Pesticide poisoning is an important cause of morbidity and mortality in India.To assess the oxidative damage, hemoglobin level and leukocyte count in acute organophosphorus pesticide poisoning.Plasma cholinesterase was assessed as a toxicity marker. Oxidative damage was assessed by estimating serum malondialdehyde (MDA) levels, plasma total antioxidant capacity (TAC), erythrocyte superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels.Progressive and significant decline (p< 0.001) in plasma cholinesterase in correlation with the severity of organophosphorus poisoning was observed. Serum MDA levels significantly increased (p< 0.001) in all grades of organophosphorus poisoning cases as compared to controls. Erythrocyte SOD, CAT and GPx were significantly increased (p< 0.05) in earlier grade and (p< 0.001) in later grades of organophosphorus poisoning cases as compared to controls. While plasma TAC (p<0.001) was significantly decreased in all grades of organophosphorus poisoning cases as compared to controls. Leucocytosis observed in these cases signifies the activation of defense mechanism which could be a positive response for survival.Organophosphorus compounds inhibit cholinesterase action leading to cholinergic hyperactivity. Increased MDA level may lead to peroxidative damages deteriorating the structural and functional integrity of neuronal membrane. Increased erythrocyte SOD, CAT and GPx activities suggest an adaptive measure to tackle the pesticide accumulation. Hence it is concluded that cholinesterase inhibition may initiate cellular dysfunction leading to acetylcholine induced oxidative damage.

Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen from dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed.

Improper use of pesticides on food plants can result in significant toxicity. In spite of regulations, enforcement, and prior episodes of poisonings, poisonings from misapplication of pesticides continues to occur. The objective of this study was to present a case series of toxicity resulting from ingestion of watermelon inappropriately treated with the carbamate insecticide aldicarb. A restrospective review of medical records, impounding the suspected watermelons, and chemical analysis of the watermelon samples using liquid chromatography and mass spectroscopy were carried out. Seven farm workers shared a watermelon and presented to a rural emergency department with symptoms of cholinergic poisoning. They were treated empirically with atropine and pralidoxime. The farmer denied use of insecticides other than rat poison on the watermelon patch. Chemical analyst verified aldicarb in the watermelon samples from the field, but none in control samples. Despite government regulations, application of restricted pesticides such as aldicarb continues to occur and cause significant poisonings.

Muscarinic acetylcholine receptors (mAChRs) have five known subtypes which are widely distributed in both the peripheral and central nervous system for regulation of a variety of cholinergic functions. Atropine is a well known muscarinic subtype non-specific antagonist that competitively inhibits acetylcholine (ACh) at postganglionic muscarinic sites. Atropine is used to treat organophosphate (OP) poisoning and resulting seizures in the warfighter because it competitively inhibits acetylcholine (ACh) at the muscarinic cholinergic receptors. ACh accumulates due to OP inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh. However, atropine produces several unwanted side-effects including dilated pupils, blurred vision, light sensitivity, and dry mouth. To overcome these side-effects, our goal was to find an alternative to atropine that emphasizes M1 (seizure prevention) antagonism but has minimum M2 (cardiac) and M3 (e.g., eye) antagonism so that an effective less toxic medical countermeasure may be developed to protect the warfighter against OP and other chemical warfare agents (CWAs). We adopted an in silico pharmacophore modeling strategy to develop features that are characteristics of known M1 subtype-selective compounds and used the model to identify several antagonists by screening an in-house (WRAIR-CIS) compound database. The generated model for the M1 selectivity was found to contain two hydrogen bond acceptors, one aliphatic hydrophobic, and one ring aromatic feature distributed in a 3D space. From an initial identification of about five hundred compounds, 173 compounds were selected through principal component and cluster analyses and in silico ADME/Toxicity evaluations. Next, these selected compounds were evaluated in a subtype-selective in vitro radioligand binding assay. Twenty eight of the compounds showed antimuscarinic activity. Nine compounds showed specificity for M1 receptors and low specificity for M3 receptors. The pKi values of the compounds range from 4.5 to 8.5nM in comparison to a value of 8.7nM for atropine. 2-(diethylamino)ethyl 2,2-diphenylpropanoate (ZW62841) was found have the best desired selectivity. None of the newly found compounds were previously reported to exhibit antimuscarinic specificity. Both theoretical and experimental results are presented.

