Organophosphorus Compound Poisoning Research Articles

Study of Levels of Creatine Phosphokinase and Lactate Dehydrogenase as Prognostic Markers in Acute Organophosphorus Poisoning

Objectives: Organophosphorus compound (OPC) poisoning is primarily a problem in developing countries. Its widespread use and easy availability have increased the likelihood of poisoning with these compounds. Serum cholinesterase levels are easier to estimate and usually depressed after organophosphorus (OP) poisoning. Peradeniya OP poisoning scale has not been studied much in the Indian scenario. It could be a simple and effective system to determine the need for ventilatory support early on in the course. Hence, this study was undertaken to assess the severity of OPC poisoning clinically using Peradeniya scoring and by estimating creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) levels. Material and Methods: A prospective observational study was performed among 100 cases of OP poisoning from January 2021 to October 2022. On patient’s fulling, inclusion criteria were investigated with serum acetylcholinesterase at the time of admission, and periodic estimation of serum CPK and serum LDH was done on the day of admission and then on day three and day 5 of admission Results: The CPK and LDH levels were significantly elevated in patients who developed respiratory failure and thus strongly correlated with clinical severity Conclusion: Serum CPK and LDH show a strong degree of positive correlation with the severity of poisoning and can be used as a predictor of outcome in OP poisoning.

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Desensitization of nicotinic acetylcholine receptors (nAChRs) can be induced by overstimulation with acetylcholine (ACh) caused by an insufficient degradation of ACh after poisoning with organophosphorus compounds (OPCs). Currently, there is no generally applicable treatment for OPC poisoning that directly targets the desensitized nAChR. The bispyridinium compound MB327, an allosteric modulator of nAChR, has been shown to act as a resensitizer of nAChRs, indicating that drugs binding directly to nAChRs can have beneficial effects after OPC poisoning. However, MB327 also acts as an inhibitor of nAChRs at higher concentrations and can thus not be used for OPC poisoning treatment. Consequently, novel, more potent resensitizers are required. To successfully design novel ligands, the knowledge of the binding site is of utmost importance. Recently, we performed in silico studies to identify a new potential binding site of MB327, MB327-PAM-1, for which a more affine ligand, UNC0646, has been described. In this work, we performed ligand-based screening approaches to identify novel analogs of UNC0646 to help further understand the structure-affinity relationship of this compound class. Furthermore, we used structure-based screenings and identified compounds representing four new chemotypes binding to MB327-PAM-1. One of these compounds, cycloguanil, is the active metabolite of the antimalaria drug proguanil and shows a higher affinity towards MB327-PAM-1 than MB327. Furthermore, cycloguanil can reestablish the muscle force in soman-inhibited rat muscles. These results can act as a starting point to develop more potent resensitizers of nAChR and to close the gap in the treatment after OPC poisoning.

Inhibition kinetics of acetylcholinesterase and butyrylcholinesterase from various species by 2-(2-cresyl)-4H-1,3,2-benzodioxaphosphorin-2-oxide (CBDP)

The aerotoxic syndrome has been associated with exposure to tricresyl phosphate (TCP), which is used as additive in hydraulic fluids and engine lubricants. The toxic metabolite 2-(2-cresyl)-4H-1,3,2-benzodioxaphosphorin-2-oxide (CBDP) is formed from the TCP isomer tri-ortho-cresyl phosphate (TOCP) in vivo and is known to react with the active site serine in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) resulting in the inhibition of the enzymes. Previous in vitro studies showed pronounced species differences in the inhibition kinetics of cholinesterases by organophosphorus compounds (OP), which must be considered in the development of relevant animal models for the investigation of OP poisoning and the aerotoxic syndrome. The present study was designed to investigate the inhibition kinetics of human, Cynomolgus monkey, pig, mini pig, guinea pig, mouse, and rat AChE as well as BChE by CBDP under standardized conditions. There were similar rate constants for the inhibition (ki) of human, Cynomolgus monkey and mouse AChE by CBDP. In contrast, the ki values obtained for guinea pig, mini pig, pig, and rat AChE were 2.8- to 5.9-fold lower than that of human AChE. The results of the present study confirmed CBDP as one of the most potent inhibitors of human BChE, indicating a ki value of 3.24 ± 0.33 ×108M−1min−1, which was about 1,140-fold higher than that of human AChE. Accordingly, a markedly more pronounced inhibition rate of BChE from the species guinea pig, mini pig, pig, rat, Cynomolgus monkey, and mouse by CBDP was found as compared to those of AChE from the respective sources, indicating 2.0- to 89.6-fold higher ki values.

