Pascal Houzé1, Thomas Berthin1, Jean-Herlé Raphalen2, Alice Hutin2, J Frédéric Baud3. 1. Laboratoire de Biochimie, Hôpital Universitaire Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 2. Département d'Anesthésie - Réanimation- SAMU de Paris, Hôpital Universitaire Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 3. UMR-8257. Cognitive Action Group. 45, rue des Saint-Pères. 75006. Paris. Université Paris Descartes, Paris, France.
Abstract
OBJECTIVE: The efficiency of pralidoxime in the treatment of human organophosphates poisoning is still unclear. In a rat model, we showed that pralidoxime induced a complete but concentration-dependent reversal of paraoxon-induced respiratory toxicity. The aim of this study was to assess the efficiency of pralidoxime in a species other than rats. METHODS: A dose of diethylparaoxon corresponding to 50% of the median lethal dose was administered subcutaneously to male F1B6D2 mice. Ascending single pralidoxime doses of 10, 50-100 and 150 mg kg-1 were administered intramuscularly 30 min after diethylparaoxon administration. Ventilation at rest was assessed using whole-body plethysmography and mice temperature was assessed using infrared telemetry. Results are expressed as mean±SE. Statistical analysis used non-parametric tests. RESULTS: From 30 to 150 min post-injection, diethylparaoxon induced clinical symptoms and a decrease in respiratory frequency, which resulted from an increase in expiratory and inspiratory times associated with an increase in the tidal volume. In the 10-, 50- and 100-mg kg-1 pralidoxime groups, there was a trend towards a non-significant improvement of paraoxon-induced respiratory toxicity. The 150 mg kg-1 dose of pralidoxime induced a significant reversal of all respiratory parameters. CONCLUSION: In the present study, a toxic but non-lethal model of diethylparaoxon in awake, unrestrained mice was observed. By administering an equipotent dose of diethylparaoxon to rats, a 150 mg kg-1 dose of pralidoxime administered alone completely reversed diethylparaoxon-induced respiratory toxicity in mice. The dose dependency of reversal suggests that further studies are needed for assessing plasma concentrations of pralidoxime resulting in reversal of toxicity.
OBJECTIVE: The efficiency of pralidoxime in the treatment of human organophosphates poisoning is still unclear. In a rat model, we showed that pralidoxime induced a complete but concentration-dependent reversal of paraoxon-induced respiratory toxicity. The aim of this study was to assess the efficiency of pralidoxime in a species other than rats. METHODS: A dose of diethylparaoxon corresponding to 50% of the median lethal dose was administered subcutaneously to male F1B6D2 mice. Ascending single pralidoxime doses of 10, 50-100 and 150 mg kg-1 were administered intramuscularly 30 min after diethylparaoxon administration. Ventilation at rest was assessed using whole-body plethysmography and mice temperature was assessed using infrared telemetry. Results are expressed as mean±SE. Statistical analysis used non-parametric tests. RESULTS: From 30 to 150 min post-injection, diethylparaoxon induced clinical symptoms and a decrease in respiratory frequency, which resulted from an increase in expiratory and inspiratory times associated with an increase in the tidal volume. In the 10-, 50- and 100-mg kg-1 pralidoxime groups, there was a trend towards a non-significant improvement of paraoxon-induced respiratory toxicity. The 150 mg kg-1 dose of pralidoxime induced a significant reversal of all respiratory parameters. CONCLUSION: In the present study, a toxic but non-lethal model of diethylparaoxon in awake, unrestrained mice was observed. By administering an equipotent dose of diethylparaoxon to rats, a 150 mg kg-1 dose of pralidoxime administered alone completely reversed diethylparaoxon-induced respiratory toxicity in mice. The dose dependency of reversal suggests that further studies are needed for assessing plasma concentrations of pralidoxime resulting in reversal of toxicity.
Authors: Madhusoodana P Nambiar; Richard K Gordon; Peter E Rezk; Alexander M Katos; Nikolai A Wajda; Theodore S Moran; Keith E Steele; Bhupendra P Doctor; Alfred M Sciuto Journal: Toxicol Appl Pharmacol Date: 2006-11-07 Impact factor: 4.219
Authors: Michael Eddleston; Peter Eyer; Franz Worek; Fahim Mohamed; Lalith Senarathna; Ludwig von Meyer; Edmund Juszczak; Ariyasena Hittarage; Shifa Azhar; Wasantha Dissanayake; M H Rezvi Sheriff; Ladislaus Szinicz; Andrew H Dawson; Nick A Buckley Journal: Lancet Date: 2005 Oct 22-28 Impact factor: 79.321
Authors: F Dorandeu; J R Mikler; H Thiermann; C Tenn; C Davidson; T W Sawyer; G Lallement; F Worek Journal: Toxicology Date: 2006-09-29 Impact factor: 4.221
Authors: J L Willems; H C De Bisschop; A G Verstraete; C Declerck; Y Christiaens; P Vanscheeuwyck; W A Buylaert; D Vogelaers; F Colardyn Journal: Arch Toxicol Date: 1993 Impact factor: 5.153