Continuous levosimendan infusion for refractory cardiogenic shock complicating severe acute dichlorvos poisoning.

Respiratory failure is the leading cause of death after organophosphorus poisoning. Cardiac complications are rare, serious and little known to clinicians. The authors present a case of a 74-year-old man with refractory cardiogenic shock after taking 200 mL of 80% dichlorvos for a suicide attempt. This study represents the first reported cardiogenic shock resulting from organophosphorus poisoning in the literature, clarifying its hemodynamic features with invasive hemodynamic monitoring (PiCCO; Pulsion Medical Systems AG, Munich, Germany). Additional levosimendan infusion was commenced after insufficient conventional therapies, resulting in an increase in cardiac power index by 236% and a decrease in systemic vascular resistance by 69% after 24 hours of continuous infusion. Despite the immense hemodynamic improvement after levosimendan treatment, the patient died of multiple organ failure 6 days after admission. The authors also discussed the inotropic and vasodilatory effects of levosimendan in this clinical scenario.

Cardiac abnormalities in severe acute dichlorvos poisoning.

OBJECTIVE: Patients with organophosphorus poisoning sometimes die suddenly during rigorous treatment, possibly from myocardial injury. This study sought to elucidate the mechanisms underlying organophosphorus poisoning-induced cardiotoxicity. DESIGN: Prospective observational study. SETTING: Urban, tertiary teaching hospital emergency intensive care unit with 10 beds. PATIENTS: Forty-one patients with severe acute dichlorvos poisoning were consecutively enrolled (n = 92) at emergency intensive care unit and followed for 3 months. MEASUREMENTS AND MAIN RESULTS: Levels of serum creatine kinase isoenzyme myocardium, cardiac troponin I, acetylcholinesterase, acetylcholine, epinephrine, and norepinephrine were tested on hospital days 1, 3, and 5 and on discharge day. Electrocardiography was recorded on admission and then every other day. Transthoracic echocardiography was performed at admission, in the acute phase, before discharge, and during follow-up. Technetium 99m-sestamibi myocardial single photon emission computed tomography was conducted in four patients. Thirty-seven (90.2%) patients survived and four (9.8%) patients died during treatment. We observed sinus tachycardia in 37 (90.2%) patients and ST-T changes in 33 (80.4%) patients. Creatine kinase isoenzyme myocardium and cardiac troponin I levels peaked at day 3 postadmission and then decreased to normal levels. Serum acetylcholine, epinephrine, and norepinephrine peaked at day 1 after admission and then decreased. Echocardiography revealed marked decreases in wall motion of the interventricular septum and left ventricle in the acute phase but returned to normal in the recovery phase. The left ventricular ejection fraction improved significantly from 42 ± 5% to 59 ± 4% (p = .001). Single photon emission computed tomography showed abnormal left ventricle perfusion. CONCLUSION: Severe acute dichlorvos poisoning is associated with reversible myocardial dysfunction, possibly through an increase in catecholamine levels.

Pesticide intoxications in Cukurova, Turkey: three years analysis.

In Cukurova region, pesticide poisonings still remain an unfortunate cause of death, which led to the present study. The autopsy records of Adana Branch of the Council of Forensic Medicine, between 2006 and 2008, were evaluated retrospectively. Deaths that were attributed to pesticide poisoning were included in the scope of the study to identify the type of pesticide, and etiology of intoxication. The frequency and distribution of intoxications were also analyzed in terms of sex and age. In the studied period, a total of 4199 autopsies were referred to the forensic toxicology laboratory for pesticide analysis. Seventy-two cases were positive for pesticide analysis. Of these, 42 (58.33%) were male and 30 (41.67%) were female, with a mean age of 38.8 ± 20.6 years. Among the inspected pesticides, endosulfan was found to be the most common with 47.2% of prevalence, followed by dichlorvos. This report showed that certain pesticides, endosulfan in particular, remains as common cause of poisonings in Cukurova region.

Effect of PON1 on dichlorvos toxicokinetics.