N-methyl-d-aspartate receptors: Structure, function, and role in organophosphorus compound poisoning.

Acute organophosphorus compound (OP) poisoning induces symptoms of the cholinergic crises with the occurrence of severe epileptic seizures. Seizures are induced by hyperstimulation of the cholinergic system, but are enhanced by hyperactivation of the glutamatergic system. Overstimulation of muscarinic cholinergic receptors by the elevated acetylcholine causes glutamatergic hyperexcitation and an increased influx of Ca2+ into neurons through a type of ionotropic glutamate receptors, N-methyl-d-aspartate (NMDA) receptors (NMDAR). These excitotoxic signaling processes generate reactive oxygen species, oxidative stress, and activation of the neuroinflammatory response, which can lead to recurrent epileptic seizures, neuronal cell death, and long-term neurological damage. In this review, we illustrate the NMDAR structure, complexity of subunit composition, and the various receptor properties that change accordingly. Although NMDARs are in normal physiological conditions important for controlling synaptic plasticity and mediating learning and memory functions, we elaborate the detrimental role NMDARs play in neurotoxicity of OPs and focus on the central role NMDAR inhibition plays in suppressing neurotoxicity and modulating the inflammatory response. The limited efficacy of current medical therapies for OP poisoning concerning the development of pharmacoresistance and mitigating proinflammatory response highlights the importance of NMDAR inhibitors in preventing neurotoxic processes and points to new avenues for exploring therapeutics for OP poisoning.

AChE reactivation in precision-cut lung slices following organophosphorus compound poisoning

Precision-cut lung slices (PCLS) are a suitable model for analyzing the acetylcholinesterase (AChE) activity and subsequent effects after exposure to organophosphorus (OP) compounds. In this study, the AChE activity was determined in intact PCLS for the first time. Since the current standard therapy for OP poisoning (atropine + oxime + benzodiazepine) lacks efficiency, reliable models to study novel therapeutic substances are needed. Models should depict pathophysiological mechanisms and help to evaluate the beneficial effects of new therapeutics. Here PCLS were exposed to three organophosphorus nerve agents (OPNAs): sarin (GB), cyclosarin (GF), and VX. They were then treated with three reactivators: HI-6, obidoxime (OBI), and a non-oxime (NOX-6). The endpoints investigated in this study were the AChE activity and the airway area (AA) change. OPNA exposure led to very low residual AChE activities. Depending on the reactivator properties different AChE reactivation results were measured. GB-inhibited PCLS-AChE was reactivated best, followed by VX and GF. To substantiate these findings and to understand the connection between the molecular and the functional levels in a more profound way the results were correlated to the AA changes. These investigations underline the importance of reactivator use and point to the possibilities for future improvements in the treatment of OPNA-exposed victims.

Socio-demographic Profile of the Causes of Death due to Organophosphorus Poisoning - A Retrospective Study

Background: Poisoning is a global issue occurring all over the world involving people of all ages and genders, from all ethnic and economic groups. It is estimated, there are 1 to 5 million cases of Organophosphorus poisoning per year worldwide with approximately 300,000 deaths. Aim of the study: To assess the demographic pattern of death due to organophosphorus poisoning with respect to age, sex, occupation, education, and socioeconomic status. Materials and Methods: A retrospective study was conducted by the department of Forensic Medicine, Sheikh Hasina Medical Colleges, Tangail, from January 2020 to December 2020. Result and discussion: 85(20.68%) were due to poisoning, out of those poisoning cases 77 (90.58%) were due to organophosphorus compound poisoning. The incidence was higher in females (51.94%) than in males. 90.00% of the victims in our study were married females, and 63.64% of cases were below Secondary education. Among the male deaths 83.78% were from rural areas, female rural deaths were 82.50%. Housewife (38.9%) were the major victims. Conclusion: Illiteracy, Poverty, Cheap availability of organophosphorus compounds, lack of employment, and stressful lifestyle were the common reasons behind suicidal poisoning. Health education of farmers, other agricultural laborers, and young people about the toxic and detrimental effects of organophosphorus compounds will help in preventing suicidal and accidental poisoning to some extent. J Shaheed Suhrawardy Med Coll 2022; 14(1): 62-64

Organophosphorus Compound as Suicidal Poison in Rural Areas of Bangladesh: A Medicolegal Study

