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Michael Eddleston - One of the best experts on this subject based on the ideXlab platform.
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reactivation of plasma butyrylcholinesterase by Pralidoxime chloride in patients poisoned by who class ii toxicity organophosphorus insecticides
Toxicological Sciences, 2013Co-Authors: Lisa A Konickx, Shaluka Jayamanne, Nicholas A Buckley, Michael Eddleston, Franz Worek, Horst ThiermannAbstract:Some clinicians assess the efficacy of Pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide, and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor Pralidoxime treatment by studying its reactivation after Pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) class II OP insecticide poisoning. Patient data were derived from 2 studies, a cohort study (using a bolus treatment of 1g Pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2g Pralidoxime over 20min, followed by an infusion of 0.5g/h, with placebo). Two grams of Pralidoxime variably reactivated BuChE in patients poisoned by 2 diethyl OP insecticides, chlorpyrifos and quinalphos; however, unlike acetylcholinesterase reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1-g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO class II OP-poisoned patients according to the Pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of Pralidoxime treatment is unlikely to be clinically useful.
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Rapid and Complete Bioavailability of Antidotes for Organophosphorus Nerve Agent and Cyanide Poisoning in Minipigs After Intraosseous Administration
Annals of Emergency Medicine, 2012Co-Authors: Douglas B Murray, Simon H. L. Thomas, Robert D Jefferson, Adrian Thompson, Mick Dunn, Daniel S. Vidler, R Eddie Clutton, Michael Eddleston, Peter G. BlainAbstract:Study objective Management of chemical weapon casualties includes the timely administration of antidotes without contamination of rescuers. Personal protective equipment makes intravenous access difficult but does not prevent intraosseous drug administration. We therefore measured the systemic bioavailability of antidotes for organophosphorus nerve agent and cyanide poisoning when administered by the intraosseous, intravenous, and intramuscular routes in a small study of Gottingen minipigs. Methods Animals were randomly allocated to sequentially receive atropine (0.12 mg/kg by rapid injection), Pralidoxime (25 mg/kg by injection during 2 minutes), and hydroxocobalamin (75 mg/kg during 10 minutes) by the intravenous or intraosseous route, or atropine and Pralidoxime by the intramuscular route. Plasma concentrations were measured for 6 hours to characterize the antidote concentration-time profiles for each route. Results Maximum plasma concentrations of atropine and Pralidoxime occurred within 2 minutes when administered by the intraosseous route compared with 8 minutes by the intramuscular route. Maximum plasma hydroxocobalamin concentration occurred at the end of the infusion when administered by the intraosseous route. The mean area under the concentration-time curve by the intraosseous route was similar to the intravenous route for all 3 drugs and similar to the intramuscular route for atropine and Pralidoxime. Conclusion This study showed rapid and substantial antidote bioavailability after intraosseous administration that appeared similar to that of the intravenous route. The intraosseous route of antidote administration should be considered when intravenous access is difficult.
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Pralidoxime in acute organophosphorus insecticide poisoning a randomised controlled trial
PLOS Medicine, 2009Co-Authors: Michael Eddleston, Franz Worek, Peter Eyer, Edmund Juszczak, Nicola Alder, Fahim Mohamed, Lalith Senarathna, Ariyasena Hittarage, Shifa AzherAbstract:Background: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of Pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of Pralidoxime chloride to atropine and supportive care offers benefit. Methods and Findings: We performed a double-blind randomised placebo-controlled trial of Pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive Pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving Pralidoxime: 30/121 (24.8%) receiving Pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving Pralidoxime compared to placebo, further decreasing the likelihood that Pralidoxime is beneficial. The need for intubation was similar in both groups (Pralidoxime 26/121 [21.5%], placebo 24/114 [21.1%], adjusted HR 1.27 [95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit. Conclusions: Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required. Trial Registration: Controlled-trials.com ISRCTN55264358. © 2009 Eddleston et al.