OBJECTIVES: To provide toxicokinetic and clinical evidence of the hydrolytic effect of paraoxonase-1 (PON1) on acute organophosphate poisoning in rats. METHODS: 40 male Wistar rats were randomised into four equal groups. Dichlorvos administration group (A group) underwent dichlorvos injection (dissolved in corn oil) using intraperitoneal (ip) dose of 10 mg/kg. PON1 pretreatment group (B group) was injected with PON1 in the tail vein (intravenous), dose 9600 U/kg, 30 min prior to dichlorvos administration. In the treatment group (C group), atropine 0.05 mg/kg and pyraloxime chloride (PAM-CI) 120 mg/kg were injected intravenously within 2 min after dichlorvos administration. Finally, in the co-treatment group (D group), PON1 was injected intravenously with a dose of 9000 U/kg 30 min prior to dichlorvos administration; atropine 0.05 mg/kg and PAM-CI 120 mg/kg were injected intravenously within 2 min after dichlorvos administration. Blood was collected after administration. Plasma dichlorvos concentration was detected by liquid chromatography-mass spectra (LC-MS) method and clinical signs were observed. Toxicokinetic parameters were calculated in a statistical moment model. RESULTS: AUC (0→∞) in group B was statistically different from that in groups A and C (p<0.05), while it was not different from group D (p>0.05); there was no statistical difference between group A and group C (p>0.05). The statistical results of Cmax were the same as those of AUC (0→∞). There were no differences of MRT between four groups (p>0.05). Clinical signs can be improved by PON1 and atropine + PAM-CI, and co-treatment can relieve signs more effectively. CONCLUSION: PON1 can decrease the amount of dichlorvos that entered the blood, lowered the peak concentration and relieved clinical signs.

[Antidotal effect of combinations obidoxime/HI-6 and memantine in mice poisoned with soman, dichlorvos or heptenophos].

INTRODUCTION/AIM: In acute organophosphate poisoning the issue of special concern is the appearance of muscle fasciculations and convulsions that cannot be adequately antagonised by the use of atropine and oxime therapy. The aim of this study was to examine atidotal effect of obidoxime or HI-6 combinations with memantine in mice poisoned with soman, dichlorvos or heptenophos. METHODS: Male Albino mice were pretreated intravenously (iv) with increasing doses of oximes and/or memantine (10 mg/kg) at various times before poisoning with 1.3 LD-50 of soman, dichlorvos or heptenophos, in order to determine the median effective dose and the efficacy half-time. In a separate experiment, cerebral extravasation of Evans blue dye (40 mg/kg iv) was examined after application of memantine (10 mg/kg iv), midazolam (2.5 mg/kg intraperitonealy--ip) and ketamine (20 mg/kg ip) 5 minutes before soman (1 LD-50 subcutaneously--sc). RESULTS: Coadministration of memantine induced a significant decrease in median effective dose in null time of both HI-6 (7.96 vs 1.79 gmoL/kg in soman poisoning) and obidoxime (16.80 vs 2.75 micromoL/kg in dichlorvos poisoning; 21.56 vs 6.63 micromoL/kg in heptenophos poisoning). Memantine and midazolam succeded to counteract the soman-induced proconvulsive activity. CONCLUSION: Memantine potentiated the antidotal effect of HI-6 against a lethal dose of soman, as well as the ability of obidoxime to antagonize the toxic effects of dichlorvos and heptenophos probably partly due to its anticonvulsive properties.

Cellular and molecular mechanisms of dichlorvos neurotoxicity: cholinergic, nonchlolinergic, cell signaling, gene expression and therapeutic aspects.

Inappropriate use of toxic chemicals is common in developing countries, where it leads to excessive exposure and high risks of unintentional poisoning. Risks are particularly high with the pesticides used in agriculture, poor rural populations live and work in close proximity to these compounds and often store these compounds in and around their homes. It is estimated that most of the death from pesticide poisoning occur in developing countries. Organophosphate insecticides have been extensively used in agriculture in developing countries. Dichlorvos is a synthetic insecticide and belongs to a family of chemically related organophosphate pesticides (OP). Toxicity of dichlorvos has been documented in accidental human poisoning, epidemiological studies, and animal models. In this review, molecular mechanisms of dichlorvos neurotoxicity have been described. Usage, biotransformation, environmental levels, general population and occupational exposure, effects on cell signaling receptors, mitochondrial metabolism, oxidative stress and gene expression of dichlorvos have been reviewed. Assessment of acute and chronic exposures as well as neurotoxicity risk for lifetime exposures to dichlorvos have also been considered. In addition special emphasis has been given to describe, the role of dichlorvos in the chronic neurotoxicity and its molecular targets that ultimately lead to neurodegeneration.

