pralidoxime and Seizures

Most childhood exposures to insecticides and herbicides do not result in poisonings. Decontamination and observation are usually adequate treatments. The most frequent exposures involve carbamate and organophosphate insecticides. These compounds inhibit acetylcholinesterase, resulting in cholinergic signs that are reversible with atropine administration. Recent reports from poison control centers indicate that organophosphates have been associated with most of the serious childhood poisonings. Pralidoxime, a cholinesterase reactivator, must be administered along with atropine to patients with serious organophosphate poisoning, to reverse nicotinic receptor effects--in particular, respiratory paralysis. Although carbamates and organophosphates may cause clinically indistinguishable physical signs, pralidoxime therapy may be contraindicated for carbamate intoxications. In the event of a serious poisoning caused by a combination of organophosphate and carbamate insecticides, or by an unknown cholinergic agent, pralidoxime should not be withheld. Many organochlorine insecticides are restricted or are no longer available in the United States. CNS excitation and seizures, manifestations of organochlorine intoxication, can occur following ingestion or inappropriate application of the 1 per cent topical formulation of lindane used to treat scabies and lice. Treatment of such intoxication consists of decontamination measures and anticonvulsant administration. Pyrethrins are generally nontoxic in doses commonly ingested. Individuals with an allergic history may be at greatest risk for the most common adverse effects, contact dermatitis and hypersensitivity reactions. Of all insecticides or herbicides, paraquat is the most toxic. Any exposure to paraquat must be evaluated, even if several days have passed since the herbicide was ingested. Signs of pulmonary status deterioration usually portend a grave prognosis in paraquat poisoning. Despite in vitro toxicity similar to paraquat, diquat does not cause lung effects in human poisonings, and reported deaths have been from other causes. Poisoned patients who receive appropriate and timely treatment are virtually assured of complete recovery from most insecticide and herbicide poisonings. Deaths and long-term sequelae most often result from respiratory complications, which may occur as complications of the intoxication or from other constituents in the insecticide or herbicide formulation. Good supportive care with metic

Topics: Absorption; Adolescent; Animals; Anticonvulsants; Atropine; Carbamates; Central Nervous System; Child; Child, Preschool; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Gastric Lavage; Herbicides; Humans; Insecticides; Nausea; Organophosphorus Compounds; Paraquat; Pralidoxime Compounds; Seizures; Vomiting

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

Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24h to all tested rats when they received only 0.65mg/kg atropine at the time of initiation of seizure-like behavior (about 30min). If 146mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24h survivors. The lethality data indicate that 24h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures.

Topics: Acetylcholinesterase; Animals; Antidotes; Behavior, Animal; Brain; Cholinesterase Inhibitors; Male; Organothiophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyrrolidines; Rats; Rats, Sprague-Dawley; Seizures; Survival Analysis

The prophylactic and neuroprotective impact of a transdermal patch containing eserine and pralidoxime chloride (2-PAM) against (±)-Anatoxin A poisoning was investigated using Wistar strain albino rats. Rats were smooth-shaved on the dorsal side, attached with a drug-in-adhesive matrix type prophylactic transdermal patch for 72 h and challenged with subcutaneous injection of three doses (1.0, 1.5 and 2.0×LD50) of (±)-Anatoxin A. The LD50 value of (±)-Anatoxin A was determined to be 1.25mg/kg, and at this particular dose (1.0×LD50) of toxin induced severe clinical symptom including extreme seizures in rats, resulting acute brain injuries in discrete brain regions, leading to 100% mortality within 5 min. The anticonvulsant effect, antiarrythmic effect, nerve conduction study, clinical observations and mortality, neuroprotective effect as well as skin histopathology of the prophylactic transdermal patch against (±)-Anatoxin A poisoning were investigated systematically. It was found that seizures, tachycardia, nerve damage, clinical symptoms, brain injuries and mortality induced by such lethal toxin were effectively prevented by the prophylactic patch treatment up to certain LD50 level. Hence, it could be a choice of potential therapeutic regimen against such lethal poisoning.

Topics: Animals; Anti-Arrhythmia Agents; Anticonvulsants; Arrhythmias, Cardiac; Brain; Cyanobacteria Toxins; Male; Neuroprotective Agents; Physostigmine; Pralidoxime Compounds; Rats, Wistar; Seizures; Skin; Transdermal Patch; Tropanes

The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at α5-, α2-, and α3- but low intrinsic efficacy at α1-containing GABA(A) receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 μg/kg pyridostigmine bromide 30 min prior to 2× LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.