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oximes in acute organophosphorus pesticide poisoning a systematic review of clinical trials
QJM: An International Journal of Medicine, 2002Co-Authors: Michael Eddleston, L Szinicz, Peter Eyer, Nicholas A BuckleyAbstract:Background: Acute organophosphorus (OP) pesticide poisoning is widespread in the developing world. Standard treatment involves the administration of intravenous atropine and an oxime to counter acetylcholinesterase inhibition at the synapse, but the usefulness of oximes is uncertain. Aim: To assess the evidence on the use of oximes in OP poisoning. Design: Systematic review. Methods: We searched Medline, Embase, and Cochrane databases (last check 01/02/02) for ‘organophosphate’ or ‘oxime’ together with ‘poisoning’ or ‘overdose’. We cross‐referenced from other articles, and contacted experts to identify unpublished studies. A Web search engine [[www.google.com][1]] was also used, with the keywords ‘organophosphate’, ‘oxime’, and ‘trial’ (last check 01/02/02). Results: We found two randomized controlled trials (RCTs) involving 182 patients treated with Pralidoxime. The RCTs found no benefit with Pralidoxime, and have been used to argue that Pralidoxime should not be used in OP poisoning. Discussion: The RCT authors must be congratulated for attempting important studies in a difficult environment. However, their studies did not take into account recently clarified issues regarding outcome, and their methodology is unclear. A generalized statement that Pralidoxime should not be used in OP poisoning is not supported by the published results. Oximes may well be irrelevant in the overwhelming self‐poisoning typical of the tropics, but a large RCT comparing the current WHO‐recommended Pralidoxime regimen (>30 mg/kg bolus followed by >8 mg/kg/h infusion) with placebo is needed for a definitive answer. Such a study should be designed to identify any patient subgroups that might benefit from oximes. [1]: http://www.google.com
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management of severe organophosphorus pesticide poisoning
Critical Care, 2002Co-Authors: Michael Eddleston, Darren M Roberts, Nicholas A BuckleyAbstract:We read with interest the paper by Sungar and Guven [1], which described a case series of organophosphorus pesticide (OP)-poisoned patients managed in their intensive care unit. It clearly demonstrates the difficulty in managing such patients in resource-poor areas [2]. However, we should like to query some issues in their management of OP poisoning and their use of Pralidoxime. We cannot understand their assessment of risk–benefit in the use of atropine. Their regimen of 0.02–0.08 mg/kg atropine as an infusion over 1 hour would provide a maximum of 5.6 mg atropine in a 70 kg person. Stopping atropine therapy '24 hours after atropinization' may cause problems with the continued release of fat-soluble OPs, such as fenthion, from the fat depot. Those authors also do not state the time it took for atropinization to be achieved; however, if patients received atropine for a mean of '3.4 ± 2.1 days', then the mean time to atropinization was 2.4 ± 2.1 days. This appears far too long. Few clinical toxicologists would disagree that full and early atropinization with 2 mg atropine stat followed by 2 mg every 5–15 min has few risks and obvious benefits [3]. Their use of intravenous diltiazem or propranolol for tachydysrhythmias associated with OP poisoning is troubling. Hypotension and cardiac dysrhythmias are significant problems in OP poisoning [3]. Do the authors have any evidence that the benefits of these negative inotropic drugs outweigh the risks in such patients? The authors state that only one randomized controlled trial (RCT) has been carried out that assessed the efficacy of Pralidoxime in OP poisoning. Unfortunately, the cited paper was a retrospective case series that compared the case fatality rate during a time when Pralidoxime was not available in Sri Lanka with the rate at a time when it was, and as such is not a RCT [4]. We recently completed a systematic review of RCTs of Pralidoxime that identified two small RCTs and two very small prospective studies [4]. The RCTs were carried out in Vellore, India, and assessed the value of 12 g Pralidoxime given in an infusion over 3–4 days versus a 1 g bolus or placebo. The trials failed to show any benefit. However, recent World Health Organization guidelines [5] recommend far higher doses – at least 30 mg/kg bolus followed by an infusion of 8 mg/kg per hour. In practice, this becomes 2 g stat followed by 500 mg/h – a dose far higher than that used in the study of Sungur and Guven [1]. The authors also state that Pralidoxime should not be used longer than 48 hours after ingestion. This may not be true for diethyl OPs. The time at which oxime administration is no longer useful depends on the rate of acetylcholinesterase ageing. In vitro, this occurs with a half-life of around 3 hours for dimethyl OPs and 33 hours for diethyl OPs. Taking four half-lives to be the latest that oximes can be effective, oximes may be useful for diethyl compounds when started up to 120 hours after ingestion [4,5]. Finally, we agree with Sungar and Guven that further controlled trials are required. We are now carrying out a large RCT in Sri Lanka in 1500 patients to test the efficacy of the dose of Pralidoxime recommended by the World Health Organization.
