Caspofungin sequestration in a polyacrylonitrile-derived filter: Increasing the dose does not mitigate sequestration.

OBJECTIVES: Critically ill patients frequently require continuous renal replacement therapy. Echinocandins are recommended as first-line treatment of candidemia. Preliminary results suggested echinocandin sequestration in a polyacrylonitrile filter. The present study aimed to determine whether increasing the dose might balance sequestration. METHODS: An STX filter (Baxter-Gambro) was used. A liquid chromatography-mass spectrometry method was used for dosage of caspofungin. In vitro drug disposition was evaluated by NeckEpur (Neckepur, Versailles, France) technology using a crystalloid medium instead of diluted/reconstituted blood, focusing on the disposition of the unbound fraction of drugs. Two concentrations were assessed. RESULTS: At the low dose, the mean measured initial concentration in the central compartment (CC) was 5.1 ± 0.6 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.6 ± 2.5 L/h. The mean percentages of elimination resulting from sequestration and diafiltration were 96.0 ± 5.0 and 4.0 ± 5.2%, respectively. At high dose, the mean measured initial concentration in the CC was 13.1 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.5 L/h. The mean percentages of elimination resulting from sequestration and filtration were 88.5% and 11.5%, respectively. CONCLUSION: Increasing the dose does not mitigate caspofungin sequestration in the STX filter. The results raise caution about the simultaneous use of caspofungin and polyacrylonitrile-derived filters. Intermittent modes of renal replacement therapy might be considered. For sensitive species, fluconazole might be an alternative.

Vancomycin Sequestration in ST Filters: An In Vitro Study.

BACKGROUND: Sequestration of vancomycin in ST® filters used in continuous renal therapy is a pending question. Direct vancomycin-ST® interaction was assessed using the in vitro NeckEpur® technology. METHOD: ST150® filter and Prismaflex dialyzer, Baxter-Gambro, were used. Two modes were assessed in duplicate: (i) continuous diafiltration (CDF): 4 L/h, (ii) continuous dialysis (CD): 2.5 L/h post-filtration. RESULTS: The mean initial vancomycin concentration in the central compartment (CC) was 51.4 +/- 5.0 mg/L. The mean percentage eliminated from the CC over 6 h was 91 +/- 4%. The mean clearances from the CC by CDF and CD were 2.8 and 1.9 L/h, respectively. The mean clearances assessed using cumulative effluents were 4.4 and 2.2 L/h, respectively. The mean percentages of the initial dose eliminated in the effluents from the CC by CDF and CD were 114 and 108% with no detectable sequestration of vancomycin in both modes of elimination. DISCUSSION: Significant sequestration adds a clearance to that provided by CDF and CD. The study provides multiple evidence from the CC, the filter, and the effluents of the lack of an increase in total clearance in comparison with the flow rates without significant sequestration in the ST® filter comparing cumulative effluents to the initial dose in the CC. CONCLUSIONS: There is no evidence ST® filters directly sequestrate vancomycin.

Elimination of cefotaxime using polysulfone and polyacrylonitrile-derived filters: An in vitro assessment.

Continuous renal replacement therapy (CCRT) efficiently eliminates cefotaxime. To our knowledge, there are no previous in vitro studies dealing with the disposition of cefotaxime. We studied the elimination of cefotaxime by two filters in a model mimicking a session of CRRT using the NeckEpur® technology. The ST150®-polyacrylonitrile filter with the Prismaflex, Baxter-Gambro, and the AV1000®-polysulfone filter with the Multifiltrate Pro, Fresenius, were studied. Continuous filtration used a flowrate of 1 L/h in post-dilution only. Simulated blood flowrate was set at 200 mL/min. Routes of elimination were assessed using the NeckEpur® technology. Cefotaxime concentrations were measured using ultra high-performance liquid chromatography, and tandem mass spectrometry. Two sessions were performed using the ST® filter and three using the AV® filter. Stability of cefotaxime during 6 h was assessed in triplicate with a mean variation of concentrations of 2.4 ± 1.5% at the end of the study. The mean measured initial concentration in the central compartment (CC) for the five sessions was 52.4 mg/L. The mean amount eliminated from the CC at the end of the sessions using the ST150®-polyacrylonitrile and the AV1000®-polysulfone filters were 72% and 73%, respectively. The clearances of cefotaxime from the central compartment (CC) were 1.1 and 1.2 L/h, respectively. The mean sieving coefficient were 0.99 and 0.99, respectively. The mean percentages of the amount eliminated from the CC by filtration/adsorption were 87/13% and 92/8%, respectively. Both adsorption percentages were below 15%. We conclude neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in clinically significant adsorption of cefotaxime.

