Cholinergic Crisis Research Articles

Organophosphates pesticide poisoning: a peculiar case report

Background: Acute organophosphate (OP) intoxication occurs following the absorption through gastrointestinal or respiratory tract, skin and rarely by intramuscular or intravenous route; in most cases is the result of suicidal attempt. These anticholinesterase compounds cause an acute cholinergic syndrome (with decreased consciousness, respiratory failure), an intermediate syndrome after 2 or 3 days from exposure (that requires prolonged ventilation), and finally a delayed neuropathy. In most cases an acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death.

Chlorpyrifos and parathion regulate oxidative stress differentially through the expression of paraoxonase 2 in human neuroblastoma cell

Organophosphate (OP) compounds are frequently linked to both chronic and acute forms of nervous system disorders. Chlorpyrifos (CPF) and parathion (PA) are two of the most widely used OP insecticides throughout the world. These compounds are acetylcholinesterase inhibitors and cause a cholinergic crisis. However, there are other non-cholinergic effects of the OP compounds as well. The role of Paraoxonase 1 (PON1) in the metabolism of OP compounds is well established owing to its significant organophosphatase activity. Since PON2 has no paraoxonase activity and the level of its expression is 20–40 fold higher in the brain, in this article the role of PON2 in response to CPF and PA exposure concerning both cholinergic and non-cholinergic effects are explored. The effect of these OPs on cell viability, reactive oxygen species (ROS), PON2 gene expression, and function was studied. Glutathione level, esterase activity, and paraoxonase activity were also measured in CPF- and PA-treated IMR-32 cells. At these levels, both CPF and PA showed different impacts on IMR-32 cells. PA at higher concentrations (50–200 µM) proved to be less toxic than CPF. Interestingly, induction of ROS was also lower in the case of PA-treated cells as compared to the CPF. However, PON2 protein expression was increased with the increasing concentration of PA and decreased with the increasing concentration of CPF. To explore the possible mechanism of the differential regulation of PON2 gene expression by CPF and PA, we investigated the possible binding and signaling through the human M2 muscarinic acetylcholine receptor (M2AChR). Since M2AChRs are similar to G-protein coupled receptors and function through cAMP signalling, we measured the cAMP level after CPF and PA treatment. CPF- and PA-treated IMR-32 cells can be used as a model to study the mechanism by which PON2 acts as a ROS scavenger in response to xenobiotics stimulation in the brain.

Prevalence, clinical manifestations, laboratory findings, treatment, and outcome of intermediate syndrome in anticholinesterase pesticide intoxication of dogs: A retrospective study

Organophosphates and carbamates are important anticholinesterase intoxicants of humans and dogs. Intermediate syndrome (IMS) typically occurs 7–96 h following a toxicity-associated acute cholinergic crisis (ACC), and manifests clinically as weakness of the proximal limb, respiratory, and neck flexor muscles. The aim of this study was to describe the prevalence, clinical findings, and outcome of IMS in dogs. The medical records of a veterinary teaching hospital were searched for dogs diagnosed with ACC, IMS, or both, between 2017 and 2021. Case files were retrospectively reviewed. Six historical IMS cases were additionally reviewed. Thirty-two dogs were diagnosed with anticholinesterase intoxication during the search period, of which 23 (72 %) were only diagnosed with ACC, seven (22 %) progressed from ACC to IMS, and two (6 %) were only diagnosed with IMS. Duration of hospitalisation was longer in the IMS group compared to the ACC only group (P = 0.005). When all dogs with IMS (n = 15, including the six historical cases) were considered, survival was 100 %, including four (27 %) that required positive pressure mechanical ventilation following respiratory failure. Serum butyrylcholine esterase activity, a marker of cholinesterase activity, was below reference interval when first measured in 14 (93 %) of dogs; however, was not a useful as a recovery marker. IMS should be suspected in dogs demonstrating respiratory, neck, and proximal limb muscle paresis or paralysis, especially following clinical signs consistent with ACC. Absence of clinical signs consistent with ACC or butyrylcholine esterase activity within the reference interval does not exclude IMS as a differential.