Topics: Acetylcholinesterase; Analysis of Variance; Animals; Atropine; Benzodiazepines; Body Weight; Brain; Chemical Warfare Agents; Cholinesterase Reactivators; Disease Models, Animal; Drug Administration Schedule; Electrocardiography; Electroencephalography; Guinea Pigs; Imidazoles; Lethal Dose 50; Male; Muscarinic Antagonists; Neuroprotective Agents; Neurotoxicity Syndromes; Pralidoxime Compounds; Seizures; Soman; Telemetry; Time Factors

Organophosphorus nerve agents irreversibly inhibit acetylcholinesterase, causing a toxic buildup of acetylcholine at muscarinic and nicotinic receptors. Current medical countermeasures to nerve agent intoxication increase survival if administered within a short period of time following exposure but may not fully prevent neurological damage. Therefore, there is a need to discover drug treatments that are effective when administered after the onset of seizures and secondary responses that lead to brain injury.. To determine potential therapeutic targets for such treatments, we analyzed gene expression changes in the rat piriform cortex following sarin (O-isopropyl methylphosphonofluoridate)-induced seizure. Male Sprague-Dawley rats were challenged with 1 × LD50 sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride (2-PAM), and the anticonvulsant diazepam. Control animals received an equivalent volume of vehicle and drug treatments. The piriform cortex, a brain region particularly sensitive to neural damage from sarin-induced seizures, was extracted at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Principal component analysis identified sarin-induced seizure occurrence and time point following seizure onset as major sources of variability within the dataset. Based on these variables, the dataset was filtered and analysis of variance was used to determine genes significantly changed in seizing animals at each time point. The calculated p-value and geometric fold change for each probeset identifier were subsequently used for gene ontology analysis to identify canonical pathways, biological functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course.. A multitude of biological functions and pathways were identified as being significantly altered following sarin-induced seizure. Inflammatory response and signaling pathways associated with inflammation were among the most significantly altered across the five time points examined.. This analysis of gene expression changes in the rat brain following sarin-induced seizure and the molecular pathways involved in sarin-induced neurodegeneration will facilitate the identification of potential therapeutic targets for the development of effective neuroprotectants to treat nerve agent exposure.

Topics: Animals; Anticonvulsants; Atropine; Brain; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diazepam; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Male; Microarray Analysis; Muscarinic Antagonists; Pralidoxime Compounds; Principal Component Analysis; Rats; Rats, Sprague-Dawley; Sarin; Seizures; Signal Transduction; Transcription, Genetic

The capability of the tertiary oximes, monoisonitrosoacetone (MINA) and diacetylmonoxime (DAM), to reactivate acetylcholinesterase (AChE) inhibited by sarin (GB) in the blood, brain, and peripheral tissues of guinea pigs was compared with that of the quaternary oximes 2-PAM, HLö7, and MMB-4. Animals were injected subcutaneously (s.c.) with 1.0 x LD(50) of GB and treated intramuscularly (i.m.) 5 min later with one of these oximes. Sixty minutes after GB exposure, tissues were collected for AChE analysis. At low doses, MINA and DAM produced significant increases in AChE activity in all brain areas examined, but no significant AChE reactivation in peripheral tissues or blood. At higher doses, MINA and DAM increased AChE activity in the brain, peripheral tissues, and blood. In contrast, the quaternary oximes produced significant reactivation in peripheral tissues and blood AChE, but no significant reactivation of brain AChE. In another study, animals were pretreated i.m. with pyridostigmine 30 min prior to s.c. challenge with 2.0 x LD(50) of GB and treated i.m. 1 min later with atropine sulfate (2.0 mg/kg), plus a varied dose of oximes. MINA and DAM prevented or terminated GB-induced seizure activity and protected against GB lethality in a dose-dependent fashion. In contrast, none of the quaternary oximes prevented or stopped GB-induced seizures. Thus, tertiary oximes reactivated AChE in the brain, improved survival, and terminated seizures following GB intoxication.

Topics: Acetylcholinesterase; Animals; Atropine; Brain; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diacetyl; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Activation; Guinea Pigs; Injections, Intramuscular; Male; Muscarinic Antagonists; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Pyridostigmine Bromide; Sarin; Seizures; Treatment Outcome; Up-Regulation

The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 microg/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicited muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI).