Disposition of gentamicin and amikacin in extracorporeal membrane oxygenation using a heparin-coated filter: An in vitro assessment.

Disposition of gentamicin and amikacin during extracorporeal membrane oxygenation has not been addressed in in vitro models. The HLS Advanced 7.0® circuit with the Cardio Help® monitor, Getinge, was used. The 5-L central compartment (CC) was loaded with gentamicin and amikacin at a targeted concentration of 40 and 80 mg/L in the same bag prior connection to the circuit. Samples were collected in the CC, the inlet and outlet ports from 15 min to 6 h post-connection. Pharmacokinetic analyses were performed using the NeckEpur® method. Analysis of results of gentamicin and amikacin showed in the filter-pump block (i) the extremely low value of the extraction coefficients, (ii) similar values of the areas under the curve (AUCs) at the inlet and outlet ports, (iii) using the Wilcoxon matched pairs signed rank test no significant differences of the inlet-outlet concentrations in the filter-pump. In the whole system (i) the amounts recovered in the CC at the end of the 6-h session were not significantly different from the initial values, (ii) the extremely low values of the total clearance of gentamicin and amikacin from the CC in comparison with the measured simulated blood flowrate, (iii) the lack of significant time-concentration interactions in the CC and the inlet and outlet ports. These findings allow concluding no detectable adsorption of gentamicin and amikacin occurred in the HLS Advanced 7.0 circuit.

[Plasmatic and urinary pyroglutamic acid measurement by capillary zone electrophoresis in chronic poisoning with acetaminophen in children]. / Dosage plasmatique et urinaire de l'acide pyroglutamique par électrophorèse capillaire de zone dans le cadre d'intoxication chronique par le paracétamol chez l'enfant.

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.

Elimination of three doses of gentamicin over three consecutive days using a polyacrylonitrile-derived filter: An in vitro assessment.

INTRODUCTION: Adsorption of gentamicin in a polyacrylonitrile filter was previously evidenced in a session lasting 6 h using the NeckEpur model. We extended the study over three consecutive days to mimic the 72-h life span of a filter. METHODS: Prismaflex® monitor and ST150® filter were used in the continuous diafiltration (CDF) mode at a 2.5 L/h flowrate. The daily session started with a 6-h session of CDF. Thereafter, the 5-L central compartment was changed using a bag free of gentamicin to assess gentamicin release over the following 18 h. Experiments were repeated on Day 2 and stopped at the end of the 6-h session of CDF on Day 3. The experiment was performed in duplicate. RESULTS: At a 2.5 L/h diafiltration flowrate, the mean daily clearances of gentamicin were 5.5, 4.0, and 3.3 L/h, respectively. The mean diafiltration and adsorption ratios in the daily elimination of gentamicin were 32/68%, 58/42%, and 88/12%, respectively. During days 1 and 2, the mean amount of gentamicin released from the ST150® filter were 14 and 34 mg, respectively. CONCLUSION: The pharmacokinetics of gentamicin over 3 days is strongly altered by adsorption in the same filter with a progressive decrease of elimination by adsorption, suggesting saturation of the filter. One limitation of our study results from the mode of administration using a bolus dose instead of an infusion over 30 min. Adsorption adds a clearance to those of diafiltration. The time-dependency of gentamicin clearance precludes using a constant dosage regimen over the filter's life span.

Are we correctly treating invasive candidiasis under continuous renal replacement therapy with echinocandins? Preliminary in vitro assessment.