Dichlorvos, chlorpyrifos oxon and Aldicarb adducts of butyrylcholinesterase, detected by mass spectrometry in human plasma following deliberate overdose.

The goal of this study was to develop a method to detect pesticide adducts in tryptic digests of butyrylcholinesterase in human plasma from patients poisoned by pesticides. Adducts to butyrylcholinesterase in human serum may serve as biomarkers of pesticide exposure because organophosphorus and carbamate pesticides make a covalent bond with the active site serine of butyrylcholinesterase. Serum samples from five attempted suicides (with dichlorvos, Aldicarb, Baygon and an unknown pesticide) and from one patient who accidentally inhaled dichlorvos were analyzed. Butyrylcholinesterase was purified from 2 ml serum by ion exchange chromatography at pH 4, followed by procainamide affinity chromatography at pH 7. The purified butyrylcholinesterase was denatured, digested with trypsin and the modified peptide isolated by HPLC. The purified peptide was analyzed by multiple reaction monitoring in a QTRAP 4000 mass spectrometer. This method successfully identified the pesticide-adducted butyrylcholinesterase peptide in four patients whose butyrylcholinesterase was inhibited 60-84%, but not in two patients whose inhibition levels were 8 and 22%. It is expected that low inhibition levels will require analysis of larger serum plasma volumes. In conclusion, a mass spectrometry method for identification of exposure to live toxic pesticides has been developed, based on identification of pesticide adducts on the active site serine of human butyrylcholinesterase.

Pharmacokinetics of OpdA, an organophosphorus hydrolase, in the African green monkey.

Organophosphorus (OP) pesticides are a broad class of acetylcholinesterase inhibitors that are responsible for tremendous morbidity and mortality worldwide, contributing to an estimated 300,000 deaths annually. Current pharmacotherapy for acute OP poisoning includes the use of atropine, an oxime, and benzodiazepines. However, even with such therapy, the mortality from these agents are as high as 40%. Enzymatic hydrolysis of OPs is an attractive new potential therapy for acute OP poisoning. A number of bacterial OP hydrolases have been isolated. A promising OP hydrolase is an enzyme isolated from Agrobacterium radiobacter, named OpdA. OpdA has been shown to decrease lethality in rodent models of parathion and dichlorvos poisoning. However, pharmacokinetic data have not been obtained. In this study, we examined the pharmacokinetics of OpdA in an African Green Monkey model. At a dose of 1.2mg/kg the half-life of OpdA was approximately 40 min, with a mean residence time of 57 min. As expected, the half-life did not change with the dose of OpdA given: at doses of 0.15 and 0.45 mg/kg, the half-life of OpdA was 43.1 and 38.9 min, respectively. In animals subjected to 5 daily doses of OpdA, the residual activity that was measured 24h after each OpdA dose increased 5-fold for the 0.45 mg/kg dose and 11-fold for the 1.2mg/kg dose. OpdA exhibits pharmacokinetics favorable for the further development as a therapy for acute OP poisoning, particularly for hydrophilic OP pesticides. Future work to increase the half-life of OpdA may be beneficial.

Detection of adduct on tyrosine 411 of albumin in humans poisoned by dichlorvos.