Physostigmine effectively reverses anticholinergic delirium. However, continuous IV infusion of physostigmine is rarely used due to concern for cardiotoxicity and signs of cholinergic excess such as seizures, nausea, and vomiting. We report the successful use of continuous IV physostigmine in a 6-year-old boy with anticholinergic delirium. A 6-year-old, 30-kg boy with attention deficit hyperactivity disorder (ADHD) ingested 15-20 olanzapine (5 mg) tablets. He was agitated and was treated with lorazepam at a local hospital. His heart rate was 148 beats per min; respiratory rate, 32 breaths per minute; blood pressure, 111/70 mmHg; temperature, 96.8°F, and O2 saturation of 98% on room air. His pupils were 5-6 mm, and his skin was warm and initially flushed. Blood chemistry results were normal. A 12-lead ECG showed sinus tachycardia with normal QRS and QT intervals. The agitation worsened and did not respond to benzodiazepines. The patient was then given a dose of 0.6 mg physostigmine (0.02 mg/kg) intravenously with reversal of the agitation. But the effect only lasted 45 min requiring administration of a second bolus of 0.6 mg (0.02 mg/kg). A physostigmine intravenous infusion was administered at a rate of 0.5 mg/h (0.0167 mg/kg/h). Overnight, the patient became more agitated. The physostigmine was discontinued, and IV dexmedetomidine (0.2 μg/kg/h) was started at 21:00. The patient became over-sedated with pinpoint pupils resulting in discontinuation of the dexmedetomidine at 04:00. The patient again became agitated and developed visual hallucinations. Three 1-mg (0.03 mg/kg) boluses of physostigmine were administered over 45 min, and the physostigmine infusion was restarted at a rate of 1 mg/h (0.03 mg/kg/h) for 16.5 h. He received 19.5 mg of physostigmine with no return of anticholinergic symptoms and no signs of cholinergic excess except for a tremor that resolved when the infusion was stopped. He was discharged home without further sequelae. There are few publications describing a continuous infusion of physostigmine to reverse anticholinergic delirium. Our patient received a total dose of 25.5 mg with complete resolution of symptoms. We report the successful use of continuous infusion of physostigmine to reverse anticholinergic delirium in a pediatric patient who unintentionally ingested olanzapine.

Acute organophosphorus (OP) poisoning is relatively common and a major cause of death from poisoning in developing countries. Magnesium has been shown to be of benefit in animal models.We conducted a phase II study of bolus doses of (MgSO4) in 50 patients with acute organophosphate poisoning. Patients eligible for inclusion had ingested OP and had cholinergic symptoms consistent with moderate or severe poisoning. All patients received standard care of atropinization titrated to control muscarinic symptoms and pralidoxime. The trial was run in 4 sequential groups of patients. Participants in each group received a different total dose of MgSO4 (20%) administered as intermittent bolus doses infused over 10-15 min or placebo. There was one control patient for every 4 patients who received MgSO4. Group A (16 patients) received a total of 4 gm MgSO4 as a single bolus, group B (8 patients) received 8 gm (in two 4 gm doses q4H), group C (8 patients) received 12 gm (in three 4 gm doses q4H) group D (8 patients) received 16 gm (in four 4 gm doses q4H) and control (10 patients) received placebo). Patients were closely monitored for any adverse reaction like significant clinical neuromuscular disturbance and respiratory depression.No adverse reactions to magnesium were observed. The 24 hour urinary magnesium concentration were statistically different between 16 gm (234.74 ± 74.18 mg/dl) and control (118.06 ± 30.76 mg/dl) (p = 0.019), while it was much lower than the 80% of the intravenous magnesium load. Six patients died in control group compared to 3 in 4 gm, 2 in 8 gm and 1 in 12 gm group. There was no mortality in 16 gm group.Magnesium was well tolerated in this study. Larger studies are required to examine for efficacy.