Microglia Remodelling and Neuroinflammation Parallel Neuronal Hyperactivation Following Acute Organophosphate Poisoning.

Organophosphate (OP) compounds include highly toxic chemicals widely used both as pesticides and as warfare nerve agents. Existing countermeasures are lifesaving, but do not alleviate all long-term neurological sequelae, making OP poisoning a public health concern worldwide and the search for fully efficient antidotes an urgent need. OPs cause irreversible acetylcholinesterase (AChE) inhibition, inducing the so-called cholinergic syndrome characterized by peripheral manifestations and seizures associated with permanent psychomotor deficits. Besides immediate neurotoxicity, recent data have also identified neuroinflammation and microglia activation as two processes that likely play an important, albeit poorly understood, role in the physiopathology of OP intoxication and its long-term consequences. To gain insight into the response of microglia to OP poisoning, we used a previously described model of diisopropylfluorophosphate (DFP) intoxication of zebrafish larvae. This model reproduces almost all the defects seen in poisoned humans and preclinical models, including AChE inhibition, neuronal epileptiform hyperexcitation, and increased neuronal death. Here, we investigated in vivo the consequences of acute DFP exposure on microglia morphology and behaviour, and on the expression of a set of pro- and anti-inflammatory cytokines. We also used a genetic method of microglial ablation to evaluate the role in the OP-induced neuropathology. We first showed that DFP intoxication rapidly induced deep microglial phenotypic remodelling resembling that seen in M1-type activated macrophages and characterized by an amoeboid morphology, reduced branching, and increased mobility. DFP intoxication also caused massive expression of genes encoding pro-inflammatory cytokines Il1β, Tnfα, Il8, and to a lesser extent, immuno-modulatory cytokine Il4, suggesting complex microglial reprogramming that included neuroinflammatory activities. Finally, microglia-depleted larvae were instrumental in showing that microglia were major actors in DFP-induced neuroinflammation and, more importantly, that OP-induced neuronal hyperactivation was markedly reduced in larvae fully devoid of microglia. DFP poisoning rapidly triggered massive microglia-mediated neuroinflammation, probably as a result of DFP-induced neuronal hyperexcitation, which in turn further exacerbated neuronal activation. Microglia are thus a relevant therapeutic target, and identifying substances reducing microglial activation could add efficacy to existing OP antidote cocktails.

Suspected cholinergic toxicity due to cevimeline hydrochloride and Bacopa monnieri interaction: a case report

BackgroundMuscarinic agonists are indicated for the treatment of many conditions including ileus, urinary retention, glaucoma, and Sjögren’s syndrome. Due to their lack of tissue specificity, these drugs can lead to undesirable side effects at off-target sites and may be potentiated by supplements that impact the half-life of these drugs.Case presentationA 58-year-old Caucasian female with history of Sjögren’s syndrome, who was being managed with cevimeline, presented to the primary care office with reported hyperhidrosis, malaise, nausea, and tachycardia. She reported taking an herbal supplement containing B. monnieri and phosphatidylserine the previous night. It has been previously demonstrated that B. monnieri alters cytochrome P450 enzymes. Electrocardiogram showed no acute ST–T changes. Clinical improvement occurred with hydration and discontinuation of the supplement.ConclusionsTo our knowledge, there has only been one other documented cevimeline overdose, and it was not associated with an herbal supplementation interaction. Physicians should actively elicit herbal supplement information from patients to anticipate possible drug–herb interactions. An additional consideration of clinical relevance is the known genetic variability that may affect drug responsiveness due to differences in metabolism and half-life of drugs that arise from common genetic variants of cytochrome P450 genes.