Studies in mice and guinea pigs have shown that albumin is a new biomarker of organophosphorus toxicant (OP) and nerve agent exposure. Our goal was to determine whether OP-labeled albumin could be detected in the blood of humans exposed to OP. Blood from four OP-exposed patients was prepared for mass spectrometry analysis by digesting 0.010 ml of serum with pepsin and purifying the labeled albumin peptide by offline high performance liquid chromatography. Dimethoxyphosphate-labeled tyrosine 411 was identified in albumin peptides VRY(411)TKKVPQVSTPTL and LVRY(411)TKKVPQVSTPTL from two patients who had attempted suicide with dichlorvos. The butyrylcholinesterase activity in these serum samples was inhibited 80%. A third patient whose serum BChE activity was inhibited 8% by accidental inhalation of dichlorvos had undetectable levels of adduct on albumin. A fourth patient whose BChE activity was inhibited 60% by exposure to chlorpyrifos had no detectable adduct on albumin. This is the first report to demonstrate the presence of OP-labeled albumin in human patients. It is concluded that tyrosine 411 of human albumin is covalently modified in the serum of humans poisoned by dichlorvos and that the modification is detectable by mass spectrometry. The special reactivity of tyrosine 411 with OP suggests that other proteins may also be modified on tyrosine. Identification of other OP-modified proteins may lead to an understanding of neurotoxic symptoms that appear long after the initial OP exposure.

Protective effects of Y-27632 on acute dichlorvos poisoning in rats.

Anticholinesterase poisoning is an important health problem in developing countries, and understanding of its underlying mechanisms is essential for the effective treatment. This study is designed to examine the effects of Y-27632, a selective Rho-kinase inhibitor, on organophosphate-induced cardiac toxicity and mortality in rats. Rats were randomly divided into 4 groups: control (corn oil), dichlorvos (30 mg/kg intraperitoneally), and 1- and 10-mg/kg Y-27632 + dichlorvos groups. After 6 hours of intraperitoneal injection, venous blood and cardiac samples were obtained, biochemical or immunohistochemical analyses were performed, and the intensity of muscle fasciculation was recorded. Serum cholinesterase activities were suppressed with dichlorvos, and these reductions were inhibited with Y-27632 pretreatment. Serum creatine kinase, creatine kinase-MB activities, and myoglobin and N-terminal probrain natriuretic peptide concentrations were not markedly affected with poisoning or Y-27632. Although serum nitric oxide concentrations did not change with dichlorvos, cardiac nitric oxide levels were markedly increased with Y-27632 pretreatment. Cardiac glutathione levels also increased with 1 mg/kg Y-27632. There was no staining for apoptosis, and immunohistochemical analyses of inducible nitric oxide synthase showed no change in cardiac tissue for all of the groups. Both doses of Y-27632 abolished mortality in rats with acute dichlorvos exposure (100% survival). These results show that administration of Rho-kinase inhibitor can produce protective effects against dichlorvos intoxication in rats. These findings may provide new possibilities for the treatment of organophosphate poisoning.

Cardiac effects of magnesium sulfate pretreatment on acute dichlorvos-induced organophosphate poisoning: an experimental study in rats.

Although atropine and oximes are traditionally used in the management of organophosphate poisoning, investigations have been directed to finding additional therapeutic approaches. Thus, the aim of this study was to evaluate the cardiac effects of magnesium sulfate pretreatment on dichlorvos intoxication in rats. Rats were randomly divided into three groups as control, dichlorvos, and magnesium sulfate groups. After 6 h of dichlorvos or corn oil (as a vehicle) injection, venous blood samples were collected, and cardiac tissue samples were obtained. Biochemical analyses were performed to measure some parameters on serum and cardiac tissue. Immunohistochemical analyses of apoptosis and inducible nitric oxide (NO) synthase showed no change in cardiac tissue. Serum cholinesterase levels were markedly depressed with dichlorvos, and further suppressed markedly with magnesium sulfate pretreatment. Although we have demonstrated that serum NO levels in dichlorvos and magnesium sulfate groups were lower than the control group, cardiac tissue NO levels in magnesium sulfate group were higher than the other two groups. Mortality was not significantly affected with magnesium sulfate pretreatment. Uncertainty still persists on the right strategies for the treatment of organophosphate acute poisoning; however, it was concluded that our results do not suggest that magnesium sulfate therapy is beneficial in the management of acute dichlorvos-induced organophosphate poisoning, and also further studies are required.