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diaphragm; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electroencephalography; Erythrocytes; Galantamine; Guinea Pigs; Male; Muscle Fatigue; Muscle Tonus; Neurotoxicity Syndromes; Organothiophosphorus Compounds; Paralysis; Phrenic Nerve; Pralidoxime Compounds; Seizures; Time Factors

Topics: Acetylcholine; Acetylcholinesterase; Animals; Atropine; Benzodiazepines; Blood-Brain Barrier; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Drug Therapy, Combination; Galantamine; Guinea Pigs; Insecticides; Neurons; Neurotransmitter Agents; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Paraoxon; Pralidoxime Compounds; Pyridostigmine Bromide; Receptors, Cholinergic; Receptors, Muscarinic; Sarin; Seizures; Soman; Time Factors

Pharmacological properties of oxime reactivators, not related to its ability to regenerate or reactivate nerve agent-inhibited acetylcholinesterase located at nerve synapses, have been reported to be important in protecting against poisoning by the nerve agent soman. Such non-reactivation effects have thus far been associated only with bispyridinium oximes. This study investigated the possibility of creating similar non-reactivation therapeutic effects in the mono-pyridinium ring oxime, pralidoxime (2-PAM) through attachment of alkyl groups of increasing chain length to the oxime functional group. Of the 4 derivatives investigated, only the O-benzyl derivative displayed strong sedative effects in mice and mitigated the development of motor convulsions following soman challenge (1.8 x LD50, subcutaneous). Anticonvulsant effects of this compound were enhanced by co-administration of a non-anticonvulsant dose of atropine sulfate. Administration of equivalent amount of other O-derivatives of pralidoxime failed to elicit similar anticonvulsant actions. Electroencephalographic (EEG) and histopathological studies using the rat model, intoxicated with a lethal dose (1.6 x LD50, s.c.) of soman, confirmed O-benzyl derivative neuroprotective capabilities when used as a pretreatment drug. Microdialysis studies revealed that its neuroprotective effect is related to its ability to attenuate soman-induced increase in acetylcholine.

Topics: 3,4-Dihydroxyphenylacetic Acid; Acetylcholine; Analysis of Variance; Animals; Anticonvulsants; Atropine; Benzene Derivatives; Cholinesterase Inhibitors; Cholinesterase Reactivators; Corpus Striatum; Dopamine; Drug Synergism; Electroencephalography; Female; Homovanillic Acid; Hydroxyindoleacetic Acid; Mice; Microdialysis; Neuroprotective Agents; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Wistar; Seizures; Serotonin; Soman; Survival Rate; Time Factors

This investigation compared the efficacy of diazepam and the water-soluble prodiazepam-avizafone-in sarin poisoning therapy. Guinea pigs, pretreated with pyridostigmine 0.1 mg/kg, were intoxicated with 4LD(50) of sarin (s.c. route) and 1 min after intoxication treated by intramuscular injection of atropine (3 or 33.8 mg/kg), pralidoxime (32 mg/kg) and either diazepam (2 mg/kg) or avizafone (3.5 mg/kg). EEG and pneumo-physiological parameters were simultaneously recorded. When atropine was administered at a dose of 3 mg/kg, seizures were observed in 87.5% of the cases; if an anticonvulsant was added (diazepam (2 mg/kg) or avizafone (3.5 mg/kg)), seizure was prevented but respiratory disorders were observed. At 33.8 mg/kg, atropine markedly increased the seizure threshold and prevented early respiratory distress induced by sarin. When diazepam was administered together with atropine, seizures were not observed but 62.5% of the animals displayed respiratory difficulties. These symptoms were not observed when using avizafone. The pharmacokinetic data showed marked variation of the plasma levels of atropine and diazepam in different antidote combination groups, where groups receiving diazepam exhibited the lowest concentration of atropine in plasma. Taken together, the results indicate that avizafone is suitable in therapy against sarin when an anticonvulsant is judged necessary.

