Neuroleptic malignant syndrome associated with acute organophosphate poisoning: Case report / Síndrome neuroléptico maligno asociado con intoxicación aguda por un organofosforado: reporte de caso.

Neuroleptic malignant syndrome is a rare and potentially fatal clinical condition frequently associated with the use of antipsychotics. In the literature, there is only one case report associated with the intake of organophosphates. We present the case of a patient who presented with a clinical picture compatible with neuroleptic malignant syndrome, after the ingestion of an organophosphate (chlorpyrifos). A 57-year-old man who consulted for attempted suicide, acute deterioration of consciousness, torpid neurological evolution, and associated autonomic instability associated with rigidity, persistent hyperthermia, and elevated CPK. Bromocriptine treatment was offered, which resolved the clinical picture. The association with the ingestion of an organophosphate was established, and he was discharged without sequelae. The diagnosis of neuroleptic malignant syndrome is clinical and should be considered in any case of exposure to substances that may lead to dysregulation of dopaminergic neurotransmission in order to initiate timely therapy and impact outcomes.

El síndrome neuroléptico maligno es una condición clínica rara y potencialmente letal que frecuentemente se asocia con el uso de antipsicóticos. En la literatura especializada se encontró únicamente un reporte de caso relacionado con la ingestión de organofosforados. Se presenta un paciente con un cuadro clínico correspondiente al síndrome neuroléptico maligno posterior a la ingestión de clorpirifós. Como resultado de un intento de suicidio con el mencionado organofosforado, el hombre de 57 años presentó deterioro agudo del estado de consciencia, evolución neurológica tórpida e inestabilidad autonómica asociada a rigidez e hipertermia persistentes, así como incremento de la creatina-fosfocinasa (creatine phosphokinase, CPK). Se le administró tratamiento con bromocriptina, con lo cual el cuadro clínico remitió, y fue dado de alta sin secuelas. El diagnóstico del síndrome neuroléptico maligno es clínico y debe contemplarse en cualquier caso de exposición a sustancias que puedan resultar en una desregulación de la neurotransmisión dopaminérgica, con el fin de iniciar el tratamiento oportuno y contrarrestar efectivamente los efectos.

Role of intravenous lipid emulsion therapy and packed red blood cell transfusion as adjuvant treatment in the management of a child with severe organophosphate poisoning (chlorpyrifos).

A previously well 3-year-old child presented with rapidly deteriorating clinical status minutes after ingestion of an orange-coloured liquid housed in a soda bottle (HomeTrek-chlorpyrifos). She had miotic pupils, copious oral secretions, crackles on lung auscultation, hyperactive bowel sounds, impending signs of respiratory failure and declining sensorium. A diagnosis of severe organophosphate (OP) toxicity was made. Despite resuscitation and atropine administration, she deteriorated and exhibited atropine toxicity. She was given 20% intravenous lipid emulsion therapy and red blood cell (RBC) transfusion as adjunctive therapy with favourable outcome. She was discharged after 11 days and her RBC cholinesterase levels were 45% and 17% below normal, taken on day 10 and day 35 postingestion, respectively. She showed no signs of intermediate syndrome and delayed polyneuropathy. This case highlights the need for timely recognition of severe OP poisoning, and the role of lipid emulsion therapy and packed RBC transfusion as adjunctive treatment.

Propolis relieves the cardiotoxicity of chlorpyrifos in diabetic rats via alleviations of paraoxonase-1 and xanthine oxidase genes expression.

Pesticides cardiotoxicity in case of diabetic-induced cardiac complications is unidentified. The probable amelioration role of propolis is gauged against the cardiotoxic effects of chlorpyrifos in the diabetic rats through paraoxonase-1 (PON1) and xanthine oxidase (XO) genes dysregulation. Fifty-six male rats were distributed (n = 7) into eight groups. The first one saved as control whereas the 2nd, 3rd, and 4th were kept for propolis aqueous extract (100 mg/kg), diabetes (60 mg/kg streptozotocin) and chlorpyrifos (2.5 mg/kg), respectively. The 5th was diabetes/chlorpyrifos combination, while 6th, 7th, and 8th were intubated with propolis for four weeks after diabetic induction, chlorpyrifos intoxication, and their combination, respectively. The plasma glucose, lipid profiles, cardiac enzymes and interleukin-6 (IL-6) significantly elevated, while insulin decreased in the diabetic and combination groups. Although the cardiac acetylcholinesterase, total thiols, and PON1 significantly reduced after diabetic and/or chlorpyrifos gavage, the protein carbonyl, superoxide dismutase, catalase, and XO significantly elevated. The mRNA genes expression of PON1 and XO have also confirmed the enzymatic activities. Interestingly, propolis significantly restored the hyperglycemia, hypoinsulinemia, hyperlipidemia, IL-6 elevations, and antioxidant defense system disorder. These records revealed that the immunomodulatory, anti-diabetic and antioxidant tasks are fine pointers for the cardiovascular defender of propolis especially during diabetes and/or pesticides exposure.