Formulation of effects of atropine, pralidoxime and magnesium sulfate on cardiac tissue levels of nitric oxide, malondialdehyde and glutathione in organophosphate poisoning using artificial neural network.

Anticholinesterase poisoning is an important health problem in our country, and a complete understanding of its underlying mechanisms is essential for the emergency physician. So, this study focused on two purposes. First one was aimed to investigate the biochemical analysis to determine the tissue levels of malondialdehyde (MDA), glutathione and nitric oxide (NO). Secondly, it was planned to model and formulate the effects of some drugs on cardiac tissues levels of NO, MDA and glutathione in acute organophosphate poisoning in rats by the application of neural network based on experimental results. It has been planned to determine whether artificial neural network (ANN) is appropriate tool to analyze and formulate it. As a result, it has been considered that ANN can be effectively used to model NO, MDA and glutathione level. The performances of ANN formulation versus target experimental values are found to be quite high. It is concluded that, proposed NN models are also presented as simple explicit mathematical functions for further use by researchers.

[Therapeutic effects of benthiactzine against respiratory failure induced by cholinesterase inhibitor in rats].

OBJECTIVE: To investigate the therapeutic effects of benthiactzine against respiratory failure induced by cholinesterase inhibitor dimethyl dichloro-vinyl phosphate (DDVP) in rats. METHODS: Forty-five male Wistar rats were divided into five groups randomly: control group, model group, and benthiactzine 0.5, 1.0, 2.0 mg/kg treatment groups (each n=9). Rats were treated with DDVP by intraperitoneal injection to reproduce respiratory failure model. The symptoms, respiratory rate (RR), blood gas analysis, electrolyte and plasma superoxide dismutase (SOD), malondialdehyde (MDA) and the pathological changes were observed before poisoning, during respiratory failure, and in different periods after the treatment. RESULTS: In rats with respiratory failure induced by DDVP, cyanosis and convulsion occurred in all groups. The success rates in three benthiactzine groups were 66.7% (6/9), 77.8% (7/9) and 88.9% (8/9). The rats of benthiactzine treatment groups recovered in 1-5 minutes after treatment and returned to normal state in 30 minutes. RR also returned to normal in 30 minutes. When respiratory failure occurred, arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2) and plasma SOD were decreased, plasma MDA was increased, and mixed acidosis was found. Thirty minutes after the treatment of benthiactzine, all above parameters in three groups returned to normal (all P<0.01). In respiratory failure rats, pathological examination of lung tissue revealed dilatation of pulmonary vessels with aggregation of erythrocytes, widening of alveolar space with presence of red blood cells in alveoli with heavy infiltration of inflammatory cells, and pulmonary edema and hemorrhage. The lungs of rats treated with benthiactzine showed less intense pathological changes. CONCLUSION: The new medicine against poisoning benthiactzine can be a favourable drug against respiratory failure induced by organophosphorus pesticides.

Myeloneuritis due to acute organophosphate (DDVP) intoxication.

Given the importance of agriculture and widespread use of pesticides, intoxication due to organophosphate insecticides is common in Turkey. Organophosphorus compounds may cause late-onset distal polyneuropathy occurring 2 or more weeks after the acute exposure. An 18-year-old woman and a 22-year-old man were admitted to the hospital with weakness, paresthesia, and gait disturbances at 35 and 22 days, respectively, after ingesting dimethyl-2,2-dichloro vinyl phosphate (DDVP). Neurological examination revealed weakness, vibration sense loss, bilateral dropped foot, brisk deep tendon reflexes, and bilaterally positive Babinski sign. Electroneurography demonstrated distal motor polyneuropathy with segmental demyelination associated with axonal degeneration prominent in the distal parts of both lower extremities.

Homicide by organophosphorus compound poisoning: a case report.