Frederic J Baud - One of the best experts on this subject based on the ideXlab platform.
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high dose of Pralidoxime reverses paraoxon induced respiratory toxicity in mice
Turkısh Journal of Anesthesıa and Reanımatıon, 2018Co-Authors: Pascal Houze, Thomas Berthin, Jeanherle Raphalen, Alice Hutin, Frederic J BaudAbstract: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.
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does modulation of organic cation transporters improve Pralidoxime activity in an animal model of organophosphate poisoning
Critical Care Medicine, 2011Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Salvatore Cisternino, Marcel Debray, Patricia Risede, Alfred H Schinkel, Jeanmichel WarnetAbstract:Objectives: Pralidoxime is an organic cation used as an antidote in addition to atropine to treat organophosphate poisoning. Pralidoxime is rapidly eliminated by the renal route and thus has limited action. The objectives of this work were as follows. 1) Study the role of organic cation transporters in the renal secretion of Pralidoxime using organic cation transporter substrates (tetraethylammonium) and knockout mice (Oct1/2 -/- ; Oct3 -/- ). 2) Assess whether sustained high plasma concentrations increase Pralidoxime antidotal activity toward paraoxon-induced respiratory toxicity. Setting: INSERM U705, Faculte de Pharmacie, Universite Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. Subjects: Rodents: Knockout mice (Oct1/2 -/- ; Oct3 -/- ) and Sprague-Dawley rats. Interventions: None. Measurements and Main Results: In rats, the renal clearance of Pralidoxime was 3.6-fold higher than the creatinine clearance. Pretreatment with tetraethylammonium (75 mg/kg) in rats or deficiencies in organic cation transporters 1 and 2 in mice (Oct1/ 2 -/- ) resulted in a significant increase in plasma Pralidoxime concentrations. Lack of Oct3 did not alter plasma Pralidoxime concentrations. The antidotal activity of Pralidoxime (50 mg/kg intramuscularly) was longer and with greater effect, resulting in a return to normal values when administered to rats pretreated with tetraethylammonium. Conclusions: Pralidoxime is secreted in rats and mice by renal Oct1 and/or Oct2 but not by Oct3. Modulation of organic cation transporter activity increased the plasma Pralidoxime concentrations and the antidotal effect of Pralidoxime with sustained return within the normal range of respiratory variables in paraoxon-poisoned rats. These results suggest a promising approach in an animal model toward the increase in efficiency of Pralidoxime. However, further studies are needed before these results are extended to human poisoning.
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Pharmacokinetics and Toxicodynamics of Pralidoxime Effects on Paraoxon-Induced Respiratory Toxicity
Toxicological sciences : an official journal of the Society of Toxicology, 2010Co-Authors: Pascal Houze, Patricia Risede, Donald E. Mager, Frederic J BaudAbstract:Empirical studies suggest that the antidotal effect of Pralidoxime depends on plasma concentrations with therapeutic effects associated with concentrations above 4 mg/l. The purpose of this study was to determine the pharmacokinetic-toxicodynamic (PK-TD) relationships for the antidotal effect of Pralidoxime on paraoxon-induced toxicity in rats. Diethylparaoxon inactivation of whole-blood cholinesterase activity was studied both in vitro and in male Sprague-Dawley rats. Toxin-induced respiratory effects were measured via whole-body plethysmography in control and Pralidoxime-treated animals (50 mg/kg im injection). In the in vitro analysis, cholinesterase reactivation by Pralidoxime in blood-poisoned diethylparaoxon (10nM) was proportional to the logarithm of drug concentrations. A mechanism-based TD model was developed, which well described the inhibition of cholinesterases by diethylparaoxon and reactivation with Pralidoxime. The in vitro Pralidoxime EC 50 was estimated to be 4.67 mg/l. Animals exposed to diethylparaoxon exhibited a decrease in respiratory rate and an increase in expiratory time, and Pralidoxime treatment resulted in a rapid complete but transient (< 30 min) correction in respiratory toxicity. In contrast, there was a fast and total reactivation of blood cholinesterase activity over the 210-min study period. The in vitro TD model was extended to capture the time-course of in vivo Pralidoxime antidotal effects, which explained the complex relationship between drug exposure and pharmacological response profile. This study provides insights into the role of oxime-rescue of paraoxon-induced toxicity, and the final PK-TD model might prove useful in optimizing the design and development of such therapy.
