Atypical central nervous system involvement in acute organophosphorous poisoning.

Extrapyramidal syndrome is an uncommon sequelae of acute organophosphorous (OP) poisoning. It is a manifestation of the intermediate syndrome described in OP poisoning. It may or may not be associated with neuroimaging changes in the striatum. We present a case of acute OP poisoning with interesting positive CT scan findings.

[Protective effects of vigabatrin and atropine against dimethoate induced-intoxication in mice].

OBJECTIVE: To investigate the protective effects of vigabatrin and atropine against the acute toxicity of dimethoate in male Kun-min mice. METHODS: The therapeutic schedules of vigabatrin (50 or 100 mg/kg) and (or) atropine (2.5 or 5.0 mg/kg) were performed according to the L(9) (3(4)) orthogonal test table. The survival time, the righting reflex and the onset of muscle fasciculations were observed after the administration of dimethoate. RESULTS: First, the main effects of vigabatrin, atropine and the interaction between them were statistically significant in the Univariate analysis of the survival time at the alpha level of 0.05 (F(V)= 4.73, P(V)= 0.015, F(A)= 50.88, P(A)= 0.000, F(VxA)= 4.17, P(VxA)= 0.007). The range of atropine was more than double of that of vigabatrin or their interaction (R(A)> 2RV or 2R(VxA)). So not only atropine and vigabatrin but also their combination interaction protected mice against dimethoate lethality. The atropine played the major role in diminishing the lethality induced by dimethoate. Second, only vigabatrin, while not atropine, delayed the mice from dimethoate-induced muscle fasciculation according its statistical results (F(V)= 6.87, P(V)= 0.003, F(A)= 0.03, P(A)= 0.968, F(VxA)= 1.134, P(VxA)= 0.356). It should be noted that vigabatrin could not completely prevent dimethoate induced-muscle fasciculation in the test. At last, both atropine and vigabatrin could maintain the righting reflex in the intoxication, however there was no interaction between them (F(V)= 5.81, P(V)= 0.006, F(A)= 9.05, P(A)= 0.001, F(VxA)= 1.34, P(VxA)= 0.257). CONCLUSION: Combined treatment with atropine and vigabatrin in the organophosphates intoxication seems reasonable and acceptable.

[Different therapeutic efficacy of pralidoxime chloride PAM-Cl on AChE against acute toxicity of methamidophos, dichlorvos and omethoate].

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study.

BACKGROUND: Although more than 100 organophosphorus insecticides exist, organophosphorus poisoning is usually regarded as a single entity, distinguished only by the compound's lethal dose in animals. We aimed to determine whether the three most common organophosphorus insecticides used for self-poisoning in Sri Lanka differ in the clinical features and severity of poisoning they cause. METHODS: We prospectively studied 802 patients with chlorpyrifos, dimethoate, or fenthion self-poisoning admitted to three hospitals. Blood cholinesterase activity and insecticide concentration were measured to determine the compound and the patients' response to insecticide and therapy. We recorded clinical outcomes for each patient. FINDINGS: Compared with chlorpyrifos (35 of 439, 8.0%), the proportion dying was significantly higher with dimethoate (61 of 264, 23.1%, odds ratio [OR] 3.5, 95% CI 2.2-5.4) or fenthion (16 of 99, 16.2%, OR 2.2, 1.2-4.2), as was the proportion requiring endotracheal intubation (66 of 439 for chlorpyrifos, 15.0%; 93 of 264 for dimethoate, 35.2%, OR 3.1, 2.1-4.4; 31 of 99 for fenthion, 31.3%, 2.6, 1.6-4.2). Dimethoate-poisoned patients died sooner than those ingesting other pesticides and often from hypotensive shock. Fenthion poisoning initially caused few symptoms but many patients subsequently required intubation. Acetylcholinesterase inhibited by fenthion or dimethoate responded poorly to pralidoxime treatment compared with chlorpyrifos-inhibited acetylcholinesterase. INTERPRETATION: Organophosphorus insecticide poisoning is not a single entity, with substantial variability in clinical course, response to oximes, and outcome. Animal toxicity does not predict human toxicity since, although chlorpyrifos is generally the most toxic in rats, it is least toxic in people. Each organophosphorus insecticide should be considered as an individual poison and, consequently, patients might benefit from management protocols developed for particular organophosphorus insecticides.

Organophosphate poisonings with parathion and dimethoate.

