pralidoxime and methamidophos

This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.

Topics: Acute Kidney Injury; Affect; Aged; Antidotes; Atropine; Chlorpyrifos; Female; Humans; Insecticides; Male; Mevinphos; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pneumonia, Aspiration; Pralidoxime Compounds; Psychotic Disorders; Respiratory Insufficiency; Retrospective Studies; Seizures; Shock; Survival Analysis; Treatment Outcome

Organophosphate poisoning (OPP) accounts for 200,000 deaths annually in developing countries. Serum cholinesterase (SChE) is of diagnostic value in patients with OPP and is checked repeatedly during the course of treatment. This study aimed to investigate the recovery pattern in patients with OPP using linear mixed models.. Using a retrospective cohort study design, we included 212 adult OPP patients who had visited the emergency department (ED) in a tertiary medical center between 2000 and 2010. One hundred and thirty-one patients were available for analysis, as 81 patients did not meet the criteria and were excluded. Information regarding basic personal characteristics, initial vital signs and severity scores, laboratory data, type and amount of organophosphate ingested, treatment, and serial SChE values was collected. A random coefficient model with a random intercept and a random slope of time were added to address the dynamic relationships of SChE with time and other associated factors.. The initial SChE activity and recovery rates varied among patients with OPP. The type of organophosphate, the first SChE activity, and the initial APACHE II score were significantly related to the SChE recovery trend. Chlorpyrifos and methamidophos had significantly slower and faster SChE recovery rates, respectively, than other organophosphates. Sex, dose of Pralidoxim (2-PAM), and delay in obtaining medical assistance did not significantly affect SChE recovery.. This study demonstrated the pattern and associated correlates of SChE activity recovery in patients with acute OPP. Chlorpyrifos appeared to have a slower SChE activity recovery rate than other organophosphates.

Topics: Acute Disease; Antidotes; Chlorpyrifos; Cholinesterases; Critical Illness; Female; Humans; Insecticides; Male; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pralidoxime Compounds; Retrospective Studies; Severity of Illness Index; Suicide, Attempted; Tertiary Care Centers; Time Factors

Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 μM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 μM, whereas 2(3-(phenylhydrazono)butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 μM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning.

Topics: Acetylcholinesterase; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Erythrocytes; Humans; Insecticides; Male; Obidoxime Chloride; Organothiophosphorus Compounds; Pralidoxime Compounds; Rats; Rats, Wistar

Acephate (AP) is a widely available organophosphorus (OP) insecticide considered to have low mammalian toxicity. In plants and insects, AP is metabolized extensively to methamidophos (MP), a more potent OP insecticide. The limited mammalian metabolism of AP to MP has been studied in laboratory rat models and suggests that initial formation of MP from AP may inhibit further formation. No case reports of human ingestion with urine AP and MP levels have been previously published.. A 4-year-old male being evaluated for altered mental status and head trauma was noted to have muscarinic and nicotinic cholinergic signs. Further history suggested possible ingestion of a commercial AP product at an unknown time. Ingestion of AP was confirmed by the presence of urinary AP and MP and severely depressed red blood cell (RBC) cholinesterase and pseudocholinesterase activity levels. The patient initially received atropine in two 0.02 mg/kg IV boluses, then was started on 0.05 mg/kg IV per hour and titrated accordingly to clinical signs of cholinergic toxicity. Pralidoxime was also given at 20 mg/kg IV bolus, followed by an infusion of 10 mg/kg per hour. The patient required mechanical ventilation for 18 days and atropine infusion for 20 days. After a complicated intensive care unit course, he recovered and was discharged after a total of 32 days of hospitalization.. Four urine samples collected at different times were analyzed for AP and MP by using high-performance liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry. Kinetic calculations were performed by using standard equations.. Suspected ingestion was confirmed by the presence of AP and MP in urine. The amount of MP found in urine suggests some limited human metabolism to this more toxic compound.. Urinary elimination kinetics of AP demonstrates low metabolic conversion of AP to MP in humans.

Topics: Antidotes; Atmospheric Pressure; Atropine; Butyrylcholinesterase; Child, Preschool; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Erythrocytes; Humans; Insecticides; Male; Muscarinic Antagonists; Organothiophosphorus Compounds; Phosphoramides; Poisoning; Pralidoxime Compounds; Respiration, Artificial; Tandem Mass Spectrometry; Treatment Outcome

An outbreak of food poisoning that affected at least ten people in various regions of Japan was traced to exposure to Chinese dumplings contaminated with the organophosphate insecticide Methamidophos. We experienced the most serious case, a five years old girl, who suffered coma. She presented with features of cholinergic overactivity and her serum cholinesterase activity was 9 U/l. We started intravenous treatment with pralidoxime iodide, atropine sulfate, and midazolam. Her symptoms improved gradually and she was discharged on day 25 without any sequelae. Though poisoning attributed to organophosphate insecticides has become less common in recent years, it is even more important to diagnose the problem rapidly based on the characteristic symptoms and to start specific treatment at the earliest possible stage after poisoning.