Topics: Animals; Anticonvulsants; Atropine; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Diazepam; Dipeptides; Drug Interactions; Electroencephalography; Guinea Pigs; Histocytochemistry; Muscarinic Antagonists; Nervous System Diseases; Pralidoxime Compounds; Prodrugs; Pyridostigmine Bromide; Respiratory Insufficiency; Sarin; Seizures

The ability of the nerve agents tabun, sarin, soman, GF, VR, and VX to produce brain seizures and the effectiveness of the anticholinergics biperiden HCl or atropine SO4 as an anticonvulsant treatment were studied in a guinea-pig model. All animals were implanted a week prior to the experiment with cortical electrodes for electroencephalogram (EEG) recordings. On the day of exposure, the animals were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min prior to challenge with a 2 x LD50 dose (s.c.) of a given agent. In separate experiments, animals were challenged with 5 x LD50 (s.c.) of soman. One minute after agent challenge, the animals were treated intramuscularly (i.m.) with 2 mg/kg atropine SO4 admixed with 25 mg/kg 2-PAM Cl and then observed for the onset of seizure activity. Five minutes after the start of nerve agent-induced EEG seizures, animals were treated i.m. with different doses of biperiden HCl or atropine SO4 and observed for seizure termination. The anticonvulsant ED50 of biperiden HCl and atropine SO4 for termination of seizures induced by each nerve agent was calculated and compared. With equally toxic doses (2 x LD50) of these agents, continuous EEG seizures (status epilepticus) developed in all animals challenged with soman, tabun, or VR, and in more than 90% of the animals challenged with GF or sarin. In contrast, only 50% of the animals developed seizures when challenged with VX. The times to onset of seizures for soman, tabun, GF, and sarin were very similar (5-8 min) while for VR, it was about 10 min. In the case of VX, not only was the time to seizure development longer (20.7 min), but the seizure activity in 19% of the animals terminated spontaneously within 5 min after onset and did not return. Under these conditions, the anticonvulsant ED50s of biperiden HCl for soman, GF, VR, tabun, sarin, and VX were 0.57, 0.51, 0.41, 0.2, 0.1, and 0.09 mg/kg, respectively, while those of atropine SO4 for soman, VR, tabun, GF, sarin, and VX were 12.2, 11.9, 10.4, 10.3, 5.1, and 4.1 mg/kg, respectively. In separate experiments, the anticonvulsant ED50 doses of biperiden for animals challenged with 2 or 5 x LD50 of soman were 0.48 (95% confidence limits 0.25-0.73) or 0.57 (95% CI 0.38-0.84) mg/kg, respectively, while the anticonvulsant ED50s for atropine (12.2 mg/kg, i.m.) were identical under these same two challenge conditions. The present study demonstrates that all nerve agents can produce status epilepticus and that the therapeutic

Topics: Animals; Anticonvulsants; Atropine; Biperiden; Cholinesterase Inhibitors; Cholinesterase Reactivators; Disease Models, Animal; Drug Therapy, Combination; Electroencephalography; Guinea Pigs; Lethal Dose 50; Male; Organophosphates; Organophosphorus Compounds; Pralidoxime Compounds; Pyridostigmine Bromide; Sarin; Seizures; Soman

Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible.

Topics: Animals; Anticonvulsants; Antidotes; Atropine; Brain; Cerebellum; Cerebral Cortex; Chemical Warfare Agents; Cholinesterase Reactivators; Cyclohexanes; Cyclohexenes; Diazepam; Drug Therapy, Combination; Electrocardiography; Excitatory Amino Acid Antagonists; Haplorhini; Macaca fascicularis; Male; Piperidines; Poisoning; Pralidoxime Compounds; Seizures; Soman; Time Factors

Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.

Topics: Animals; Anticonvulsants; Atropine; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Cyclohexanes; Cyclohexenes; Diazepam; Drug Combinations; Excitatory Amino Acid Antagonists; Injections, Intravenous; Macaca fascicularis; Male; Muscarinic Antagonists; Neuroprotective Agents; Piperidines; Pralidoxime Compounds; Seizures; Soman; Staining and Labeling; Time Factors

Changes in serum biochemical and hematological parameters were studied in 20 male rhesus monkeys following acute poisoning by the organophosphate nerve agent cyclohexylmethylphosphonofluoridate (CMPF or GF). Animals were challenged with 5 x LD50 GF (233 micrograms/kg, IM) following pretreatment with pyridostigmine (0.3-0.7 mg/kg per 24 h) and treated with atropine (0.4 mg/kg, IM) and either 2-PAM (25.7 mg/kg, IM) or H16 (37.8 mg/kg, IM) at the onset of clinical signs or at 1 min after exposure. Muscle fasciculations, tremors, or convulsions occurred in 19 of 20 animals. Serum biochemical and hematologic parameters were analyzed 2 days and 7 days after exposure and compared to pre-exposure baseline values. Significant increases in creatine kinase (CK), lactate dehydrogenase (LD), aspartate transaminase (AST), alanine transaminase (ALT) and potassium ion (K+), associated with damage to striated muscle and metabolic acidosis, occurred in both oxime-treated groups 2 days after exposure. Total protein, albumin, red blood cell (RBC) count, hemoglobin concentration (Hb) and hematocrit (Hct), were decreased in both oxime-treated groups at 7 days. The results demonstrate that animals exposed to a single high dose of GF and treated with standard therapy exhibit changes in serum biochemical and hematological indices directly and indirectly associated with their clinical presentations.