Background: Suicide by poisoning is a major public health problem in Bangladesh and other developing countries in the world. Among the poisonous substances, Organophosphorus compounds (OPC) poisoning is more common. Easy accessibility of the poison is the number one reason for the preference of OPCs as suicidal agents. Objective: This study was designed to find out demographic characteristics and postmortem findings related to suicide by OPC poisoning in Manikganj. Methodology: This retrospective cross-sectional study was carried out during January, 2019 to December, 2020 in the district hospital, Manikganj, Bangladesh. Results: During the study period, a total of 381 medico-legal autopsy have been done- among them, 83 (21.78%) cases were death due to OPC poisoning. Maximum (24, 28.91%) deaths were between ages of 21-30 years, among them majority were males (49, 59.03%). People of different occupations were involved in OPC poisoning- maximum of them were housewives (27, 32.53%), followed by agricultural workers (13, 15.66%). Regarding motive of poisoning, the most common was suicidal intent (58, 69.88%) among both males (22, 37.93%) and females (36, 62.07%), followed by accidental (25, 30.12%). About one third of the cases were illiterate (26, 31.33%). Financial constraint was the main cause of suicide. Conclusion: OPC poisoning is a burning problem in our health sector. Improvement of awareness, elimination of unemployment, financial stability, limiting availability and banning more toxic compounds would reduce the OPC poisoning rate to a considerable number. Journal of Monno Medical College, June 2023; 9 (1): 07-10

Epidemiological Evaluation of Suicidal Deaths due to Organophosphorus Compound Poisoning

Background: One of the most widespread suicide methods, especially emerging in developing countries like Bangladesh, is poisoning. Organophosphorus compound (OPC) is a common chemical used for self-poisoning that is also inexpensive and easily accessible. Objectives: To evaluate the demography of suicidal deaths due to OPC poisoning. Methods: This was a retrospective study with the departmental records of autopsy among deaths due to OPC poisoning. The study was carried out to ascertain the epidemiological evaluation of 242 OPC poisoning suicidal deaths during January, 2016 to December, 2017 at the mortuary of Sylhet MAG Osmani Medical College, Bangladesh. Results: Majority of the victims (184, 76.03%) were below 40 years of age and females were predominant (142, 58.67%). Most of the victims resided in Companygonj (47, 19.42%), followed by Kotwali (40, 16.52%), and Gowainghat (35, 14.52%) of Sylhet district. Most of the dead bodies (192, 79.33%) were brought to the morgue under Kotwali police station. The most common (218, 90.08%) cause of death was respiratory failure. Conclusion: Suicide with OPC was the most common in younger women. Establishment of national suicide surveillance is now a time demanded step and responsible authority should take some necessary steps to address it. Journal of Monno Medical College, June 2023; 9 (1): 20-23

Serum creatinine phosphokinase: A potential prognostic marker in assessing clinical severity with organophosphorus poisoning.

Organophosphorus compound (OPC) poisoning undoubtedly being a major concern in cultivation sites of the developing world, including Bangladesh. Two potential biomarkers, for example, serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), are widely used in OPC poisoning severity indicators in patients. In this study, we sought to correlate the severity score of acute OPC poisoning with CPK or LDH level and subsequently explore their prognostic value. This study was performed on a total of 70 patients with OPC poisoning admitted to the inpatient care unit at a territory-based hospital in Bangladesh. Sociodemographics and poison types were recorded, and severity was assessed according to Peradeniya Organophosphorus Poisoning (POP) scale. Serum CPK and LDH levels were measured and recorded. A total of seventy OPC patients were included with male to female ratio of 1.33:1, respectively, with a mean age of 28.7 ± 12.8 years. Chlorpyrifos and methylparathion were the most commonly utilized OP compounds, accounting for 42.9% and 28.6%, respectively. Among the OPC patients, the majority were married homemakers from rural areas. According to POP score, 55.7% and 37.1% of patients were categorized as mild and moderate, whereas very few were found to be severe. The mean serum CPK and LDH of OPC-patients at admission time were 235.6 ± 79.8 IU/L and 348.3 ± 154.1 IU/L, respectively. Serum CPK, atropine dose and hospital stay strongly correlated with clinical severity. We conclude that the serum CPK level strongly correlates with the degree of OPC poisoning and can be used as a predictor of the clinical intervention approaches.

