the m1-cholinoceptors is responsible for the antidotal effect of the antagonists, whereas block ing of m2-cholinoceptors prevents it. It is suggested that the negative effect of m2-cholinoceptor blocking on the protective effect of the drugs in OPC poisoning is mediate d by increased excretion of the mediator into the synaptic cleft as a result of interaction of the ligands with the presynaptic autochol inoceptors.

[The effect of antidote preparations on the immune reactions in acute dimethyl dichlorovinyl phosphate poisoning]. / Vliianie antidotnykh preparatov na immunnye reaktsii pri ostroi intoksikatsii dimetildikhlorvinilfosfatom.

Experiments on CBA mice established that acute intoxication with dimethylchlorovinyl phosphate given in a single LD50 of 1.0 increased mice splenic colony-forming cells, decreased thymic T cells, delayed hypersensitivity, natural and antibody-dependent cellular cytotoxicities, sheep splenic red blood cells, thymus-independent Vi antigen antibody production. The antidote therapy with atropine (20 mg/kg) did not stop the main manifestations of posttoxication immunodeficiency and enhanced the suppression of a humoral immune response to sheep red blood cells. Dipyroxim (15 mg/kg) diminished manifestations of postintoxication immunodeficiency.

[The mechanisms of the antidotal action of bispyridinium oximes when used in combination with M-cholinolytics in dimethyl dichlorovinyl phosphate poisoning]. / Mekhanizmy antidotnogo deistviia bispiridinievykh oksimov v usloviiakh ikh kombinirivannogo primeneniia s M-kholinolitikami pri otravlenii dimetildikhlorvinilfosfatom.

The results of in vitro and in vivo experiments were used to compare the capacity of bispiridinium oximes to modulate the presynaptic secretion of acetylcholine and to demonstrate the protective activity against organophosphate intoxication during combined application with various M-cholinolytics. It is suggested that bispiridinium oximes combined with M-cholinolytics can play a corrective role in eliminating the adverse presynaptic effect of a cholinolytic, thus lowering the severity of intoxication.

[The selectivity and protective properties of m-cholinolytics in dichlorodivinylphosphate poisoning]. / Selektivnost' i zashchitnye svoistva m-kholinolitikov pri otravlenii dikhlordivinilfosfatom.

The activity of selective and nonselective muscarinic antagonists was examined in different experimental models. According to the results obtained, the protective effect of muscarinic antagonists during acute dichlordivinyl phosphate (DDVP) poisoning depends on the M1-subtype cholinoreceptor blockade. Meanwhile the efficiency of muscarinic antagonists in inhibition of tremor reaction induced by arecoline administration is associated with interaction between the drugs and the M2-subtype. The blocking of presynaptic M2-cholinoreceptors is likely to cause the decrease of protective potency of muscarinic antagonists in acute DDVP poisoning.

[The possible role of presynaptic effects in realizing the protective action of M-cholinolytics in dimethyl dichlorovinyl phosphate poisoning]. / Vozmozhnaia rol' presinapticheskikh éffektov v osushchestvlenii zashchitnogo deistviia M-kholinolitikov pri otravlenii dimetildikhlorvinilfosfatom.

Under the conditions of the constancy of the postsynaptic effect of two M-cholinolytics atropine and amizil the relationship between the presynaptic and protective effects of the drugs in DDVF intoxication was studied. The indication of the level of the postsynaptic activity was the suppression by the cholinolytics of tremor reaction in rats induced by the action of arecoline. The presynaptic effect of the drugs was judged by the charge of the "bound" acetylcholine content in the brains of the animals. It was found that when administered in the equieffective by the choline-blocking activity doses, atropine to a greater extent reduced the content of the "bound" acetylcholine which was increased due to the action of DDVF and at the same time it possessed the less pronounced protective activity in intoxication with DDVF than amizil. It is supposed that the removal of the presynaptic suppression of acetylcholine release due to the anticholinesterase substance action deteriorates the prognosis of the course of DDVF intoxication.

Observations on the accidental poisoning of birds by organophosphate insecticides and other toxic substances.

Details of cases involving the inadvertent exposure of birds to eight toxic substances are recorded. The organophosphate insecticides dichlorvos, diazinon and malathion produced respiratory symptoms which in the former and latter cases were initially thought to be caused by infectious disease. Birds which consumed feed containing fenitrothion showed nervous signs before death. On three separate occasions feral starlings (Sternus vulgaris) were found dead and their gizzard contents contained mevinphos. The rodenticide warfarin was associated with petechial haemorrhages in the skeletal muscles and on the serosal surfaces of one hen. Cyanogenic glycosides from Eucalyptus cladocalyx were responsible for the sudden deaths of ducks and guinea fowl. 'Ornamental dough' containing sodium chloride was fed to birds which were deprived of water and they showed diarrhoea and nervous disorders before death.

[Experimental data on a new cholinesterase reactivator from the group of thiohydroximic esters]. / Eksperimental'nye dannye o novom reaktivatore kholinésterazy iz gruppy tiogidroksimovykh éfirov

Experimental data on the effectiveness of p-brombenzothiohydroximic S-diethylaminoethylate (diethyxime) -a new cholinesterase reactivator - are presented. The diethyximetoxicity with its single and multiple administration to animals was studied. The drug is shown to display a marked antidotal action when used in a dosage range of 490-10 mg/kg. Diethyxime is shown capable of restoring the activity of cholinesterase inhibited by dimethyldichlorovenylphosphate, of preventing the neuro-muscular block of the impulses conduction and of normalizing the function of the cardiovascular system. The drug is less toxic than is presently employed reactivator diproxime and it does not produce any side-effects on a number of organs and systems of the organism with its multiple administration to worm-blooded animals.