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Effect of intravenous thiamine on pralidoxime kinetics.

Subjects were given pralidoxime chloride (5 mg/kg, intravenously) alone and again while they were receiving an infusion of thiamine hydrochloride. After the addition of thiamine: (1) overall, the urinary excretion of oxime was the same but the amount excreted in the first three hours was smaller; (2) the plasma half-life of oxime lengthened; (3) the plasma concentrations of oxime rose; and (4) the intercompartmental clearances and rate constant for elimination for oxime fell. These changes suggest that thiamine and oxime compete for a common renal secretory mechanism or that thiamine alters the membrane transport of oxime.

Adult↗

Protection and inflammatory markers following exposure of guinea pigs to sarin vapour: comparative efficacy of three oximes.

The purpose of the present study was to compare the antidotal efficacy and the combined effects on inflammatory markers of three oximes--toxogonine, TMB4 and 2-PAM--in combination with anticholinergic drugs following exposure to sarin vapour by inhalation. Guinea pigs restrained in plethysmographs were exposed to various doses of sarin vapour (in the range of 1.4-4.4LD50). The antidotal mixture was injected immediately (5-20 s) following exposure (3 mg kg(-1) atropine and 1 mg kg(-1) benactyzine in combination with 6 mg kg(-1) toxogonine, 2 mg kg(-1) TMB4 or 12 mg kg(-1) 2-PAM). Bronchoalveolar lavage (BAL) samples were taken from surviving animals 24 h after exposure to determine the levels of inflammatory markers. A differential cell count was performed in BAL samples on Giemsa-stained slides. The inflammatory markers--histamine and prostaglandins (PGE)--were measured in BAL using radioimmunoassay (RIA) techniques. The survival rate in the various treatment groups and analysis of BAL samples showed that: (i) Toxogonine, TMB4 and 2-PAM, without pyridostigmine pretreatment, at doses that were proportional to their doses in the respective auto-injectors, exhibited similar antidotal efficacy against sarin exposure. (ii) The results demonstrated that a centrally acting anticholinergic drug is essential in the antidotal mixture to ensure survival. (iii) Histamine release and eosinophilia following sarin inhalation might require additional intervention, aimed at reducing the symptoms of allergic reaction and possibly expediting recovery.

Animals↗

Comparison of in vitro potency of oximes (pralidoxime, obidoxime, HI-6) to reactivate sarin-inhibited acetylcholinesterase in various parts of pig brain.

The potency of currently used oximes to reactivate sarin-inhibited acetylcholinesterase (AChE) in various parts of pig brain and whole pig brain was evaluated using in vitro methods. Significant differences in reactivation potency among all tested oximes were observed. At concentrations (10(-4) M) corresponding to recommended doses in vivo, the oxime HI-6 seems to be a more efficacious reactivator of sarin-inhibited AChE in whole pig brain as well as in cerebral hemispheres and cerebellum compared with the other oximes studied. Nevertheless, there are not any differences in the potency of oximes tested to reactivate sarin-inhibited AChE in medulla oblongata. Thus, the oxime HI-6 appears to be the most promising oxime among currently available oximes for the antidotal treatment of acute sarin poisoning, although it is not more efficacious than other currently used oximes in medulla oblongata, whose function is necessary for the vital functions of respiration and circulation.

Acetylcholinesterase↗

Relationship between insecticide-induced short and wry neck and cervical defects visible histologically shortly after treatment of chick embryos.

In order to clarify the anatomical precursor of short and wry neck, 48-hr chick embryos were injected with 6.25-200 micrograms of the organophosphate (OP) insecticide diazinon and recovered either at 96 hr for histological evaluation or at 19 days for gross observation. Among embryos recovered at 96 hr, all receiving a dose of 25-200 micrograms showed, in serial cross sections, the cervical notochord severely folded in the vertical, horizontal, and diagonal planes and the adjacent neural tube variously folded (often with branching of its canal), deformed by the notochord, rotated, and/or displaced from the midline. Virtually all embryos injected with 6.25 or 12.5 micrograms were fully free of such abnormalities. The coinjection of 2-pyridinealdoxime methochloride (2-PAM, which protects the embryo from certain OP insecticide-induced teratisms) along with 200 micrograms of diazinon markedly reduced the notochord and neural wry neck at 19 days paralleled the 96-hr cervical histology: pronounced in all embryos receiving greater than or equal to 25 micrograms, virtually nonexistent in those receiving 6.25 or 12.5 micrograms. Though more marked at higher doses, wry neck occurred to varying extents at all doses, 6.25-100 micrograms. We conclude that 1) the primary insecticide effect is upon the notochord rather than the neural tube, 2) short neck is a direct consequence of notochord folding, 3) wry neck is apparently not linked with notochord folding, and 4) vertebral fusion is not the consequence solely of muscle paralysis as argued elsewhere. We propose that the notochord folds because diazinon disrupts normal formation of its sheath.

Abnormalities, Drug-Induced↗

Kinetics of absorption and elimination of pralidoxime chloride in dogs.

The kinetics of the absorption and elimination of pralidoxime chloride were investigated in the dog. Similar apparent elimination rate constants were obtained after intravenous, intramuscular, and oral administration. Although oral absorption occurred slowly, intramuscular absorption proceeded rapidly. With in situ techniques, it was found that no absorption occurred from the isolated stomach and duodenum but that absorption did take place from the jejunum and ileum.

Absorption↗

Stability of concentrated aqueous solutions of pralidoxime chloride.

Concentrated aqueous solutions of pralidoxime chloride degrade more rapidly than dilute solutions. The rate and degree of degradation is dependent on the initial and final pH as well as the container in which the solution is stored. The effects of glass, metal, plastic, and rubber stoppers on the stability of concentrated and dilute solutions are discussed. The stability and shelf lives of 50% aqueous concentrates at different temperatures were determined.

Drug Packaging↗