Organophosphorous (OP) pesticides are used frequently in agriculture, particularly in Asian countries over the past decades. Poisoning by these agents, either as acute or chronic in these nations, is a serious health problem. OP pesticides residue in fruits and vegetables that may not induce early clinical features, could also affect the human health. Therefore, medical and health professionals should be aware and learn more on the toxicology, prevention and proper management of OP poisoning. The well-known mechanism of OP toxicity is the inhibition of acetyl cholinesterase, resulting in an accumulation of acetylcholine and continued stimulation of acetylcholine receptors. Therefore, they are also called anticholinesterase agents. Determination of blood acetyl cholinesterase and butyryl cholinesterase activities remains a mainstay for the rapid initial screening of OP pesticides. Quantitative analysis of OP and their degradation products in plasma and urine by mass spectrometric methods is a more specific method, but is expensive and limited to specialized laboratories. Therefore, history of OP pesticides exposure and clinical manifestations of a cholinergic syndrome is sufficient for management of the exposed patients. However, electrophysiological tests may be required for the diagnosis of delayed neuropathy of OP poisoning. The standard management of OP poisoning includes decontamination, atropine sulphate with an oxime. Recent advances focus on blood alkalinisation and magnesium sulphate as promising adjunctive therapies. Preventive measures in OP exposure are of great importance in human health in developing countries. Therefore, regulations and controls on safe use of OP particularly in Asian countries are recommended.

To investigate the morphological changes in the peripheral motor system of the rat induced by exposure to lead.This study was conducted at the Anatomy Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia from January 2011 to January 2012. Female adult albino rats (n=10) were given lead acetate in their drinking water (500mg/L) for a period of 30 days. Female adult albino rats (n=5) were used as control. The soleus and gastrocnemius muscles were dissected and processed for electron microscopy.Lead administration induced morphological changes in all constituents of the peripheral motor system of the rat, including; extension of long processes by Schwann cells, engorgement of nerve terminals, withdrawal of some terminals, and muscle fiber alterations.Lead toxicity is detrimental to all constituents of the peripheral motor system of the rat. The histopathological changes explain some of the clinical manifestations of lead toxicity.

Botulinum neurotoxin type A (BoNT/A), despite its high toxicity, is approved for therapy of many neurological (e.g., dystonia, spasticity) and non-neurological (e.g., achalasia, hyperhidrosis) disorders. Its mode of action is well understood. This has led to more and more indications (e.g., pain, gastrointestinal and urologic disorders), in which the toxin can reduce disturbing symptoms. In general the application is safe (pharmacological index 20-100, depending on indication). Few unwanted reactions may occur. In worst cases BoNT treated patients may develop neutralizing antibodies. These patients are excluded from further treatment. A more recently approved second serotype (BoNT/B) could be effective in those secondary non-responders, however, due to less potency in humans higher doses have to be applied leading to an only transient successful treatment. Other serotypes as BoNT/A and B, e.g., BoNT/C should be approved as medicines.

There are few reports of acetaminophen overdose in hypothermic patients and even fewer reports describing profound hypothermia. The kinetics, risk of hepatotoxicity, and the possible dose adjustments to N-acetylcysteine (NAC) therapy are not known in this setting.A 37-year-old female was found unconscious outside in December and was brought by ambulance to a tertiary care Emergency Department (ED) following a presumed overdose of acetaminophen and diphenhydramine. She later confirmed the ingestion and reported the ingestion had occurred approximately 18 hours prior to being found. On arrival, she was profoundly hypothermic, with a core rectal temperature of 17°C. Her initial serum acetaminophen concentration was 232 mcg/mL 19 hours post ingestion of a reported dose of approximately 50 grams of acetaminophen and 2.5 grams of diphenhydramine. Active rewarming was started immediately and IV NAC was initiated using the standard treatment protocol. The patient did not develop serious signs of hepatic injury or NAC toxicity. The patient's AST and ALT peaked 12 hours after admission at 84 IU/L (ref 10-37 U/L) and 104 IU/L (ref 12-78 U/L), respectively. Her INR peaked 2 hours after admission at 1.46 (ref < 1.2).Despite the significant ingestion of acetaminophen, delayed presentation, prolonged period of decreased responsiveness, and profound hypothermia, the patient did not develop any signs/symptoms of liver injury. NAC was administered in a standard dose during her rewarming period without apparent toxicity. The patient's absorption and/or metabolism of acetaminophen were likely slowed by her hypothermia and possibly by the anticholinergic coingestant. Initiation of IV NAC at a standard dose was apparently safe and effective in preventing hepatotoxicity as the patient was rewarmed.Profound hypothermia may be protective of hepatic injury in acetaminophen overdose. Delayed absorption from the coingestant, diphenhydramine, may also have played a role. IV NAC was given in a standard dose without apparent toxicity in the setting of profound hypothermia. Lastly, IV NAC, in standard dosing, appeared to be effective in preventing hepatotoxicity during rewarming in a patient with a potentially hepatotoxic concentration of acetaminophen with a coingestion of the anticholinergic agent, diphenhydramine.