Hydroxybenzoic Acids as Acetylcholinesterase Inhibitors: Calorimetric and Docking Simulation Studies.

One of the symptoms of Alzheimer’s disease (AD) is low acetylcholine level due to high acetylcholinesterase (AChE) activity. For this reason, AChE inhibitors are used in the treatment of AD, the prolonged use of which may cause a cholinergic crisis. There is a need to search for safe natural AChE inhibitors. The study analyzed 16 hydroxybenzoic acids using calorimetry and docking simulation as AChE inhibitors. All tested compounds were shown to inhibit the hydrolysis of ACh. The best properties were shown by methyl syringinate, which acted as competitive inhibitor at a catalytic site. The tested compounds also interacted with the anionic or peripheral binding site known to block β-amyloid plaques formation. The activity of the tested hydroxybenzoic acids IC50 ranged from 5.50 to 34.19 µmol/µmol of AChE, and the binding constant Ka from 20.53 to 253.16 L/mol, which proves their reversible, non-toxic effect, and activity at physiological concentrations.

Roles of Syzygium in Anti-Cholinesterase, Anti-Diabetic, Anti-Inflammatory, and Antioxidant: From Alzheimer's Perspective.

Alzheimer’s disease (AD) causes progressive memory loss and cognitive dysfunction. It is triggered by multifaceted burdens such as cholinergic toxicity, insulin resistance, neuroinflammation, and oxidative stress. Syzygium plants are ethnomedicinally used in treating inflammation, diabetes, as well as memory impairment. They are rich in antioxidant phenolic compounds, which can be multi-target neuroprotective agents against AD. This review attempts to review the pharmacological importance of the Syzygium genus in neuroprotection, focusing on anti-cholinesterase, anti-diabetic, anti-inflammatory, and antioxidant properties. Articles published in bibliographic databases within recent years relevant to neuroprotection were reviewed. About 10 species were examined for their anti-cholinesterase capacity. Most studies were conducted in the form of extracts rather than compounds. Syzygium aromaticum (particularly its essential oil and eugenol component) represents the most studied species owing to its economic significance in food and therapy. The molecular mechanisms of Syzygium species in neuroprotection include the inhibition of AChE to correct cholinergic transmission, suppression of pro-inflammatory mediators, oxidative stress markers, RIS production, enhancement of antioxidant enzymes, the restoration of brain ions homeostasis, the inhibition of microglial invasion, the modulation of ß-cell insulin release, the enhancement of lipid accumulation, glucose uptake, and adiponectin secretion via the activation of the insulin signaling pathway. Additional efforts are warranted to explore less studied species, including the Australian and Western Syzygium species. The effectiveness of the Syzygium genus in neuroprotective responses is markedly established, but further compound isolation, in silico, and clinical studies are demanded.

Evaluation of the Effectiveness of Atropine Administration for Prevention of Acute Cholinergic Syndrome Associated with Irinotecan

Evaluation of the Effectiveness of Atropine Administration for Prevention of Acute Cholinergic Syndrome Associated with Irinotecan

Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro.