Topics: Atropine; Child, Preschool; China; Coma; Female; Foodborne Diseases; Humans; Insecticides; Japan; Midazolam; Organothiophosphorus Compounds; Pralidoxime Compounds

To observe the treatments on the patients with acute methamidophos dichlorvos (DDV) and omethoate poisoning and provide the reliable basis for the rational treatments on these three organophosphorus pesticides poisoning.. 101 patients with AOPP in 7 hospitals were divided into three groups: Group A, 59 patients with acute methamidophos poisoning, Group B, 32 patients with acute DDV/dipterex (DEP) poisoning, Group C, 10 patients with acute omethoate/dimethoate poisoning. The levels of erythrocyte AChE and the therapeutic efficacies of pralidoxime chloride (PAM-Cl) were compared among the three groups.. The AChE activities of all the three groups were inhibited on level of (9.12 +/- 7.99) U/g Hb (group A), 7.32 +/- 4.62 U/g Hb (group B) and (12.01 +/- 9.53) U/g Hb (group C), among which no significant difference was found (P > 0.05). All the patients recovered from acute cholinergic excitation or crisis after the treatment of PAM-Cl. The erythrocyte AChE activities were obviously reactivated in group A three hours later after admission to hospital, each on level of (11.37 +/- 8.67) U/g Hb, (12.51 +/- 6.98) U/g Hb, (15.90 +/- 7.31) U/g Hb, (18.33 +/- 4.78) U/g Hb and (18.91 +/- 7.00) U/g Hb at the 12th, 24th, 48th, 72nd hour and discharge (P < 0.05), and the upgrade tendency was continuous. AChE activities in group B were also reactivated after treatment, each on level of (8.91 +/- 5.89) U/g Hb, (1.31 +/- 6.61) U/g Hb, (13.00 +/- 7.55) U/g Hb, (14.22 +/- 7.80) U/g Hb, (12.78 +/- 7.07) U/g Hb and (16.87 +/- 7.06) U/g Hb at the 3rd, 12th, 24th, 48th, 72nd hour and discharge, but the upgrade tendency turned slowly after 12 hours, the inhibited AChE activities were not reactivated in group C from the beginning to the end.. After the treatment of PAM-Cl, the AChE activities of the patients with acute methamidophos poisoning could be continuously reactivated, the AChE activities of the patients with acute DDV/DEP poisoning could also be reactivated in 12 hours, and then keep stable, but the AChE activities of the patients with acute omethoate/dimethoate poisoning could not be reactivated. However, PAM-Cl has therapeutic efficacy against acute toxicity of all the three organophosphorus pesticides. Oximes should be vigorously used in the treatment of AOPP, including acute omethoate/dimethoate poisoning.

Topics: Acetylcholinesterase; Acute Disease; Adult; Cholinesterase Reactivators; Dichlorvos; Dimethoate; Female; Humans; Male; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pralidoxime Compounds; Retrospective Studies

The objective of this study was to evaluate the effects of an adenosine A1 agonist, phenylisopropyl adenosine (PIA), on metamidophos poisoning compared to specific antidotes. Rats were poisoned with metamidophos (30 mg/kg, oral) and observed for 24 hours. One group received sodium chloride (1 mL/kg) and four experimental groups received atropine (5 mg/kg), pralidoxime (PAM, 20 mg/kg), atropine/PAM (5/20 mg/kg) or PIA (1 mg/kg) intraperitoneally. Atropine reduced salivation and prevented respiratory distress when compared to sodium chloride-treated rats. Treatment with PAM did not cause any suppression of cholinergic signs. Atropine and PAM combination prevented salivation, convulsion and respiratory distress. PIA delayed initial time of the salivation, convulsion and time to death. However, PIA was found ineffective against the metamidophos-induced cholinergic symptoms and mortality. All treatments, except PIA, lead to survival of these animals. Acetylcholinesterase (AChE) activity was not normalized by PIA or PAM. PIA prevented metamidophos-induced diaphragmatic muscle necrosis as much as PAM. In conclusion, a single dose of PIA was unable to protect the rats from metamidophos toxicity. Further studies are needed involving a combination of PAM and/or atropine with repeated doses of PIA to clarify the efficacy of adenosine agonists in OP poisoning.