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acute renal failure enhances the antidotal activity of Pralidoxime towards paraoxon induced respiratory toxicity
Toxicology Letters, 2009Co-Authors: Maya Kayouka, Pascal Houze, Marcel Debray, Frederic J BaudAbstract:We recently showed in a rat model of dichromate-induced acute renal failure (ARF) that the elimination but not the distribution of Pralidoxime was altered resulting in sustained plasma Pralidoxime concentrations. The aim of this study was to compare the efficiency of Pralidoxime in normal and acute renal failure rats against paraoxon-induced respiratory toxicity. Ventilation at rest was assessed using whole-body plethysmography after subcutaneous administration of either saline or paraoxon (50% of the LD(50)), in the control and ARF rats. Thirty minutes after administration of paraoxon, either saline or 50mg/kg of Pralidoxime was administered intramuscularly. ARF had no significant effects on the ventilation at rest. The effects of paraoxon on respiration were not significantly different in the control and ARF group. Paraoxon increased the total time (T(TOT)), expiratory time (T(E)) and tidal volume (V(T)), and decreased the respiratory frequency (f). In paraoxon-poisoned rats with normal renal function, Pralidoxime had a significant but transient effect regarding the T(TOT) and V(T) (p<0.05). In the ARF group, the same dose of Pralidoxime significantly decreased the T(TOT), T(E), and V(T) and increased f during 90 min (p<0.01). In conclusion, Pralidoxime had partial and transient effects towards paraoxon-induced respiratory toxicity in control rats; and a complete and sustained correction in ARF rats.
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acute renal failure alters the kinetics of Pralidoxime in rats
Toxicology Letters, 2006Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Marcel Debray, Patricia RisedeAbstract:Abstract There is a trend towards increasing doses of Pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, Pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of Pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague–Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received Pralidoxime methylsulfate (50 mg/kg of Pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma Pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of Pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of Pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of Pralidoxime.
Maya Kayouka - One of the best experts on this subject based on the ideXlab platform.
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does modulation of organic cation transporters improve Pralidoxime activity in an animal model of organophosphate poisoning
Critical Care Medicine, 2011Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Salvatore Cisternino, Marcel Debray, Patricia Risede, Alfred H Schinkel, Jeanmichel WarnetAbstract:Objectives: Pralidoxime is an organic cation used as an antidote in addition to atropine to treat organophosphate poisoning. Pralidoxime is rapidly eliminated by the renal route and thus has limited action. The objectives of this work were as follows. 1) Study the role of organic cation transporters in the renal secretion of Pralidoxime using organic cation transporter substrates (tetraethylammonium) and knockout mice (Oct1/2 -/- ; Oct3 -/- ). 2) Assess whether sustained high plasma concentrations increase Pralidoxime antidotal activity toward paraoxon-induced respiratory toxicity. Setting: INSERM U705, Faculte de Pharmacie, Universite Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. Subjects: Rodents: Knockout mice (Oct1/2 -/- ; Oct3 -/- ) and Sprague-Dawley rats. Interventions: None. Measurements and Main Results: In rats, the renal clearance of Pralidoxime was 3.6-fold higher than the creatinine clearance. Pretreatment with tetraethylammonium (75 mg/kg) in rats or deficiencies in organic cation transporters 1 and 2 in mice (Oct1/ 2 -/- ) resulted in a significant increase in plasma Pralidoxime concentrations. Lack of Oct3 did not alter plasma Pralidoxime concentrations. The antidotal activity of Pralidoxime (50 mg/kg intramuscularly) was longer and with greater effect, resulting in a return to normal values when administered to rats pretreated with tetraethylammonium. Conclusions: Pralidoxime is secreted in rats and mice by renal Oct1 and/or Oct2 but not by Oct3. Modulation of organic cation transporter activity increased the plasma Pralidoxime concentrations and the antidotal effect of Pralidoxime with sustained return within the normal range of respiratory variables in paraoxon-poisoned rats. These results suggest a promising approach in an animal model toward the increase in efficiency of Pralidoxime. However, further studies are needed before these results are extended to human poisoning.