There is major concern regarding the pharmacokinetics of drugs under continuous renal replacement therapy (CRRT), including anti-infectious agents and more especially antifungal agents. From a regulatory viewpoint, only dialysis and filtration are considered meanwhile there is growing evidence that adsorption may also significantly alter the pharmacokinetics of anti-infectious agents. Adsorption results from a complex drug-filter interaction and might be considered an unexpected adverse effect induced by CRRT. Measurement of total plasma concentrations instead of the unbound, free, active concentrations in in vitro as well as in clinical studies hides this major adverse effect, which may jeopardise the therapeutic effect and even result in treatment failure. Noteworthy, minimal inhibitory concentrations (MIC) of anti-infectious agents are performed using solid and liquid medium without proteins testing only the antimicrobial activity of the free fraction of drugs. In a new in vitro model using crystalloid solution instead of blood, we report data supporting the assumption that the assessment of the disposition of the free fraction of caspofungin and micafungin unveils adverse effects of ST150® filter, which might eventually result in non-detectable drug concentrations and treatment failure. From a technical viewpoint, we conclude the measurement of the free fraction of drugs that largely bound to plasma proteins, including caspofungin and micafungin, should be considered instead of total plasma concentrations to assess all effects induced by filters used in CRRT.

Alteration of the pharmacokinetics of aminoglycosides by adsorption in a filter during continuous renal replacement therapy. An in vitro assessment.

OBJECTIVES: Filters used in continuous renal replacement therapy (CRRT) induce elimination by filtration, dialysis, and adsorption. The worldwide used ST150® filter adsorbs cytokines. However, adsorption is a non-specific process which might alter the pharmacokinetics of drugs. Pharmacodynamic/pharmacokinetic relationship of aminoglycosides evidences the importance of the peak concentration at the first dose. We hypothesize an in vitro study may clarify the routes of elimination of aminoglycosides using the ST150® filter. METHODS: Prismaflex® and the STX150® filter, Baxter-Gambro were used. The diafiltration mode combined flowrates of dialysis and filtration at 2.5/1.5L/h, respectively, over 6h. One ionic solute was used in the different compartments. Pharmacokinetic analyses were performed using the NeckEpur® software. RESULTS: Percentages of gentamicin, tobramycin, and amikacin eliminated from the central compartment were 97±1, 95±3, and 94±6, %, respectively. The clearances were 8.4±2.3, 5.4±5, and 4.2±0.4L/h, respectively. The contributions of dialysis, filtration, and adsorption for gentamicin, tobramycin, and amikacin were 34.3±2.1, 0±0, and 67.7±2.1; 51.1±1.6, 6.3±3.1, and 46.3±2.0, and 37.8±6.3, 46.3±2.0, and 16.0±5.7%, respectively. Among physico-chemical properties, the rate of adsorption linearly and inversely correlated with the polar surface area of aminoglycosides (Y=-0.44X+161.7; R2=0.9993). DISCUSSION: Using the ST150® filter, dialysis, filtration, and adsorption play a role depending on the chemical structure of aminoglycosides. In the diafiltration mode, elimination of gentamicin and tobramycin by filtration is not detected or weak, respectively. Adsorption should be considered as a potential adverse effect of CRRT. Polar surface area of drugs is a physico-chemical parameter which should be considered regarding adsorption of drugs in filters. The risk needs to be systematically assessed.

Elimination of fluconazole during continuous renal replacement therapy. An in vitro assessment.

INTRODUCTION: Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur® model. Two filters were studied. METHODS: The AV1000®-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150®-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur® model. RESULTS: The mean measured initial fluconazole concentration (mean ± SD) for the four sessions in the central compartment (CC) was 14.9 ± 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000®-polysulfone and the ST150®-polyacrylonitrile filters were 90%-93% and 96%-94%, respectively; the clearances from the central compartment (CC) were 2.5-2.6 and 2.4-2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%-0.91% and 0.99%-0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%-95/5% and 100/0%-100/0%, respectively. CONCLUSION: Neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in any significant adsorption of fluconazole.

Correction to: Suspected paracetamol overdose in Monrovia, Liberia: a matched case-control Study.

An amendment to this paper has been published and can be accessed via the original article.

Concentration-dependent mortality of chloroquine in overdose.

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.