OBJECTIVE: Organophosphate toxicity is the leading cause of morbidity and death in poisoning by insecticides. The clinical symptoms of pesticide toxicity range from the classic cholinergic syndrome to flaccid paralysis and intractable seizures. The mainstays of therapy are atropine, oximes, benzodiazepines and supportive care. The toxicokinetics vary not only with the extent of exposure, but also with the chemical structure of the agent. PATIENTS: We report two cases of poisoning with parathion-ethyl and dimethoate. The patients developed a cholinergic syndrome immediately, accompanied by bradycardia and hypotension. INTERVENTIONS: The patients were admitted to the intensive care unit (ICU) a few hours after ingestion. Atropine was administered according to the cholinergic symptoms. The patients recovered in the ICU after 10-12 days and were discharged after 3 and 4 weeks. MEASUREMENTS AND RESULTS: Organophosphate blood and urine levels were determined on admission and during hospitalisation. The pesticides were rapidly distributed and slow elimination rate of the poisons was documented. In the case of parathion-ethyl the distribution half-life estimated was t(1/2alpha) = 3.1h while the terminal half-life was t(1/2beta) = 17.9 h. Using a one-compartment model for dimethoate the elimination half-life was t(1/2beta) = 30.4 h in plasma and 23.8 h in urine. The serum pseudo-cholinesterase activity was below the limit of detection at admission and recovered during the following 3weeks.

Extrapyramidal parkinsonism complicating acute organophosphate insecticide poisoning.

The aim of this study is to report our experience with a child who developed extrapyramidal perturbations complicating acute organophosphate insecticides poisoning and to review the literature reporting on basal ganglia impairment associated with this poisoning. Our patient had developed overt parkinsonism presenting with a resting tremor, expressionless face, and lack of blinking along with marked cogwheel rigidity and a stooped, slow gait. He was alert, coherent, and cooperative, yet agitated. The parkinsonian perturbations developed 5 days after an accidental ingestion of a raw eggplant sprayed with the organophosphate dimethoate (Rogor) when he had already recovered from the acute cholinergic crisis, the first stage of organophosphate poisoning. Such a presentation was initially perceived by his caregivers as severe reactive depression or even psychosis. Once a parkinsonian syndrome was diagnosed, he was begun on amantadine and completely recovered within 1 week with no relapse of symptoms. Basal ganglia impairment should be considered in any patient who develops extrapyramidal symptoms such as marked rigidity and bradykinesia or choreoathetosis while recovering from the acute cholinergic phase of organophosphate insecticide poisoning. Thus, administration of a drug such as amantadine, which probably enhances neurotransmission, may hasten the rate of recovery and prevent long-term neurologic and emotional sequelae.

The importance of electrodiagnostic studies in acute organophosphate poisoning.

Six patients with acute organophosphate pesticide poisoning in whom electrodiagnostic studies influenced or supported specific decisions in management are described. One patient was admitted to hospital with a diagnosis of acute alcoholic intoxication. Electrodiagnostic studies revealed single stimulus induced repetitive responses and decrement-increment responses at 30 and 50 Hz repetitive nerve stimulation, findings that are indicative of a depolarization block due to inactivation of acetylcholinesterase at the motor end-plate. The patient was subsequently treated as a case of acute organophosphate poisoning. The administration of edrophonium (0.1 mg) to another patient with normal neuromuscular transmission studies unmasked the latent electrophysiological abnormalities. Three instances are described in which electrodiagnostic studies were useful in predicting whether pralidoxime administration was likely to be useful and for how long was pralidoxime therapy to be continued. Phrenic nerve conduction study in one patient with impending respiratory failure revealed an unstimulable phrenic nerve. The potential role of phrenic nerve conduction studies and neuromuscular transmission studies in influencing decisions like intubation and mechanical ventilation is discussed.

Orthodeoxia and platypnoea after acute organophosphorus poisoning reversed by CPAP: a newly described cause and review of the literature.

The case of a 60-year-old male patient, who survived severe organophosphorus poisoning, and subsequently developed platypnoea and orthodeoxia is described. The patient was mechanically ventilated for a long period of time in the intensive care unit. During the weaning trial, he developed platypnoea and orthodeoxia (PaO2 85 mmHg in recumbency, and 40 mmHg in upright position). Interestingly, the patient's orthodeoxia was alleviated on continuous positive airway pressure (CPAP) treatment. This is a newly described cause of the platypnoea-orthodeoxia syndrome. The possible pathophysiological mechanisms are discussed and a review of the reported abnormal states associated with this condition is presented.