The neuropathological substrate of dementia with Lewy bodies (DLB) is defined by the inextricable cross-seeding accretion of amyloid-β (Aβ) and α-synuclein (α-syn)-laden deposits in cholinergic neurons. The recent revelation that neuropeptide kisspeptin-10 (KP-10) is able to mitigate Aβ toxicity via an extracellular binding mechanism may provide a new horizon for innovative drug design endeavors. Considering the sequence similarities between α-syn’s non-amyloid-β component (NAC) and Aβ’s C-terminus, we hypothesized that KP-10 would enhance cholinergic neuronal resistance against α-syn’s deleterious consequences through preferential binding. Here, human cholinergic SH-SY5Y cells were transiently transformed to upsurge the mRNA expression of α-syn while α-syn-mediated cholinergic toxicity was quantified utilizing a standardized viability-based assay. Remarkably, the E46K mutant α-syn displayed elevated α-syn mRNA levels, which subsequently induced more cellular toxicity compared with the wild-type α-syn in choline acetyltransferase (ChAT)-positive cholinergic neurons. Treatment with a high concentration of KP-10 (10 µM) further decreased cholinergic cell viability, while low concentrations of KP-10 (0.01–1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated toxicity. Correlating with the in vitro observations are approximations from in silico algorithms, which inferred that KP-10 binds favorably to the C-terminal residues of wild-type and E46K mutant α-syn with CDOCKER energy scores of −118.049 kcal/mol and −114.869 kcal/mol, respectively. Over the course of 50 ns simulation time, explicit-solvent molecular dynamics conjointly revealed that the docked complexes were relatively stable despite small-scale fluctuations upon assembly. Taken together, our findings insinuate that KP-10 may serve as a novel therapeutic scaffold with far-reaching implications for the conceptualization of α-syn-based treatments.

Cardiovascular and core temperature responses to acute organophosphate intoxication in rats

IntroductionOrganophosphates (OP) are cholinesterase inhibitors that are used as pesticides in agriculture and as nerve agents in chemical warfare. Surprisingly, we have limited information on the time course of cardiovascular responses to acute OP intoxication at doses that cause cholinergic crisis in humans. OP‐induced QT prolongation has been shown to lead to fatal ventricular arrhythmia and delayed death, however, not all cardiac failures are associated with QT prolongation.MethodsRats were implanted with a BP/ECG telemetry device and 14 d later, acutely intoxicated with the OP diisopropylfluorophosphate (DFP, 4 mg/kg, sc) followed 1 min later by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im) to block peripheral cholinergic toxicity. BP/ECG data were grouped based on the rat’s survival time: <15 min (n=11, group A), >15 min and <17 hours (n=9, group B), and >17 hours (n=4, group C).ResultsIn conscious, freely moving rats, DFP injection significantly increased BP (+87±10 mmHg), HR (+177±32 bpm), core temperature (+4.0±0.7 °C), and occurrences of premature ventricular complexes (PVC). These increases were similar in all three groups. Around the peak pressor response, group A had abrupt drops in BP and HR (cardiovascular collapse) that was triggered by supra‐ventricular events (sinus bradycardia and/or AV blocks). A similar pattern of cardiovascular collapse was observed in group B, hours after DFP injections. Furthermore, after the initial pressor response, half of the rats in group B had significant lower pulse pressure and BP despite a maintained HR.ConclusionOur data suggest that DFP‐induced cardiovascular collapse may be centrally mediated and that compromised cardiac function may also contribute to the cardiovascular collapse in delayed death.

Developing a Prenatal Acute Exposure and Medical Countermeasure Evaluation Model for Organophosphate Compounds in a Genetically Modified Mouse

Organophosphate (OPs) compounds make up the most common class of pesticides as well as chemical warfare nerve agents (CWNA), all of which covalently inhibit the active site of acetylcholinesterase (AChE), resulting in intoxication via a cholinergic crisis. While the biochemical mechanism of action resulting in acute intoxication of an exposed individual is well understood, less is known about the mechanism of OP intoxication via other exposure routes, particularly prenatal exposure. The clinical effects of non‐acute prenatal OP exposure have been previously studied primarily in cases involving diet and agricultural labor, while case studies documenting the effects on conception of acute exposure during chemical warfare attacks (Japan 1995, Syria 2013 and 2017) have also been published. Such exposure events were linked to a range of serious neurodevelopmental anomalies in children, but the underlying mechanism of action as well as the potential benefits of medical countermeasures have not been clearly elucidated. A robust human‐relevant animal model to test both is therefore essential for evaluating current and future OP countermeasures. The present study used a novel humanized mouse strain expressing human AChE and an inactivated native serum carboxylesterase to create a prenatal acute exposure and emergency medical countermeasure evaluation model. Pregnant mice were acutely exposed to an OP at a critical point in cholinergic development, generally equivalent to the first trimester in humans. Dams were challenged with either sarin or the pesticide paraoxon, followed by either a saline vehicle control or 2‐PAM and an atropine/midazolam cocktail, the currently fielded emergency treatment for OP intoxication. Mice were allowed to carry pups to term, and upon reaching maturity, cortex, cerebellum, bone marrow and gonads were collected from offspring in each exposure group. Phenotypical and histopathological evaluation of tissues and other factors in dams and offspring were evaluated. Gene expression analyses conducted for each tissue generated a detailed profile associated with each OP exposure/treatment group, providing robust criteria for model development. The resulting data demonstrated a significant beneficial impact of medical countermeasures for both sarin and paraoxon exposures, significantly reducing the amount and the scope of gene expression changes induced by OP exposure. This model provides insight into the developmental pathologies resulting from prenatal acute OP exposure as well as serves as an evaluation model for future treatments.