Topics: Adenosine A1 Receptor Agonists; Animals; Antidotes; Atropine; Cholinesterase Reactivators; Cholinesterases; Diaphragm; Drug Interactions; Insecticides; Male; Models, Animal; Muscarinic Antagonists; Organothiophosphorus Compounds; Phenylisopropyladenosine; Poisoning; Pralidoxime Compounds; Rats; Rats, Wistar; Respiration; Salivation; Survival Rate; Time Factors

We investigated the ultrastructural effects of the organophosphate compound methamidophos and treatment with atropine and pralidoxime (2-PAM) on rat kidneys. Male Wistar albino rats were assigned to four groups. Group 1 received 30 mg/kg methamidophos, the LD50 for this compound in rats, via oral gavage. Group 2 received only physiologic saline. Group 3 rats received 30 mg/kg methamidophos and were treated with 2-PAM and atropine via intraperitoneal injection when cholinergic symptoms were noted. Group 4 served as a control, and received physiologic saline in equivalent volumes and routes to Group 3. Kidney tissues were prepared for electron microscopic studies. No ultrastructural changes were detected in Group 1 after acute poisoning with methamidophos and in Group 3 treated with antidotes after poisoning. Acute organophosphate poisoning and antidotal treatment in this model are not associated with histopathological changes in the rat kidney but the models with different organophosphate compounds, by administrating the different dosages, may be more illuminative in explaining the effects of these chemicals in kidney.

Topics: Acute Disease; Animals; Antidotes; Disease Models, Animal; Kidney; Kidney Diseases; Kidney Function Tests; Male; Organothiophosphorus Compounds; Pralidoxime Compounds; Random Allocation; Rats; Rats, Wistar; Reference Values

We investigated the ultrastructural effects of methamidophos and the positive effects of 2-pralidoxime (2-PAM) on the liver. Male Wistar-albino rats were assigned to 4 groups and all were treated per os: Group 1 (n=10) received 30 mg/kg methamidophos; Group 2 (n=7) (serving as controls for Group 1) received physiologic NaCl; Group 3 (n=10) received 30 mg/kg methamidophos and was treated with 2-PAM and atropine when cholinergic symptoms were noted; and Group 4 (n=7) (serving as controls for Group 3) was treated with physiologic NaCl. Plasma cholinesterase was measured using radioimmunoassay. Liver tissues were prepared for electron microscopic studies. Methamidophos treatment of Group 1 led to serious changes in hepatocytes and organelles. These changes were not detected in Group 3. In Group 1, the chromatin content of some hepatocyte nuclei and cytoplasmic density increased; these cells also became vacuolar in appearance as a result of lysis in the mitochondrial matrices. In some cells, the lipid content constituted the majority of the cytoplasm. Furthermore, these cells were surrounded by glycogen accumulation. In some areas of the perisinusoidal zone, collagen fibers had increased to form bands. None of these changes were noted in Group 3. These findings suggest that acute organophosphate poisoning causes serious histopathological effects in rat liver, but that these changes are reversible with appropriate treatment strategies.

Topics: Acute Disease; Animals; Animals, Laboratory; Antidotes; Insecticides; Liver; Organothiophosphorus Compounds; Pralidoxime Compounds; Rats; Rats, Wistar

Severe organophosphate poisoning (OPP) has a high mortality rate. Respiratory and neurological complications are common in OPP. Multiple organ distress syndrome (MODS) and renal impairment are relatively rare but correlated with death. In previous publications, in patients who did not survive OPP, their deaths were due to MODS or acute renal failure. A case of intentional ingestion of an organophosphate with renal and multiple organ complications is described. In addition to the standard atropine/oxime regimen, continuous venous-venous haemofiltration (CVVH) therapy was started; the patient survived this intoxication. The pathogenesis of renal injury by OPP is unclear and more insight is required. In our experience, CVVH can be a valid therapy, considering in particular the toxicokinetics of the organophosphate.

Topics: Acute Kidney Injury; Adult; Antidotes; Atropine; Hemofiltration; Humans; Insecticides; Male; Organothiophosphorus Compounds; Pralidoxime Compounds; Suicide, Attempted; Treatment Outcome

The objective of the present investigation was to study the protection afforded by a single administration of pralidoxime against the muscle necrosis induced by the organophosphate compound metamidophos at different times after intoxication. The fiber necrosis of the diaphragm muscle was quantified by a morphometric technique, comparing the area fraction occupied by necrotic muscle fibers in animals that received pralidoxime at different times after intoxication, i.e., 0, 1, 3, 6, and 12 h. Pralidoxime administration protected metamidophos-induced muscle necrosis in all groups studied except for the 12-h group. The earlier the administration of pralidoxime the greater the protection against muscle necrosis. This protection was not accompanied by complete reactivation of plasma cholinesterase activity. Results support the current opinion that pralidoxime should be administered as soon as possible after organophosphate intoxication, because in addition to reversing the muscarinic effects, early administration of pralidoxime also prevents muscle necrosis--which could impair muscular function and respiratory condition. The time difference between recovery of plasma cholinesterase activity and muscle necrosis protection indicates that this method is not completely trustworthy for patient follow-up, since some improvement may occur in spite of the low plasma cholinesterase activity.