Electroneurophysiological studies in rats of acute dimethoate poisoning.

In order to investigate the mechanism of muscular weakness in the intermediate myasthenia syndrome (IMS) following acute organophosphate poisoning, the effect of dimethoate on the neuromuscular transmission was studied in rats by using the electrical stimulation single fiber electromyography (SSFEMG) and repetitive nerve stimulation (RNS). The results showed that there was a prolongation of mean consecutive difference (MCD) of the latencies of single fiber potential shown by SSFEMG in dimethoate intoxicated rats during the presence of muscle weakness when the stimuli were given at 10 or 20 Hz, and there was a remarkable decrement of compound muscle action potential (CMAP) of gastrocnemius muscle evoked by RNS on the sciatic nerve at 20 Hz in some rats with myasthenia. The frequency of neuromuscular transmission abnormalities detected by SSFEMG was significantly higher than those detected by RNS. This study demonstrates that the SSFEMG is a more sensitive electrophysiological method in the detection of neuromuscular transmission block occurred in rats of acute organophosphate poisoning with muscle weakness.

A case of unusual suicidal poisoning by the organophosphorus insecticide dimethoate.

A 20-year-old male who attempted suicide by injecting subcutaneously 10 ml of Sistemin 40 (40% dimethoate) was admitted 16 h later. General weakness, muscular fibrillations and a marked inhibition of red blood cell and serum cholinesterases were the prominent signs of intoxication. The antidotal treatment of intermittent boluses of atropine, oxime HI-6 and diazepam was combined with symptomatic therapy. Cholinesterase activity decreased within the next 3 d. In contrast to the marked general improvement of the patient, the return of cholinesterase activities was very slow. The patient was discharged 24 d after the poisoning with no notable consequences which could be ascribed to the intoxication.

Self-limiting cerebellar ataxia following organophosphate poisoning.

Deliberate self-harm by ingestion of organophosphate insecticides is a common health problem in Sri Lanka. The poisoning results in an initial life-threatening cholinergic crisis and several intermediate and late neurological and psychiatric manifestations. A patient who developed self-limiting cerebellar signs 8 days after ingestion of dimethoate, an organophosphorous insecticide, is reported on.

Serum and red cell cholinesterase activity in people exposed to organophosphate insecticides.

Serum and red cell cholinesterase activities were determined in 2 groups of subjects namely:-I) a group of 10 patients who took organophosphate insecticide and were admitted into the hospital for treatment and II) a group of 65 workers from an organophosphate insecticide factory. Serum cholinesterase levels were considerably depressed in all patients in group I and one patient died. The low serum cholinesterase activities increased very slowly and were still very low on day 4 of admission. Serum cholinesterase level in 65 workers were significantly lower than that of the normal subjects. The exposed subjects had still further lower serum cholinesterase activity than those of the non-exposed subjects. There was no significant difference between their red cell cholinesterase activities and those of the normal subjects. Serum and red cell cholinesterase levels in these workers also showed no correlation to the duration of insecticide exposure. These findings indicated that serum cholinesterase activity was a good diagnostic aid in acute exposure because it responded more rapidly than red cell cholinesterase level but it was not sensitive for follow up of the treatment since its recovery rate was too slow. Findings of low serum cholinesterase with normal red cell cholinesterase levels without signs or symptoms of toxicity indicated that these workers had been exposed to some degree of organophosphate insecticides.

[Experimental treatment of respiratory failure caused by omethoate poisoning in rats].

OBJECTIVE: To examine the therapeutic effect of combined use of pralidoxime-Cl and atropine with artificial ventilation on respiratory muscle paralysis caused by omethoate poisoning in rats. METHODS: Rats were administered with same doses of 2LD(50) omethoate and then treated with atropine (10 mg/kg) to resist effectively chlolinergic symptoms. When the rats had slow respiratory frequency and breathed with difficulty, the trachea was intubated and artificial ventilation was carried out (except for group A). The rats in group B were continuously treated with atropine. The doses of pralidoxime-Cl for group C, D and E were 15 mg/kg, 20 mg/kg and 40 mg/kg respectively, given at the same time as artificial ventilation and 1, 2 and 3 hours later. The dose of atropine was reduced to 1/3 to 2/3 of the first dose so as to maintain the rats atropinized. If the rat survived beyond 60 minutes after withdrawal of artificial ventilation, the combined treatment was considered successful. The function of isolated phrenic diaphragm of the rats was observed with MS-302 analyses instrument physiologically and pharmacologically. RESULTS: None of the rats in group B successfully withdraw from artificial ventilation. The rats in group C all successfully withdraw from artificial ventilation in 3 hours and the function of the isolated phrenic muscle remained good. The survival rats in group D and E were very low after withdrawal, even though the function of isolated phrenic muscle was good. CONCLUSIONS: The therapeutic effect of the combined use of suitable dose of pralidoxime-Cl and atropine with artificial ventilation on respiratory muscle paralysis caused by omethoate poisoning in rats was significant. This measure can facilitate reversal of the function of poisoned diaphragm and reduced the death rate in poisoned rats.