In vitro and in vivo effects of chlorpyrifos and cypermethrin on blood cholinesterases in sheep.

The combination of the organophosphate (OP) chlorpyrifos (CPF) and the pyrethroid cypermethrin (CPM) is commonly marketed as pour-on formulations for the control of sheep lice, ked, and blowflies. CPF irreversibly inhibits acetylcholinesterases (AChE), while pyrethroids are not AChE inhibitors. However, combinations of pyrethroids with OPs showed a highly synergistic effect on AChE inhibition. Thus, the aim of the current work was to evaluate in vitro and in vivo the inhibitory potency of both pesticides, alone and in combination with AChE and butyrylcholinesterase (BChE) activities in sheep blood. In vitro, IC50 values were similar after CPF or CPF plus CPM incubations. The pour-on coadministration of recommended doses of CPF and CPM did not cause a significant inhibition of AChE and BChE in sheep blood. Only slight percentages of inhibition of their catalytic activities were observed when both drugs were given at 4-fold higher dose rates. The lower systemic availability of topical administration of OPs in sheep may help to explain the lower degree of inhibition of blood AChE and BChE in vivo. The results emerged from this research are a further contribution to the knowledge of the risks of implementing higher dosage regimens of OPs-containing antiparasitic formulations.

Efficacy profile of Cypermethrin and Chlorpyrifos based acaricides on Rhipicephalus microplus control on cattle in the rearing phase, naturally infested and exposed to tick fever agents in central Brazil.

The objective of this work was to evaluate the efficacy of two cypermethrin- and chlorpyrifos-based acaricides in controlling Rhipicephalus microplus in a naturally infested bovine herd and in in vitro tests, as well as to monitor the animals for tick fever. Male bovines in the rearing phase were used, with 30 Brangus and 30 Nellore animals naturally infested. The groups were composed as follows: 15 Nellore treated, 15 Nellore control, 15 Brangus treated and 15 Brangus control. Every 18 days, the animals were monitored for tick count, acaricide treatment, weight, blood pack cell volume, and clinical signs. For in vitro tests, the larval packet test, adult immersion test and DNA amplification for tick fever diagnosis were performed. In the first animal treatment period, product 1 (cypermethrin, 15 g + chlorpyrifos, 25 g + citronellal, 1 g) was used; in the second period, product 2 (cypermethrin, 15 g + chlorpyrifos, 30 g + fenthion, 15 g) was used. In Brangus animals, the mean efficacy was 35.1% and 95.8% in the first and second periods, respectively, for the same animals. For Nellore animals, the efficacy in periods one and two was 51% and 97.1%, respectively. The in vitro results showed efficacy above 95% for the two challenged acaricides. The Brangus animals showed a high production of ticks associated with the presence of tick fever agents, which could generate risks for the disease's enzootic stability.

Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during development.