Topics: Animals; Antidotes; Cholinesterases; Insecticides; Male; Muscle, Skeletal; Organothiophosphorus Compounds; Pralidoxime Compounds; Rats; Rats, Wistar

To determine the protective effect of pralidoxime on muscle fiber necrosis induced by organophosphate acute intoxication in rats.. Adult male Wistar rats were given oral organophosphate compounds dissolved in glycerol formal: dichlorvos, isofenphos, metamidophos, and diazinon. Half of the animals also received pralidoxime mesylate (20 mg/kg, intraperitoneal). Control animals received only the solvent. Twenty-four hours after treatment, the diaphragm muscle was collected for histological counts of necrotic muscle fibers in transverse sections.. Metamidophos- and isofenphos-treated animals showed the highest percentage of necrotic muscle fibers: 1.66 +/- 1.112 and 1.34 +/- 0.320, respectively. Diazinon-treated animals had a lower percentage of necrotic fibers: 0.40 +/- 0.032 (p < 0.05) compared to the first 2 products, and dichlorvos-treated animals showed the smallest: 0.05 +/- 0.021 (p < 0.05) when compared to the other 3 products. Pralidoxime reduced necrotic fibers about 20 times in metamidophos-treated animals, 10 times in isofenphos-treated animals and 6 times in diazinon-treated animals. Pralidoxime administration did not increase plasma cholinesterase activity in any group, although symptoms were reduced.. Oxime reduced diaphragmatic muscle necrosis in experimental organophosphate intoxication, despite little effect on plasma cholinesterase. Since respiratory insufficiency is an important cause of mortality and morbidity in organophosphate intoxications, early oxime administration may be particularly beneficial.

Topics: Acetylcholinesterase; Animals; Antidotes; Diaphragm; Diazinon; Dichlorvos; Insecticides; Male; Muscle Fibers, Skeletal; Muscle, Smooth; Necrosis; Organothiophosphorus Compounds; Pralidoxime Compounds; Rats; Rats, Wistar

Organophosphate insecticides strongly inhibit both true cholinesterase and pseudocholinesterase activities. In this report, we have reported a patient who injected himself a strong organophosphate compound, methamidophos, and showed the typical clinical picture of organophosphate intoxication. As far as we know, this is the first case of intoxication by intravenous (i.v.) injection. With the appropriate therapy, his symptoms disappeared in a few days.

Topics: Adult; Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Humans; Injections, Intravenous; Insecticides; Male; Muscarinic Antagonists; Nervous System Diseases; Organothiophosphorus Compounds; Pralidoxime Compounds; Schizophrenia; Suicide, Attempted

The toxicity of acephate to four species of aquatic insects, as well as the metabolism and cholinesterase-inhibiting properties of the chemical in the rat were studied. The results indicated that mayfly larvae were very sensitive to the toxic effects of acephate, whereas larvae of the stonefly, damselfly and mosquito were much less sensitive. In the rat, orally-administered acephate was rapidly absorbed from the intestines and severely inhibited the cholinesterases in the blood and brain. The enzymes began to recover after 24 hours, while the chemical was completely eliminated within three days. The amount of methamidophos observed in the liver was extremely low. The cholinesterase-inhibiting properties of acephate and methamidophos were compared in vitro to that of paraoxon, a known strong anticholinesterase. Enzymes from four vertebrates were used. In all cases, except one, acephate was found to be six orders of magnitude weaker than paraoxon, whereas methamidophos was three orders weaker. Trout brain cholinesterase was the exception; it was as sensitive to paraoxon as it was to methamidophos. Finally, four cholinesterases were inhibited with methamidophos, and their ability to reactivate spontaneously or to recover by induction with pyridine aldoxime methiodide (PAM) in vitro were determined. The results suggested that methamidophos-inhibited cholinesterases did not reactivate spontaneously; instead the enzymes remained inhibited either in a phosphorylated or an aged state. The significance of these results are discussed in relation to the use of acephate for forest insect pests.

Topics: Animals; Cholinesterase Inhibitors; Cholinesterase Reactivators; Erythrocytes; Insecta; Insecticides; Lethal Dose 50; Liver; Organothiophosphorus Compounds; Paraoxon; Phosphoramides; Pralidoxime Compounds; Rats; Rats, Inbred Strains; Trout