From the discovery of combat gases to insecticides and bioterrorism – a brief history

The identification of organophosphate (OP) compounds dates back to the 1800s. OPare largely used pesticides in the agricultural field and households but prior use as a chemical weapon was considered during wars. Their toxicity on humans has been previously studied and addresses both acute intoxication and low-level chronic exposure. Symptoms of acute exposure describe a cholinergic syndrome with bradycardia, miosis, confusion, fasciculations, tearing, sialorrhea, diarrhea, bronchorrhea, and bronchospasm. The intermediate syndrome causes paralysis of the gait muscles, neck flexors, and respiratory failure. Moreover, unrestricted access to OP has increased the rate of suicide, accounting for around 30% of cases, increasing concern about OP availability. Western countries have drastically restricted access to OP by imposing regulations regarding handling these hazardous substances, but efforts have to be made to globally reduce this struggle

Clinical manifestations, laboratory findings, treatment and outcome of acute organophosphate or carbamate intoxication in 39 cats.

Organophosphates and carbamates are important sources of intoxication for humans and animals. However, large-scale studies of these intoxications in cats are unavailable. The medical records of 39 cats presented to a veterinary teaching hospital with acute organophosphate or carbamate intoxication were reviewed retrospectively. Mortality in intoxicated cats was 15%. Low respiratory rate and low rectal temperature at presentation were associated with death. Other common clinical signs included weakness, ataxia, apathy, recumbency, anorexia and bradycardia, but these were unassociated with the outcome. The common biochemical abnormalities included decreased serum butyryl-choline esterase activity, acidaemia, hypercarbaemia and total hypocalcaemia, and increased creatine kinase activity and total plasma protein concentration. There were no significant differences in haematological, biochemical and blood gas analytes between survivors and non-survivors. Common medications and treatments included 2-pyridine aldoxime methyl-chloride-pralidoxime (2-PAM) (74%), metoclopramide (64%), antibiotics (64%), diphenhydramine (59%) and atropine sulphate (54%). There were no significant drug and treatment differences between survivors and non-survivors. The secondary complications of the intoxication included pneumonia (10%), acute kidney injury (10%) and pancreatitis (8%). Acute cholinergic crisis due to organophosphate or carbamate intoxication has a fair prognosis in cats. Low respiratory rate and low rectal temperature at presentation were associated with death. The most commonly used specific medications in this study included 2-PAM, diphenhydramine and atropine sulphate.

Pro: Oximes should be used routinely in organophosphate poisoning.