Hydroxychloroquine and chloroquine are closely-related drugs used for the treatment of malaria and rheumatological conditions, such as lupus. Laboratory tests have indicated that these drugs could also be used against the virus that causes COVID-19. Given the urgent need, these drugs have been fast-tracked into large-scale clinical trials, bypassing the usual stages that would provide estimates for suitable dosage. The dosage is a critical factor in a clinical trial: too low and the drug will not have an effect, too high and the side effects may counteract any potential benefits. Laboratory tests suggest that higher doses of chloroquine or hydroxychloroquine are needed for treating COVID-19 compared to malaria or lupus. However, there are concerns about the high doses used in some trials, as the drugs can have lethal side effects. Indeed, chloroquine has been used extensively in suicide attempts, particularly in France. To address these concerns, Watson et al. set out to determine the highest dosage of chloroquine (and thus of hydroxychloroquine, approximately) that does not cause unacceptable side effects. First, data was analysed regarding the concentration of chloroquine in the blood of 302 patients who had intentionally overdosed on the drug, since this concentration is tightly correlated with their risk of death. Watson et al. used a statistical model to calculate the maximal chloroquine concentration in a person's blood associated with a one per cent risk of death. This is taken to be the threshold above which any potential benefit of chloroquine treatment would be outweighed by the possibility of lethal toxicity. Watson et al. also estimated the relationship between chloroquine concentrations and changes in electrocardiogram patterns, which record the electrical activity of the heart. This makes it possible to determine whether a high dose of chloroquine has led to dangerous levels in the blood. Using a mathematical model of how chloroquine is metabolised, Watson et al. predicted that most of the trials that tested chloroquine as a treatment for COVID-19 did not reach the calculated threshold concentration. An exception was the CloroCovid-19 trial in Brazil, which was stopped early because people in the higher dosage group suffered more heart problems and died in greater numbers than those in the lower dosage group. Two large randomised trials, RECOVERY and SOLIDARITY, have shown no benefit of hydroxychloroquine or chloroquine in the treatment of COVID-19, changing clinical practice worldwide. Both of these trials used high doses resulting in higher hydroxychloroquine or chloroquine concentrations than normally observed in the treatment of malaria or rheumatological conditions. The results from Watson et al demonstrate that the lack of benefit seen in these two large clinical trials is not due to the drug dosage being too high.

Safety and Efficacy of New Oximes to Reverse Low Dose Diethyl-Paraoxon-Induced Ventilatory Effects in Rats.

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.

Suspected paracetamol overdose in Monrovia, Liberia: a matched case-control study.

BACKGROUND: A cluster of cases of unexplained multi-organ failure was reported in children at Bardnesville Junction Hospital (BJH), Monrovia, Liberia. Prior to admission, children's caregivers reported antibiotic, antimalarial, paracetamol, and traditional treatment consumption. Since we could not exclude a toxic aetiology, and paracetamol overdose in particular, we implemented prospective syndromic surveillance to better define the clinical characteristics of these children. To investigate risk factors, we performed a case-control study. METHODS: The investigation was conducted in BJH between July 2015 and January 2016. In-hospital syndromic surveillance identified children with at least two of the following symptoms: respiratory distress with normal pulse oximetry while breathing ambient air; altered consciousness; hypoglycaemia; jaundice; and hepatomegaly. After refining the case definition to better reflect potential risk factors for hepatic dysfunction, we selected cases identified from syndromic surveillance for a matched case-control study. Cases were matched with in-hospital and community-based controls by age, sex, month of illness/admission, severity (in-hospital), and proximity of residence (community). RESULTS: Between July and December 2015, 77 case-patients were captured by syndromic surveillance; 68 (88%) were under three years old and 35 (46%) died during hospitalisation. Of these 77, 30 children met our case definition and were matched with 53 hospital and 48 community controls. Paracetamol was the most frequently reported medication taken by the cases and both control groups. The odds of caregivers reporting supra-therapeutic paracetamol consumption prior to admission was higher in cases compared to controls (OR 6.6, 95% CI 2.1-21.3). Plasma paracetamol concentration on day of admission was available for 19 cases and exceeded 10 µg/mL in 10/13 samples collected on day one of admission, and 4/9 (44%) collected on day two. CONCLUSIONS: In a context with limited diagnostic capacity, this study highlights the possibility of supratherapeutic doses of paracetamol as a factor in multi-organ failure in a cohort of children admitted to BJH. In this setting, a careful history of pre-admission paracetamol consumption may alert clinicians to the possibility of overdose, even when confirmatory laboratory analysis is unavailable. Further studies may help define additional toxicological characteristics in such contexts to improve diagnoses.

