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An increase of pyroglutamic acid, or 5-oxoproline plasmatic concentration was reported in metabolic acidosis observed after chronic intake of some drugs, as acetaminophen. We developed a simple, fast and reproducible method by capillary zone electrophoresis using a commercial Anion Analysis Kit ® to quantify pyroglutamic acid, in plasma after acetonitrile precipitation, and after simple dilution in urines. Fumaric acid was used as internal standard in both. In less than 7 min, the method separates pyroglutamic acid from other organic and inorganic anions. The method is linear between 0.25 and 10 mmol/L in plasma, and 0.15 and 10 mmol/L in urines. The quantification limits are 0.25 mmol/L and 0.15 mmol/L for plasma and urines, respectively. For repeatability and intermediate precision, the variation coefficients are less than 15% and the bias values are between ± 10%. For the 2 matrices, the recoveries are between 88% and 101%. The method does not interfere with physiological organic and inorganic anions. Pyroglutamic acid concentrations measured in 9 children were between 0.45 and 3.96 mmol/L in the plasma and between 0.15 and 3.2 mmol/L in the urine. No correlation between pyroglutamic acid and acetaminophen concentrations were found, regardless of the biological media. In conclusion, our method measures pathophysiological concentrations of pyroglutamic acid and highlights the increase in other organic acids that may explain metabolic acidosis due to chronic acetaminophen intake.

Background: Oximes are used in addition to atropine to treat organophosphate poisoning. However, the efficiency of oximes is still a matter of debate. In vitro experiments suggested than new oximes are more potent than the commercial oximes. However, the antidotal activity of new oximes has not been assessed in vivo., Methods: The aim of this work was to assess the safety and efficiency of new oximes compared to pralidoxime in a rat model of diethyl paraoxon-induced non-lethal respiratory toxicity., Results: Safety study of oximes showed no adverse effects on ventilation in rats. KO-33, KO-48, KO-74 oximes did not exhibit significant antidotal effect in vivo. In contrast, KO-27 and BI-6 showed evidence of antidotal activity by normalization of respiratory frequency and respiratory times. KO-27 became inefficient only during the last 30 min of the study. In contrast, pralidoxime demonstrated to be inefficient at 30 min post injection. Inversely, the antidotal activity of BI-6 occurred lately, within the last 90 min post injection., Conclusion: This study showed respiratory safety of new oximes. Regarding, the efficiency, KO-27 revealed to be a rapid acting antidote toward diethylparaoxon-induced respiratory toxicity, meanwhile BI-6 was a late-acting antidote. Simultaneous administration of these two oximes might result in a complete and prolonged antidotal efficiency.

The chemical structure of organophosphate compounds (OPs) is a well-known factor which modifies the acute toxicity of these compounds. We compared ventilation at rest and cholinesterase activities in male Sprague-Dawley rats poisoned with dimethyl paraoxon (DMPO) and diethyl paraoxon (DEPO) at a subcutaneous dose corresponding to 50% of the median lethal dose (MLD). Ventilation at rest was recorded by whole body plethysmography. Total cholinesterase activities were determined by radiometric assay. Both organophosphates decreased significantly the respiratory rate, resulting from an increase in expiratory time. Dimethyl-induced respiratory toxicity spontaneously reversed within 120 min post-injection. Diethyl-induced respiratory toxicity was long-lasting, more than 180 min post-injection. Both organophosphates decreased cholinesterase activities from 10 to 180 min post-injection with the same degree of inhibition of total cholinesterase within an onset at the same times after injection. There were no significant differences in residual cholinesterase activities between dimethyl and diethyl paraoxon groups at any time. The structure of the alkoxy-group is a determinant factor of the late phase of poisoning, conditioning duration of toxicity without significant effects on the magnitude of alteration of respiratory parameters. For same duration and magnitude of cholinesterase inhibition, there was a strong discrepancy in the time-course of effects between the two compounds.

High dose of the cobalt atom is toxic for mammals. Hydroxocobalamin is considered safe due to the inclusion of the cobalt atom into the heminic moiety. The tissue distribution of cobalt following repeated doses of either hydroxocobalamin or cobalt chloride was studied in Wistar rats. In both cases, cobalt was administered in equimolar doses daily for an overall period of three weeks. Three groups were designed. In the hydroxocobalamin treated group, ten rats received hydroxocobalamin 17.5 mg by intraperitoneal route daily. In the cobalt-treated group, ten rats received cobalt chloride 3 mg i.p. daily. In the control group, six rats received a daily injection of 0.35 mL isotonic sodium chloride i.p. Cobalt concentrations were measured by Inductively Coupled Plasma Atomic Emission. Ours results showed that in rats having received either hydroxocobalamin or cobalt chloride, the tissue concentrations of cobalt were greater than those in the control group. The present study documented that in naive rats, the repeated administration of high doses of cobalt as hydroxocobalamin leads to tissue concentrations of the atom of cobalt significantly lower than those induced by equimolar doses of cobalt administered as cobalt chloride (p <0.05). We conclude that hydroxocobalamin reduced the tissue distribution of the cobalt atom in comparison with cobalt chloride.