Pesticides are responsible for less than 1% of deaths from poisoning in the UK while various studies in India indicate that the figures range from 20% to a staggering 70% (Sharma, 1998). Organophosphorus compounds are reported to be the most commonly used substances for suicidal purposes (Dixit, 2007). Homicidal poisoning involving pesticides has always been rare owing to the disagreeable odour and taste rendered to them by their hydrocarbon solvents (Pillay, 2008). An unusual case of homicide using an organophosphorus compound is presented here. The body of a 28-year-old woman was brought for post-mortem examination at the mortuary of the Government Medical College and New Civil Hospital, Surat, Gujarat, India. It had been exhumed after forty-five days of burial under the supervision of a medical officer from the nearby primary health centre, the police and a magistrate. There was a history of marital discord between the deceased and her husband. Their ten-year-old daughter, who was the only witness to the incident, revealed later that her mother was struck by a wooden block and forcibly made to ingest some medicine. The 'medicine' was identified on chemical analysis as an organophosphorus compound (dichlorvos).

Parenteral ophthalmic tropicamide or cyclopentolate protects rats from lethal organophosphate poisoning.

We determine the efficacy of parenteral ophthalmic antimuscarinic agents (tropicamide ophthalmic 1% and cyclopentolate hydrochloride ophthalmic 1%) on survivability in a rat model of acute, lethal organophosphate pesticide (OP) poisoning. After obtaining an appropriate dose-response for study comparison, rodents were randomized to receive 1 of 4 intraperitoneal antidotes; (1) 0.3 mL normal saline, (2) atropine 10 mg/kg, (3) ophthalmic tropicamide 20 mg/kg, or (4) ophthalmic cyclopentolate 20 mg/kg. Five minutes after pretreatment, 15 mg/kg of dichlorvos was administered subcutaneously. Mortality rates and time to death were compared using Fisher exact test and the Kaplan-Meier method with log-rank test, respectively. If alive at 120 minutes, survival was assumed and the study was terminated. Survival in rats pretreated with atropine (10 mg/kg) was 90%. Survival in rats pretreated with tropicamide (20 mg/kg) and cyclopentolate (20 mg/kg) were 90% [P < 0.01; 95% confidence interval (CI) 0.71-1.09] and 90% (P < 0.01; 95% CI 0.71-1.09), respectively, compared with controls (10% survival; 95% CI 0.04-0.45). Time of death ranged between 6 and 13 minutes in nonsurvivors. Overall comparison of survival time revealed a statistically significant improvement in experimental groups compared with controls (P < 0.0001). Pretreatment with parenteral ophthalmic solutions (tropicamide or cyclopentolate) was equivalent to standard atropine in preventing lethality in this rat model of acute, lethal OP poisoning.

Cardiac damage in acute organophosphate poisoning in rats: effects of atropine and pralidoxime.

Anticholinesterase poisoning is an important health problem in our country, and a complete understanding of its underlying mechanisms is essential for the emergency physician. Thus, we aimed to investigate the cardiac biochemical parameters and mortality in dichlorvos-induced poisoning in rats. Rats were randomly divided into 5 groups as control (corn oil), dichlorvos, atropine, pralidoxime, and atropine+pralidoxime groups. Immunohistochemical analyses of apoptosis and inducible nitric oxide synthase showed no change in cardiac tissue for all of the groups. Serum cholinesterase levels were suppressed with dichlorvos, and these reductions were inhibited with atropine and/or pralidoxime pretreatment. Serum levels of creatine kinase, creatine kinase-MB, cardiac troponin I, myoglobin, and N-terminal probrain natriuretic peptide were not affected with poisoning. Malondialdehyde and glutathione levels were not statistically significant between the groups. Although serum nitric oxide levels in the dichlorvos group were lower than those in the control group, cardiac nitric oxide levels in the atropine+pralidoxime group were markedly higher than those in the dichlorvos group. Atropine, pralidoxime, and atropine+pralidoxime pretreatments markedly reduced the mortality. In conclusion, our results implied that measured cardiac markers especially N-terminal probrain natriuretic peptide may not contribute to the early (first 6 hours) diagnosis of cardiotoxicity in dichlorvos-induced poisoning in rats. These results also showed that acute dichlorvos administration did not cause significant cardiac damage, and oxidative stress does not play a marked role in dichlorvos-induced poisoning. Besides, cardiac nitric oxide may produce protective effect on myocardium with atropine+pralidoxime therapy in rats.