Evaluating lactate prognostic value in children suspected of acetaminophen-induced liver failure in Liberia.

BACKGROUND: The prognostic significance of hyperlactatemia in young children with liver injury suspected to be attributed to repeated supratherapeutic doses of acetaminophen remain understudied. METHODS: We conducted a retrospective medical chart review including children aged <5 years admitted with hepatocellular injury. The study was conducted in Bardnesville Junction Hospital operated by Médecins Sans Frontières in Monrovia, Liberia. RESULTS: We analyzed 95 children with liver injury in whom a blood lactate measurement on admission was available. Eighty children (84%) were aged <2 years; 49 children (52%) died during hospitalization. The median acetaminophen concentration on admission was 20 mg/L with 60 (70%) children presenting concentrations exceeding 10 mg/L. Median lactate was significantly higher in children who died (10.7 mmol/L; interquartile range (IQR): 8.5-15.7) than those who survived (6.1 mmol/L; IQR: 4.1-8.5), P value < 0.001). The optimal threshold obtained was 7.2 mmol/L with a sensitivity of 84% and specificity 70% (area under curve = 0.80). The previously established thresholds of 3.5 and 4 mmol/L lactate had very low specificity identifying non-survival in children included in this study. CONCLUSION: In this setting, young children with ALF possibly attributed to acetaminophen toxicity were unlikely to survive if the venous blood lactate concentration exceeded 7.2 mmol/L.

Predictors of Extubation Failure Related to Aspiration and/or Excessive Upper Airway Secretions.

BACKGROUND: Extubation failure may have several causes, including swallowing dysfunction, aspiration, and excessive upper airway secretions. We hypothesized that a bedside global swallowing pattern assessment including 9 criteria (volume of pharyngeal secretions, 5 swallowing motor items, swallowing reflex, and 2 gag reflexes) performed prior to extubation could identify patients at risk of extubation failure. METHODS: In a multicenter prospective observational study, all consecutive patients intubated and mechanically ventilated for ≥6 d were included. Before a planned extubation, a physiotherapist evaluated the 9 criteria of the swallowing assessment. The final extubation decision was left to the physician's discretion, blinded to the swallowing assessment. Extubation failure was defined as the need for re-intubation related to aspiration or excessive upper airway secretions within the first 72 h after extubation. Results are expressed as median (interquartile range [IQR]). RESULTS: The study included 159 subjects (age 61 y [IQR 48-75]; male/female ratio 1.5; Simplified Acute Physiologic score II 54 [IQR 42-66]; duration of mechanical ventilation 11 d [IQR 8-17]). A total of 23 subjects (14.5%) required re-intubation, with 16 occurring within the first 72 h after extubation and 7 related to aspiration or excessive secretions. Swallowing assessment was significantly lower in subjects with re-intubation related to aspiration or excessive secretions within the first 72 h after extubation versus those not re-intubated for aspiration or excessive secretions (6 [IQR 5-7] vs 8 [IQR 7-8], P = .008, respectively). Among the 9 swallowing assessment criteria, normal right pharyngeal gag reflex was associated with a lower incidence of re-intubation related to aspiration or excessive secretions (odds ratio 0.12, 95% CI 0.03-0.59, P = .01), as well as normal left pharyngeal gag reflex (odds ratio 0.13, 95% CI 0.03-0.63, P = .01), with a negative predictive value of 0.98 for each reflex. CONCLUSIONS: In subjects with prolonged ventilation, the presence of one or both gag reflexes could predict a reduction in extubation failure related to aspiration or excessive upper airway secretions. (Clinical trials.gov registration NCT00780078.).

Comparison of the Respiratory Toxicity and Total Cholinesterase Activities in Dimethyl Versus Diethyl Paraoxon-Poisoned Rats.

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.