In poisoning with organophosphorus compounds (OP), patients can only profit from the regeneration of acetylcholinesterase, when the poison load has dropped below a toxic level. Every measure that allows an increase of synaptic acetylcholinesterase (AChE) activity at the earliest is essential for timely termination of the cholinergic crisis. Only drug-induced reactivation allows fast restoration of the inhibited AChE. Obidoxime and pralidoxime have proved to be able to reactivate inhibited cholinesterase thereby saving life of poisoned animals. A plasma level of obidoxime or pralidoxime allowing reactivation in humans poisoned by OP can be adjusted. There is no doubt that obidoxime and pralidoxime are able to reactivate OP-inhibited AChE activity in poisoned patients, thereby increasing AChE activity and contributing substantially to terminate cholinergic crisis. Hence, a benefit may be expected when substantial reactivation is achieved. A test system allowing determination of red blood cell AChE activity, reactivatability, inhibitory equivalents and butyrylcholinesterase activity is available for relatively low cost. If any reactivation is possible while inhibiting equivalents are present, oxime therapy should be maintained. In particular, when balancing the benefit risk assessment, obidoxime or palidoxime should be given as soon as possible and as long as a substantial reactivation may be expected.

Effects of short-term sub-lethal diazinon® exposure on behavioural patterns and respiratory function in Clarias batrachus: inferences for adaptive capacity in the wild

ABSTRACT The potentials for neurotoxicity and respiratory distress under 96 h acute diazinon exposures was examined using behavioural indices and opercular movement respectively in walking catfish, Clarias batrachus. Diazinon exposure concentrations were correlated with toxicological (lethal and sublethal) endpoints. The LC50 values and 95% confidence limits at 24, 48, 72 and 96 h, were 21.85 (19.09- 28.199 mg/L), 19.081 (17.15-21.65 mg/L), 16.07 (14.49- 17.86 mg/L) and 12.85 (10.92-14.39 mg/L) respectively. Concentration-dependent mortality and altered behavioural responses including uncoordinated swim movements, excessive mucus secretion, imbalanced and erratic swimming patterns and brief inactivity prior to mortality was observed. The altered behavioural patterns reflecting neurotoxicity, and increased opercular movement indicating respiratory distress in the catfish increased proportionally with elevated levels diazinon and exposure time. The inactive and almost non-motile state prior to death indicates paralysis and muscle seizure typical in the late stages of cholinergic toxicity. The severity of behavioural and respiratory effects on adult C. batrachus, a hardy species, portends catastrophic consequences for less hardy and more susceptible aquatic taxa like fish in the field, including considerable loss of adaptive ability.

An insight into neurotoxicity effects associated with Organophosphate exposure

Organophosphates comprise several groups of chemicals derived from phosphonic, phosphinic and phosphoric acids. The chemicals cause four major neurotoxic disorders: cholinergic syndrome, chronic organophosphate-induced neuropsychiatric disorder (COPIND), intermediate syndrome and organophosphate-induced delayed polyneuropathy (OPIDP). In the cholinergic syndrome, organophosphates exert their toxic effect through the inhibition of acetylcholinesterase. Patients with cholinergic syndrome experience several symptoms including sweating, lacrimation, salivation and rhinorrhea and respiratory difficulties. The primary symptoms in the intermediate syndrome are respiratory and proximal limb muscle weakness. In contrast, psychiatric conditions, such as depression and anxiety, have been reported in patients with COPIND. In OPIDP, patients experience acute cramping pain inside their calves and itchiness in the hands and feet, paresthesia and distal unresponsiveness.

An insight into neurotoxicity effects associated with Organophosphate exposure

Organophosphates comprise several groups of chemicals derived from phosphonic, phosphinic and phosphoric acids. The chemicals cause four major neurotoxic disorders: cholinergic syndrome, chronic organophosphate-induced neuropsychiatric disorder (COPIND), intermediate syndrome and organophosphate-induced delayed polyneuropathy (OPIDP). In the cholinergic syndrome, organophosphates exert their toxic effect through the inhibition of acetylcholinesterase. Patients with cholinergic syndrome experience several symptoms including sweating, lacrimation, salivation and rhinorrhea and respiratory difficulties. The primary symptoms in the intermediate syndrome are respiratory and proximal limb muscle weakness. In contrast, psychiatric conditions, such as depression and anxiety, have been reported in patients with COPIND. In OPIDP, patients experience acute cramping pain inside their calves and itchiness in the hands and feet, paresthesia and distal unresponsiveness.