Topics: Alanine Transaminase; Animals; Antidotes; Aspartate Aminotransferases; Atropine; Biomarkers; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Creatine Kinase; Injections, Intramuscular; L-Lactate Dehydrogenase; Lethal Dose 50; Macaca mulatta; Male; Organophosphorus Compounds; Oximes; Potassium; Pralidoxime Compounds; Pyridinium Compounds; Pyridostigmine Bromide; Seizures

We report a 60-yr-old woman with schizophrenia, who manifested a neuroleptic malignant (NM)-like syndrome after acute organophosphate poisoning (OPP). She attempted suicide by ingesting 40% emulsions of DMTP (S-2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadizol-3-yl-methyl O,O-dimethyl phosphorodithioate) 100 ml. On admission, she was unconscious and demonstrated convulsions, depressed respiratory movements, miosis and profuse salivation. Plasma cholinesterase concentration (842 IU.L-1) was very low and OPP was diagnosed. She was treated with gastric lavage, atropine and pralidoxime (PAM). By the seventh day after admission, symptoms of OPP disappeared and serum ChE had recovered to a sub-normal level. On the 13th day, she demonstrated coma, high fever (41.0 degrees C) and lead-pipe rigidity. Serum CPK was increased (1631 IU.L-1). Dantrolene sodium iv was administered for three days. Body temperature began to decrease in 24 hr, and her consciousness, muscle rigidity and other neurological symptoms returned to normal by the 16th day after admission. She was discharged from the hospital without sequelae 55 days after admission. We conclude that OPP can predispose to an NM-like syndrome and that dantrolene may be effective in the management.

Topics: Atropine; Cholinesterase Reactivators; Cholinesterases; Dantrolene; Female; Humans; Middle Aged; Miosis; Muscarinic Antagonists; Muscle Relaxants, Central; Neuroleptic Malignant Syndrome; Organophosphate Poisoning; Organothiophosphorus Compounds; Poisoning; Pralidoxime Compounds; Respiration; Salivation; Schizophrenia; Seizures; Suicide, Attempted; Therapeutic Irrigation

After cutaneous application of the organophosphate insecticide Diazinon for pubic lice, our patient had symptoms of cholinergic excess, lost consciousness, and had a seizure. Because of the high index of clinical suspicion for potentially lethal organophosphate poisoning, the patient received empiric therapy with pralidoxime and atropine and completely recovered.

Topics: Atropine; Coma; Diazinon; Humans; Insecticides; Lice Infestations; Male; Middle Aged; Pralidoxime Compounds; Seizures; Self Medication; Skin Absorption

The present study demonstrates that dose combinations of atropine sulfate and 2-pyridine aldoxime methylchloride (2-PAM), which do not produce any overt toxic effects on the behavior of mice or guinea pigs in a stable environment, elicit clonic-tonic convulsions and death when the animals are physically stressed by cold water swimming. Phenoxybenzamine (1-6 mg/kg), diazepam (0.625 and 1.25 mg/kg) and pilocarpine (2.5 and 5 mg/kg) significantly decreased (or abolished) the occurrence of atropine and 2-PAM stressed-induced convulsions and/or lethality. In contrast, propranolol (20 mg/kg), was ineffective in preventing either convulsions or lethality. Changes in plasma glucose levels and internal body temperature did not appear to explain the precipitation of convulsions or ensuing death. These results suggest that during acute physical stress, relatively low doses of atropine and 2-PAM produce toxic and lethal effects due to the activation of alpha-adrenergic mechanisms along with a concomitant inactivation of cholinergic mechanisms.

Topics: Animals; Atropine; Blood Glucose; Body Temperature; Cold Temperature; Diazepam; Drug Interactions; Guinea Pigs; Male; Mice; Mice, Inbred ICR; Pralidoxime Compounds; Seizures; Species Specificity; Stress, Physiological; Swimming; Time Factors