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acute renal failure enhances the antidotal activity of Pralidoxime towards paraoxon induced respiratory toxicity
Toxicology Letters, 2009Co-Authors: Maya Kayouka, Pascal Houze, Marcel Debray, Frederic J BaudAbstract:We recently showed in a rat model of dichromate-induced acute renal failure (ARF) that the elimination but not the distribution of Pralidoxime was altered resulting in sustained plasma Pralidoxime concentrations. The aim of this study was to compare the efficiency of Pralidoxime in normal and acute renal failure rats against paraoxon-induced respiratory toxicity. Ventilation at rest was assessed using whole-body plethysmography after subcutaneous administration of either saline or paraoxon (50% of the LD(50)), in the control and ARF rats. Thirty minutes after administration of paraoxon, either saline or 50mg/kg of Pralidoxime was administered intramuscularly. ARF had no significant effects on the ventilation at rest. The effects of paraoxon on respiration were not significantly different in the control and ARF group. Paraoxon increased the total time (T(TOT)), expiratory time (T(E)) and tidal volume (V(T)), and decreased the respiratory frequency (f). In paraoxon-poisoned rats with normal renal function, Pralidoxime had a significant but transient effect regarding the T(TOT) and V(T) (p<0.05). In the ARF group, the same dose of Pralidoxime significantly decreased the T(TOT), T(E), and V(T) and increased f during 90 min (p<0.01). In conclusion, Pralidoxime had partial and transient effects towards paraoxon-induced respiratory toxicity in control rats; and a complete and sustained correction in ARF rats.
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acute renal failure alters the kinetics of Pralidoxime in rats
Toxicology Letters, 2006Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Marcel Debray, Patricia RisedeAbstract:Abstract There is a trend towards increasing doses of Pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, Pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of Pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague–Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received Pralidoxime methylsulfate (50 mg/kg of Pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma Pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of Pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of Pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of Pralidoxime.
Pascal Houze - One of the best experts on this subject based on the ideXlab platform.
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high dose of Pralidoxime reverses paraoxon induced respiratory toxicity in mice
Turkısh Journal of Anesthesıa and Reanımatıon, 2018Co-Authors: Pascal Houze, Thomas Berthin, Jeanherle Raphalen, Alice Hutin, Frederic J BaudAbstract: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.
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does modulation of organic cation transporters improve Pralidoxime activity in an animal model of organophosphate poisoning
Critical Care Medicine, 2011Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Salvatore Cisternino, Marcel Debray, Patricia Risede, Alfred H Schinkel, Jeanmichel WarnetAbstract:Objectives: Pralidoxime is an organic cation used as an antidote in addition to atropine to treat organophosphate poisoning. Pralidoxime is rapidly eliminated by the renal route and thus has limited action. The objectives of this work were as follows. 1) Study the role of organic cation transporters in the renal secretion of Pralidoxime using organic cation transporter substrates (tetraethylammonium) and knockout mice (Oct1/2 -/- ; Oct3 -/- ). 2) Assess whether sustained high plasma concentrations increase Pralidoxime antidotal activity toward paraoxon-induced respiratory toxicity. Setting: INSERM U705, Faculte de Pharmacie, Universite Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. Subjects: Rodents: Knockout mice (Oct1/2 -/- ; Oct3 -/- ) and Sprague-Dawley rats. Interventions: None. Measurements and Main Results: In rats, the renal clearance of Pralidoxime was 3.6-fold higher than the creatinine clearance. Pretreatment with tetraethylammonium (75 mg/kg) in rats or deficiencies in organic cation transporters 1 and 2 in mice (Oct1/ 2 -/- ) resulted in a significant increase in plasma Pralidoxime concentrations. Lack of Oct3 did not alter plasma Pralidoxime concentrations. The antidotal activity of Pralidoxime (50 mg/kg intramuscularly) was longer and with greater effect, resulting in a return to normal values when administered to rats pretreated with tetraethylammonium. Conclusions: Pralidoxime is secreted in rats and mice by renal Oct1 and/or Oct2 but not by Oct3. Modulation of organic cation transporter activity increased the plasma Pralidoxime concentrations and the antidotal effect of Pralidoxime with sustained return within the normal range of respiratory variables in paraoxon-poisoned rats. These results suggest a promising approach in an animal model toward the increase in efficiency of Pralidoxime. However, further studies are needed before these results are extended to human poisoning.