Pharmacist intervention in the detection of cholinergic crisis in a fasting patient treated with distigmine bromide : A case report

Pharmacist intervention in the detection of cholinergic crisis in a fasting patient treated with distigmine bromide : A case report

Post-VX exposure treatment of rats with engineered phosphotriesterases

The biologically stable and highly toxic organophosphorus nerve agent (OP) VX poses a major health threat. Standard medical therapy, consisting of reactivators and competitive muscarinic receptor antagonists, is insufficient. Recently, two engineered mutants of the Brevundimonas diminuta phosphotriesterase (PTE) with enhanced catalytic efficiency (kcat/KM = 21 to 38 × 106 M−1 min−1) towards VX and a preferential hydrolysis of the more toxic P(−) enantiomer were described: PTE-C23(R152E)-PAS(100)-10-2-C3(I106A/C59V/C227V/E71K)-PAS(200) (PTE-2), a single-chain bispecific enzyme with a PAS linker and tag having enlarged substrate spectrum, and 10-2-C3(C59V/C227V)-PAS(200) (PTE-3), a stabilized homodimeric enzyme with a double PASylation tag (PAS-tag) to reduce plasma clearance. To assess in vivo efficacy, these engineered enzymes were tested in an anesthetized rat model post-VX exposure (~ 2LD50) in comparison with the recombinant wild-type PTE (PTE-1), dosed at 1.0 mg kg−1 i.v.: PTE-2 dosed at 1.3 mg kg−1 i.v. (PTE-2.1) and 2.6 mg kg−1 i.v. (PTE-2.2) and PTE-3 at 1.4 mg kg−1 i.v. Injection of the mutants PTE-2.2 and PTE-3, 5 min after s.c. VX exposure, ensured survival and prevented severe signs of a cholinergic crisis. Inhibition of erythrocyte acetylcholinesterase (AChE) could not be prevented. However, medulla oblongata and diaphragm AChE activity was partially preserved. All animals treated with the wild-type enzyme, PTE-1, showed severe cholinergic signs and died during the observation period of 180 min. PTE-2.1 resulted in the survival of all animals, yet accompanied by severe signs of OP poisoning. This study demonstrates for the first time efficient detoxification in vivo achieved with low doses of heterodimeric PTE-2 as well as PTE-3 and indicates the suitability of these engineered enzymes for the development of highly effective catalytic scavengers directed against VX.

Manajemen Perawatan Neurointensif pada Miastenia Gravis

Myasthenia gravis (MG) is an autoimmune disorder that affects neuromuscular transmission, causing generalized or localized weakness characterized by fatigue. Myasthenia gravis is most commonly associated with antibodies to the acetylcholine receptor (AChR) on the motor end plate in the postsynaptic neuron. This article aims to determine the appropriate neurointensive management in patients with myasthenia gravis with complications of myasthenic crisis. The writing of this article includes various sources originating from scientific journals and government guidelines and related agencies. Source searches were carried out on online portals for journal publications such as MedScape, Google Scholar (scholar.google.com) and the National Center for Biotechnology Information (ncbi.nlm.nih.gov), with the keyword “Myasthenia Gravis”. The management of myasthenia gravis can be done in various ways, namely, mechanical intubation and ventilation, non-invasive ventilation, pridostigmine as an anticholinesterase inhibitor, immunosuppressant therapy, short term immunotherapy, intravenous immunoglobulin, and surgical therapy. In the treatment of myasthenia gravis, the main goal is to restore muscle condition, especially patient productivity where the management of myasthenia gravis consists of management of myasthenic crisis, cholinergic crisis, symptoms, immunosuppressant therapy, and thymectomy surgical therapy if a tumor is indicated.