Antidotal effect of glucoside extracted from Astragalus membranaceus on dimethoate intoxication in guinea pigs.

Therapeutic effect of the glucoside extracted from the root of Astragalus Membranaceus (AM) was studied in guinea pigs intoxicated with 600 mg/kg doses of Dimethoate (D). Four groups of guinea pigs, each consisting of two males and two females, were treated with (a) D, (b) D + Atropine, and (c) D + AM, (d) D + Atropine + AM. The survival time of the animals increased from an average of 70 minutes without AM to an average of 235 minutes with AM. Severe changes in ECG were observed prior to respiratory distress in groups without AM, and Atropine did not modify such changes. Differently, severe ECG disorders appeared only after respiratory distress in groups treated with AM. Prolongation of the Q-T interval and changing of the T wave configuration were significantly mitigated in the AM treated animals, while, arrhythmias were minimized and postponed. Moreover, muscular fasciculation and fibrillation, seizures and secretion in the respiratory tract were also significantly reduced by AM treatment. Results have shown that AM could be a promising drug to be used after cholinergic crisis in the treatment of cardiac complications with severe organophosphate intoxication.

[Antimutagenic protection of the human genetic system in acute intoxication]. / Antimutagennaia zashchita geneticheskogo apparata cheloveka v usloviiakh ostroi intoksikatsii.

The results of clinical studies and model experiments have shown that human genome damages are widely spread in patients with acute intoxication. For neutralization of the negative effects, biologically active compounds-antimutagens, alpha-tocopherol, and new plant mutagen were used. The application of antimutagens has been found to increase the level of genetic damages induced by acute intoxication.

[Study on the therapeutic effect of combined use of obidoxime and atropine with respiratory machine on respiratory muscle paralysis caused by omethoate poisoning of rats].

OBJECTIVE: To examine the therapeutic effect of combined use of obidoxime and atropine with artificial ventilation on respiratory muscle paralysis caused by omethoate poisoning in rats. METHODS: Rats were exposed to 2 times the dose of LD50 omethoate and treated with atropine (10 mg/kg) to counteract cholinergic symptoms. When the rats' respiratory frequency became slower and breathed with difficulty, the trachea intubation and artificial ventilation was carried out. The rats in group A were continuously treated with atropine. The dose of obidoxime for Group B, C and D were 8, 15, 20 mg/kg respectively, given at the same time as artificial ventilation and 1, 2, 3 hours later. The doses of atropine was reduced to 1/3 - 2/3 of the first dose so as to maintain the rats atropinized. If the rat survival was beyond 60 minutes after withdrawal of artificial ventilation, the combined treatment was considered successful. The function of isolated phrenic diaphragm of the rats was observed with MS-302 physiological and pharmacological analysis instrument. RESULTS: None of the rats in Group A was successful after withdrawal from artificial ventilation and the function of phrenic diaphragm appeared poor; whereas > 80% of the rats in B, C, D Group were successful after withdrawal from artificial ventilation in 3 h and the function of phrenic diaphragm remained well. The survival rate in B, C and D groups were higher after withdrawal from artificial ventilation than that in Group A(P < 0.01). The function of phrenic diaphragm in Group B, C and D were gradually decreased after ACh was added into the container. CONCLUSIONS: Combined use of suitable dose of obidoxime and atropine with artificial ventilation for respiratory muscle paralysis caused by omethoate poisoning could promote the recovery of diaphragm function and reduce the death rate in poisoned rats.

[Expression of M3 receptor gene in peripheral blood lymphocytes of workers exposed to dimethoate].