Exposure to chlorpyrifos (CPF) during the late preweanling period in rats inhibits the endocannabinoid metabolizing enzymes fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), resulting in accumulation of their respective substrates anandamide (AEA) and 2-arachidonylglycerol (2-AG). This occurs at 1.0mg/kg, but at a lower dosage (0.5mg/kg) only FAAH and AEA are affected with no measurable inhibition of either cholinesterase (ChE) or MAGL. The endocannabinoid system plays a vital role in nervous system development and may be an important developmental target for CPF. The endocannabinoid system plays an important role in the regulation of anxiety and, at higher dosages, developmental exposure to CPF alters anxiety-like behavior. However, it is not clear whether exposure to low dosages of CPF that do not inhibit ChE will cause any persistent effects on anxiety-like behavior. To determine if this occurs, 10-day old rat pups were exposed daily for 7 days to either corn oil or 0.5, 0.75, or 1.0mg/kg CPF by oral gavage. At 12h following the last CPF administration, 1.0mg/kg resulted in significant inhibition of FAAH, MAGL, and ChE, whereas 0.5 and 0.75mg/kg resulted in significant inhibition of only FAAH. AEA levels were significantly elevated in all three treatment groups as were palmitoylethanolamide and oleoylethanolamide, which are also substrates for FAAH. 2-AG levels were significantly elevated by 0.75 and 1.0mg/kg but not 0.5mg/kg. On day 25, the latency to emerge from a dark container into a highly illuminated novel open field was measured as an indicator of anxiety. All three CPF treatment groups spent significantly less time in the dark container prior to emerging as compared to the control group, suggesting a decreased level of anxiety. This demonstrates that repeated preweanling exposure to dosages of CPF that do not inhibit brain ChE can induce a decline in the level of anxiety that is detectable during the early postweanling period.

Low-level repeated exposure to diazinon and chlorpyrifos decrease anxiety-like behaviour in adult male rats as assessed by marble burying behaviour.

Occupational exposure to organophosphate (OPs) pesticides is reported to increase in the risk of developing anxiety and depression. Preclinical studies using OP levels, which inhibit acetylcholinesterase activity, support the clinical observations, but little is known of the effects of exposure below this threshold. We examined the effects of low level OP exposure on behaviours and neurochemistry associated with affective disorders. Adult rats were administered either diazinon (1 mg/kg i.p.) which is present in sheep dip and flea collars, chlorpyrifos (1 mg/kg i.p.) which is present in crop sprays, or vehicle for 5 days. OP exposure did not affect acetylcholinesterase activity (blood, cerebellum, caudate putamen, hippocampus, prefrontal cortex), anhedonia-like behaviour (sucrose preference), working memory (novel object recognition), locomotor activity or anxiety-like behaviour in the open field arena. In contrast OP exposure attenuated marble burying behaviour, an ethological measure of anxiety. The diazinon-induced reduction in marble burying persisted after exposure cessation. In comparison to vehicle, dopamine levels were lowered by chlorpyrifos, but not diazinon. 5-HT levels and turnover were unaffected by OP exposure. However, 5-HT transporter expression was reduced by diazinon suggesting subtle changes in 5-HT transmission. These data indicate exposure to occupational and domestic OPs, below the threshold to inhibit acetylcholinesterase, can subtly alter behaviour and neurochemistry.

Integrated control of an acaricide-resistant strain of the cattle tick Rhipicephalus microplus by applying Metarhizium anisopliae associated with cypermethrin and chlorpyriphos under field conditions.

The efficacy of the fungus Metarhizium anisopliae to control ticks has been shown in several in vitro experiments. However, few studies have been undertaken in field conditions in order to demonstrate the applicability of its use as a biological control of ticks and its combination with chemical acaricides. The aim of the present study was to evaluate the efficacy of M. anisopliae to control an acaricide-resistant strain of Rhipicephalus microplus under laboratory and field conditions. First, the compatibility of M. anisopliae strain (TIS-BR03) with commercial acaricides and its potential to control the cattle tick were evaluated in vitro. In general, acaricide treatments had mild effects on fungus viability. In the field experiment, the median of treatment efficacy with acaricide only, M. anisopliae only and combination of M. anisopliae with acaricide were 71.1%, 56.3% and 97.9%, respectively. There is no statistical difference between groups treated with M. anisopliae and acaricide alone. Thus, in this work we have demonstrated the applicability of M. anisopliae use associated or not with chemical acaricides on field conditions in order to control an acaricide-resistant strain of the cattle tick R. microplus.

The efficacy and safety of chlorpyrifos (Dursban) for control of Myobia musculi infestation in mice.

Mite infestation in laboratory mice is a common, but troublesome problem in animal facilities. Recommended treatment regimens are frequently ineffective because of the short period of exposure to the control agent. In an effort to develop a time-release approach, we have investigated the use of Dursban granules applied in animal bedding. Initial toxicity studies indicated that this pesticide can be added to shoebox cage litter at levels three times that used for outdoor application (6 g per 27 by 48 cm shoebox cage) without producing clinical signs of toxicity. Metabolism studies demonstrated that although individual mice showed decreased brain acetylcholinesterase activity following treatment, liver cytosolic glutathione-S-transferase, liver microsomal aminopyrine N-demethylase, or aryl hydrocarbon hydroxylase were not induced after 1 week of exposure. Parasitological studies indicated elimination of mites and itching in an experimental infestation, as well as reduction of itching in severely symptomatic, naturally infested mice, following treatment with the granules. These studies demonstrate the nontoxic efficacy of Dursban in the control of Myobia musculi.