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Pharmacokinetics and Toxicodynamics of Pralidoxime Effects on Paraoxon-Induced Respiratory Toxicity
Toxicological sciences : an official journal of the Society of Toxicology, 2010Co-Authors: Pascal Houze, Patricia Risede, Donald E. Mager, Frederic J BaudAbstract:Empirical studies suggest that the antidotal effect of Pralidoxime depends on plasma concentrations with therapeutic effects associated with concentrations above 4 mg/l. The purpose of this study was to determine the pharmacokinetic-toxicodynamic (PK-TD) relationships for the antidotal effect of Pralidoxime on paraoxon-induced toxicity in rats. Diethylparaoxon inactivation of whole-blood cholinesterase activity was studied both in vitro and in male Sprague-Dawley rats. Toxin-induced respiratory effects were measured via whole-body plethysmography in control and Pralidoxime-treated animals (50 mg/kg im injection). In the in vitro analysis, cholinesterase reactivation by Pralidoxime in blood-poisoned diethylparaoxon (10nM) was proportional to the logarithm of drug concentrations. A mechanism-based TD model was developed, which well described the inhibition of cholinesterases by diethylparaoxon and reactivation with Pralidoxime. The in vitro Pralidoxime EC 50 was estimated to be 4.67 mg/l. Animals exposed to diethylparaoxon exhibited a decrease in respiratory rate and an increase in expiratory time, and Pralidoxime treatment resulted in a rapid complete but transient (< 30 min) correction in respiratory toxicity. In contrast, there was a fast and total reactivation of blood cholinesterase activity over the 210-min study period. The in vitro TD model was extended to capture the time-course of in vivo Pralidoxime antidotal effects, which explained the complex relationship between drug exposure and pharmacological response profile. This study provides insights into the role of oxime-rescue of paraoxon-induced toxicity, and the final PK-TD model might prove useful in optimizing the design and development of such therapy.
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acute renal failure enhances the antidotal activity of Pralidoxime towards paraoxon induced respiratory toxicity
Toxicology Letters, 2009Co-Authors: Maya Kayouka, Pascal Houze, Marcel Debray, Frederic J BaudAbstract:We recently showed in a rat model of dichromate-induced acute renal failure (ARF) that the elimination but not the distribution of Pralidoxime was altered resulting in sustained plasma Pralidoxime concentrations. The aim of this study was to compare the efficiency of Pralidoxime in normal and acute renal failure rats against paraoxon-induced respiratory toxicity. Ventilation at rest was assessed using whole-body plethysmography after subcutaneous administration of either saline or paraoxon (50% of the LD(50)), in the control and ARF rats. Thirty minutes after administration of paraoxon, either saline or 50mg/kg of Pralidoxime was administered intramuscularly. ARF had no significant effects on the ventilation at rest. The effects of paraoxon on respiration were not significantly different in the control and ARF group. Paraoxon increased the total time (T(TOT)), expiratory time (T(E)) and tidal volume (V(T)), and decreased the respiratory frequency (f). In paraoxon-poisoned rats with normal renal function, Pralidoxime had a significant but transient effect regarding the T(TOT) and V(T) (p<0.05). In the ARF group, the same dose of Pralidoxime significantly decreased the T(TOT), T(E), and V(T) and increased f during 90 min (p<0.01). In conclusion, Pralidoxime had partial and transient effects towards paraoxon-induced respiratory toxicity in control rats; and a complete and sustained correction in ARF rats.
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acute renal failure alters the kinetics of Pralidoxime in rats
Toxicology Letters, 2006Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Marcel Debray, Patricia RisedeAbstract:Abstract There is a trend towards increasing doses of Pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, Pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of Pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague–Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received Pralidoxime methylsulfate (50 mg/kg of Pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma Pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of Pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of Pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of Pralidoxime.