OBJECTIVE: To study the expression of muscarinic receptor M(3) gene in peripheral blood lymphocytes of workers exposed to organophosphorus pesticides (OPPs) and to explore its role in the adverse effects of OPPs. METHODS: The lymphocytes of peripheral blood from 33 workers exposed to dimethoate and 15 control people were isolated and treated with saline and dimethoate respectively in vitro. RT-PCR technique was used to determine M(3) gene expression. Basal and inducible gene expression levels were measured. RESULTS: There was no significant difference in basal gene expression level between exposed group and control group, while the inducible gene expression level was significantly higher in exposure group (1.92 +/- 1.07) than in control group (1.22 +/- 0.19) and basal level (1.49 +/- 0.45, P < 0.05). No differences in basal and inducible gene expression level were found between male and female people in both exposed and control group. The level of inducible M(3) gene expression increased with the increase in length of exposure time [< 5 a: (1.69 +/- 0.95), 5 - 25 a: (1.91 +/- 1.03), > 25 a: (2.09 +/- 1.25), the latter was significantly different from that of < 5 a (P < 0.05)]. CONCLUSION: After long-term exposure to OPPs, the basal M(3) receptor gene expression level in the exposed workers did not show any difference from the control group, but the inducible gene expression level (treated with dimethoate in vitro) was increased and related to the extent of exposure to dimethoate.

[Stimulation single fiber electromyography in rats with myasthenia induced by organophosphorus insecticides and their mixtures poisoning].

OBJECTIVE: To study the neuromuscular function and its relation with the occurrence of myasthenia in rats poisoned by dimethoate (D), phoxim (P), methomyl (M), M + D and M + P respectively. METHODS: The stimulation single fiber electromyography(SSFEMG) at different stimulus frequencies(5, 10 and 20 Hz) was used. The whole blood cholinesterase (ChE) activity was measured 1 h before and after poisoning. RESULTS: (1) Myasthenia occurred in 5 out of 9.5 out of 10.5 out of 5, and 8 rats poisoned by D, P, M + D, and M + P, respectively. (2) The average mean consecutive differences(MCD) at 5, 10, and 20 Hz in myasthenic rats were significantly higher than those of poisoned rats without myasthenia and the control ones. (3) SSFEMG changes at 5, 10 and 20 Hz were significantly consistent with the clinical manifestation of myasthenia, especially at 10 Hz and 20 Hz. (4) ChE activity was significantly lower in rats with P or D poisoning while ChE inhibition was of no difference in rats with M, M + D, and M + P poisoning. In the D poisoning and P poisoning groups, there was no significant difference in ChE inhibition between the rats with and without myasthenia. CONCLUSION: Muscle weakness was associated with neuromuscular transmission dysfunction, but not well correlated with ChE inhibition. The SSFEMG with stimulus frequency at 10 Hz or 20 Hz could be used to detect the neuromuscular dysfunction during myasthenia induced by organophosphate insecticides and their mixtures poisoning.

Quantification of pralidoxime (2-PAM) in urine by ion pair chromatography-diode array detection: application to in vivo samples from minipig.

Pralidoxime (2-PAM) is a monopyridinium oxime used as an antidote for the treatment of poisoning with organophosphorus (OP) compounds, for example, pesticides and nerve agents, reactivating OP-inhibited acetylcholinesterase. However, appropriate dosing and efficacy remains a matter of discussion requiring experimental data. Therefore, we developed and validated an ion pair chromatography-diode array detection (IPC-DAD) method suitable for quantitative analysis of 2-PAM in human and porcine urine. Before injection of 20 µl, urine was acidified with trichloroacetic acid, mixed with internal standard (pyridine-4-aldoxime, 4-PAO), and diluted with IPC solvent yielding a total dilution of 1:49.5 and a 100% recovery. Isocratic separation was carried out at 25 °C on a LiChrospher 60 RP-select B column (125 x 4.0 mm I.D.) using phosphate buffer (7.5 mM Na(2) HPO(4) , 7.5 mM KH(2) PO(4) , pH 2.6) mixed with octanesulfonate (2.5 mM) as ion pair reagent and acetonitrile (6% v/v) as organic modifier (1 ml/min). 2-PAM was detected at 293 nm and 4-PAO at 275 nm. The method is rugged, selective, and characterized by good intra-day and inter-day precision (RSD, 1.3-6.0%) and accuracy (88-100%) with a limit of detection at 4.9 µg/ml, a limit of quantification at 9.8 µg/ml, and a broad calibration range from 4.9-2500 µg/ml. The procedure was applied to urine samples obtained from dimethoate poisoned minipigs receiving 2-PAM therapy (intravenous bolus injection and infusion). Results indicate that 60-80% of infused 2-PAM is rapidly (within 1-2 h) excreted in the urine.