Chlorpyrifos for control of the short-nosed cattle louse, Haematopinus eurysternus (Nitzsch) (Anoplura, Haematopinidae) during winter.

Two groups (A and C) of range cows were treated in February with chlorpyrifos (16 mL Dursban 44/cow) for the control of heavy infestations of the short-nosed cattle louse. Group A was treated in 1977 and group C in 1979 and each treated group was compared with a separate untreated group. Some of the treated cows were identified as carriers of louse infestation (subgroups A1 and C1), while others were noncarriers (subgroups A2 and C2). The maximum level of reduction in louse populations was 99% at week 4 posttreatment in subgroup A1, 99% from weeks 2-16 posttreatment in subgroup A2, 92% at week 3 posttreatment in subgroup C1 and 100% at weeks 15-17 in subgroup C2. Clinically, the treated cows, which were anemic at the time of treatment, recovered from anemia during the posttreatment period of 25 weeks for group A and 17 weeks for group C. Remission of anemia also occurred in the two untreated groups, possibly because of natural summer decline in louse population. The treatment had no effect on the whole blood cholinesterase of the cows and the treated cows showed no signs of organophosphorous toxicity.

Efficiency and safety of methidathion applied as a pour-on systemic insecticide for control of cattle lice.

Methidathion applied to cattle as a pour-on insecticide for control of lice (predominantly Linognathus vituli, but also Haematopinus eurysternus and Damalinia bovis) caused a reduction in the lice population of approximately 98% to 99% in laboratory trials at the minimum recommended dose of 4 mg/kg and a 98.8% to 100% efficiency was achieved in field trials. In a comparative efficiency trial in the laboratory methidathion at 3.5 to 5 mg/kg reduced the lice population by 98.8% to 99%, fenthion by 98.5% at 4.5 mg/kg and famphur by 99.7% at 16.5 mg/kg. Methidathion was tolerated by calves aged 15 to 20 weeks at dose rates up to 40 mg/kg indicating an approximate 7 fold safety margin, but 1 of 4 calves treated at 50 mg/kg died following treatment. Treatment with fenthion at 50 mg/kg, 7.4 times the average recommended rate, famphur at 75 mg/kg, 3 times the average rate and chlorpyrifos at 85 mg/kg, 5 times average rate, caused reductions in whole blood cholinesterase activity of 52%, 27% and 47% respectively which were similar to the reductions in cholinesterase activity found in calves treated with methidathion at similar levels above the recommended commercial dose rates. It was found that 2 day old calves were more sensitive to treatment with methidathion than calves 9 or 16 days old. A further 11,900 cattle of varying age, breed and sex were treated with methidathion under field conditions at the recommended rate of 4 to 8 mg/kg, and 534 cattle were treated at 24 mg/kg without any signs of toxicity.

Trials with chlorpyrifos (Dursban) as a systemic insecticide against the cattle louse.

Data for louse control are presented chiefly on chlorpyrifos (Dursban) 0, 0-diethyl 0-(3, 5, 6-trichloro-2-pyridyl) phosphorothioate and fenchlorphos in one trial and chlorpyrifos and famphur in three trials. These animal systemics were tested on 168 dairy calves in four herds located in three regions of the North Island, New Zealand. Louse control, following single backline, dermal applications, showed 80%, 87% and 100% with dosages of chlorpyrifos at 5 mg, 13 mg and 20 to 200 mg per kg, respectively, and 100% and 93% with dosages of famphur at 20 mg per kg, respectively. Poor louse control (24 to 58%) with fenchlorphos was expected since this compound requires two applications 14 days apart. Ovicidal effect was demonstrated with chlorpyrifos and famphur. Minor scurfing and hair loss occurred on some calves with all compounds, but hair coats were normal 28 days after treatment. Calves given 100 mg to 200 mg per kg chlorpyrifos showed signs of organophosphate toxicity from 5 mins to 90 mins post-treatment but were normal thereafter.