Marcel Debray - One of the best experts on this subject based on the ideXlab platform.
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does modulation of organic cation transporters improve Pralidoxime activity in an animal model of organophosphate poisoning
Critical Care Medicine, 2011Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Salvatore Cisternino, Marcel Debray, Patricia Risede, Alfred H Schinkel, Jeanmichel WarnetAbstract:Objectives: Pralidoxime is an organic cation used as an antidote in addition to atropine to treat organophosphate poisoning. Pralidoxime is rapidly eliminated by the renal route and thus has limited action. The objectives of this work were as follows. 1) Study the role of organic cation transporters in the renal secretion of Pralidoxime using organic cation transporter substrates (tetraethylammonium) and knockout mice (Oct1/2 -/- ; Oct3 -/- ). 2) Assess whether sustained high plasma concentrations increase Pralidoxime antidotal activity toward paraoxon-induced respiratory toxicity. Setting: INSERM U705, Faculte de Pharmacie, Universite Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. Subjects: Rodents: Knockout mice (Oct1/2 -/- ; Oct3 -/- ) and Sprague-Dawley rats. Interventions: None. Measurements and Main Results: In rats, the renal clearance of Pralidoxime was 3.6-fold higher than the creatinine clearance. Pretreatment with tetraethylammonium (75 mg/kg) in rats or deficiencies in organic cation transporters 1 and 2 in mice (Oct1/ 2 -/- ) resulted in a significant increase in plasma Pralidoxime concentrations. Lack of Oct3 did not alter plasma Pralidoxime concentrations. The antidotal activity of Pralidoxime (50 mg/kg intramuscularly) was longer and with greater effect, resulting in a return to normal values when administered to rats pretreated with tetraethylammonium. Conclusions: Pralidoxime is secreted in rats and mice by renal Oct1 and/or Oct2 but not by Oct3. Modulation of organic cation transporter activity increased the plasma Pralidoxime concentrations and the antidotal effect of Pralidoxime with sustained return within the normal range of respiratory variables in paraoxon-poisoned rats. These results suggest a promising approach in an animal model toward the increase in efficiency of Pralidoxime. However, further studies are needed before these results are extended to human poisoning.
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acute renal failure enhances the antidotal activity of Pralidoxime towards paraoxon induced respiratory toxicity
Toxicology Letters, 2009Co-Authors: Maya Kayouka, Pascal Houze, Marcel Debray, Frederic J BaudAbstract:We recently showed in a rat model of dichromate-induced acute renal failure (ARF) that the elimination but not the distribution of Pralidoxime was altered resulting in sustained plasma Pralidoxime concentrations. The aim of this study was to compare the efficiency of Pralidoxime in normal and acute renal failure rats against paraoxon-induced respiratory toxicity. Ventilation at rest was assessed using whole-body plethysmography after subcutaneous administration of either saline or paraoxon (50% of the LD(50)), in the control and ARF rats. Thirty minutes after administration of paraoxon, either saline or 50mg/kg of Pralidoxime was administered intramuscularly. ARF had no significant effects on the ventilation at rest. The effects of paraoxon on respiration were not significantly different in the control and ARF group. Paraoxon increased the total time (T(TOT)), expiratory time (T(E)) and tidal volume (V(T)), and decreased the respiratory frequency (f). In paraoxon-poisoned rats with normal renal function, Pralidoxime had a significant but transient effect regarding the T(TOT) and V(T) (p<0.05). In the ARF group, the same dose of Pralidoxime significantly decreased the T(TOT), T(E), and V(T) and increased f during 90 min (p<0.01). In conclusion, Pralidoxime had partial and transient effects towards paraoxon-induced respiratory toxicity in control rats; and a complete and sustained correction in ARF rats.
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acute renal failure alters the kinetics of Pralidoxime in rats
Toxicology Letters, 2006Co-Authors: Maya Kayouka, Pascal Houze, Frederic J Baud, Marcel Debray, Patricia RisedeAbstract:Abstract There is a trend towards increasing doses of Pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, Pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of Pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague–Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received Pralidoxime methylsulfate (50 mg/kg of Pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma Pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of Pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of Pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of Pralidoxime.