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., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

We quantify the impact of several variables including site of blood draw, delay in measurement, and use of the cyanide antidote hydroxocobalamin on detection of both normal (<2 mmol/L) and elevated (>6 mmol/L) human plasma lactate. An in vivo study assessed effects of venous or arterial origin of blood samples. Two in vitro studies assessed the effect of a 2 h delay in measuring plasma lactate concentrations, as well as the interference of low (100 μmol/L) and high (300 μmmol/L) plasma hydroxocobalamin concentrations on detecting normal and elevated levels of lactate. A relative change of 20% in the measured lactate concentration was considered clinically significant. There was no clinically relevant effect of the site of blood draw on lactate measurements. Plasma lactate concentrations were artificially increased by a delay of 2 h between blood draw and sample measurement. Under conditions where plasma lactate levels were in a normal range, the dose equivalent to 300 μmol/L hydroxocobalamin concentration caused an artificial increase in lactate measurements that could possibly be misinterpreted clinically as an elevation. Under conditions where plasma lactate levels were elevated, as would occur in cases of acute cyanide poisoning, neither the low nor high concentration of hydroxocobalamin caused a clinically relevant change in lactate measurements. Clinicians should be cautious in interpreting lactate concentrations if there has been a significant delay between blood draw and laboratory analysis, or when blood was collected shortly after the completion of hydroxocobalamin administration.

Conflicting results have been reported on the influence of Polymyxin-B hemoperfusion treatment on systemic inflammation markers. The aim of the study was to assess in a randomized control trial the influence on plasma cytokine concentrations of Polymyxin-B hemoperfusion in septic shock due to peritonitis. A panel of 10 pro- or anti-inflammatory cytokines was measured in 213 patients with peritonitis-induced septic shock enrolled in the randomized trial ABDOMIX testing the impact of 2 Polymyxin-B hemoperfusion sessions with standard treatment. Gram-negative bacteria were identified in 69% of patients. In the overall population, baseline plasma cytokine concentrations were not different between the two groups. Circulating tumor necrosis factor-α, interleukin (IL)-1β, IL-10, IL-6, and IL-1RA decreased significantly over time in both groups (P <0.0001 for all in controls, and P = 0.0002, 0.003, and <0.0001 in patients treated with Polymyxin-B hemoperfusion). IL-17A decreased significantly in patients treated with Polymyxin B hemoperfusion (P = 0.045) but not in controls. At the end of the second Polymyxin-B hemoperfusion session or at corresponding time in controls, plasma levels of cytokines did not differ between the two groups. Similar results were found in the subgroup of patients with gram-negative peritonitis who completed two Polymyxin-B hemoperfusion sessions. These results do not support a significant influence of Polymyxin-B hemoperfusion on circulating cytokines assessed except for IL-17A which clinical significance remains to be elucidated.

Objectives: Regarding the different disciplines that encompass the pharmacology and the toxicology, none is specifically dedicated to the description and analysis of the time-course of relevant toxic effects both in experimental and clinical studies. The lack of a discipline devoted to this major field in toxicology results in misconception and even in errors by clinicians., Material and Methods: Review of the basic different disciplines that encompass pharmacology toxicology and comparing with the description of the time-course of effects in conditions in which toxicological analysis was not performed or with limited analytical evidence., Results: Review of the literature clearly shows how misleading is the current extrapolation of toxicokinetic data to the description of the time-course of toxic effects., Conclusion: A new discipline entitled toxicodynetics should be developed aiming at a more systematic description of the time-course of effects in acute human and experimental poisonings. Toxicodynetics might help emergency physicians in risk assessment when facing a poisoning and contribute to a better assessment of quality control of data collected by poison control centres. Toxicodynetics would also allow a quantitative approach to the clinical effects resulting from drug-drug interaction., (Copyright © 2016. Published by Elsevier Masson SAS.)

Objectives: Extracorporeal life support (ECLS) has become a common technique for treating refractory cardiogenic shock and cardiac arrest induced by drug overdose. The aim of this paper is to present our group's 10-year experience (2002-2012) using ECLS to treat drug-induced, refractory cardiogenic shock and cardiac arrest. We review 112 consecutive cases of acute poisoning requiring arteriovenous ECLS. We provided ECLS with a Rotaflow pump (Jostra-Maquette). In 71 cases (63%) the patient presented with refractory cardiac arrest; 41 (37%) presented with refractory cardiogenic shock. The dose ingested was very high in all cases. Survival was strongly related to presentation (cardiogenic shock vs cardiac arrest) and the type of drug taken. Survival was highest after overdoses of β-blockers and antiarrhythmic drugs and lowest after overdoses of chloroquine, colchicine, or verapamil. Survival rates were very low in the subgroup of patients presenting with cardiac arrest who had taken hypnotics or sedatives, suggesting that the heart stopped more because of anoxia than because of a direct cardiotoxic effect. In contrast, in cardiotoxic drug-induced cardiac arrest, the survival rate of 10% was significantly higher than the rate in non cardiotoxic arrests. Survival rates in drug-induced cardiogenic shock ranged from 45% to 100%. We conclude that ECLS should be considered for the management of cardiotoxic drug overdose. Close cardiovascular monitoring should be initiated if a patient has taken a particularly high dose of a cardiotoxic drug. Severe cardiotoxicity is rare but life threatening. The use of ECLS in these cases should be based on clinical criteria. Early use of ECLS in drug-induced cardiogenic shock significantly improves survival. Delays in applying ECLS in severe drug-induced cardiotoxicity-diagnosed based on type of drug, dose, and hemodynamic effects-can lead to cardiac arrest and a worse outcome.