A comparative study of atropine and atropine plus pralidoxime in the management of organo-phosphorous poisoning

Background: Poisoning with organophosphorus compounds (OP) is a common problem throughout the world particularly in developing countries. Standard treatment involves resuscitation, administration of the anti-muscarinic agent atropine, an acetylcholinesterase reactivator (pralidoxime) and assisted ventilation if necessary. In this study we compared the efficacy of add-on pralidoxime therapy over therapy with atropine alone in OP poisoning. Methods: The study included 103 patients, out of 103 OP poisoning cases, 54 patients received both atropine and PAM (group A) and 49 received only atropine (group B). Main outcome parameters of the study were total hospital stay and mortality. The data was compared using ‘t’ test while mortality was compared using Fisher’s exact test. Data was tabulated, analysed, reviewed and evaluated. Results: There was no difference in duration of hospital stay between the two group. The mean hospital stay in group A was 3.71±1.92 days and in group B was 3.14±2.01 days (p value >0.05). No difference in mortality was seen between the two group. Out of 54 in group A, 8 died and in group B out of 49, 7 died (p value >0.05). Importantly cost burden is very high in the pralidoxime added group. Conclusions: There is no significant difference in use of atropine alone or atropine-pralidoxime combination in terms of morbidity and mortality in OP poisoning rather the later incurs more economic burden which may not be practicable in poor countries like India. However, a larger multicentric prospective study needs to be conducted, to be able to draw a definitive conclusion.

Assessment of the Peradeniya Organophosphorus Poisoning Scale as a Severity and Prognostic Marker in Patients With Acute Organophosphorus Poisoning Presenting to an Emergency Medicine Department.

Background Organophosphorus (OP)compound poisoning is the most common toxicological medical emergency in India, where the majority of the population lives on agriculture. The Peradeniya Organophosphorus Poisoning (POP) scale can be a simple and effective system to determine the need for ventilatory support early in the course of admission. The objective of this study was to evaluate the prognostic value of the clinical parameters of the POP scale in predicting the severity of organophosphorus compound poisoning, by comparing early predicted patient prognosis evaluated by the POP scale on admission with the patient outcome. Methods This was a prospective observational study of acute organophosphorus compound poisoning presenting to the emergency department of Sir Sayajirao General (SSG) Hospital and Medical College, Baroda. We included patients over 12 years of age with a history of, or symptoms suggestive of, acute OP poisoning. The patients receivedinitial resuscitation according to airway, breathing, circulation, disability, and exposure simultaneously with decontamination and gastric lavage by Ryle's tube. They also received the standard antidotes of atropine and pralidoximeimmediately. We appliedthe POP scale to each patient uponadmission and graded the poisoning severity as mild (a POP scale score of 0-3), moderate (4-7), or severe (8-11). This scale assessed the patients' need for mechanical ventilation and ICU management and their final clinical outcome. Results We enrolled 60 patients in the study. Most of themwere under 20 years of age, and 65% of them were male. Social laborers were the major population, and most of them had suicidal intention. Monocrotophos was the most commonly consumed OP compound. Most of the patients were brought to the hospital within two to sixhours of consumption. Vomiting and profuse secretions were the primary presenting symptoms. A majority of the patients (47) fell into the mild POP scale range. None of the patients had severe poisoning. Out of 60 patients, 49 patients improved and 11 patients died. Seven patients (15%) with mild POP scale scores and four patients (31%) with moderate scores died. Overall, 61.7% of patients with mild POP scale scores and 100% of patients with moderate scores needed mechanical ventilation. Conclusion The POP scale is an effective tool to measure severity and make a prognosisin patients with acute OP compound exposure. It may be asimple, inexpensive tool that may help predict the need for ventilatory support at admission. Early identification of danger signs may help in the reduction of mortality and morbidity when resources are limited. However, we found incorporating other clinical parameters and biochemical markers provides better prognostication than using the POP scale alone.

SIGNIFICANCE OF ACID BASE STATUS AT ADMISSION IN ACUTE ORGANOPHOSPHORUS POISONING AND ITS IMPACT ON OUTCOMEHOSPITAL BASED OBSERVATIONAL STUDY FROM NORTH EAST INDIA

BACKGROUND: Organophosphorus compounds (OPCs) are being used worldwide as an insecticide, herbicide, fungicide in agriculture field and household garden. Acute respiratory failure has been found to be the most common cause of death in OPC poisoning due to increased secretions and decreased ventilation leading to acid base disturbances. This study was undertaken to assess acid base status in patients with acute OPCs poisoning and to determine its association with the clinical outcome in patients with acute OPCs poisoning. MATERIALS AND METHODS This was a prospective observational study conducted in Dept of General Medicine, Silchar Medical College and Hospital from 1st June 2021 to 31st May 2022 for a period of one year. It was a hospital based observational study. A total of 100 patients were evaluated, with history of ingestion of OP compound and clinical features suggestive of acute OPCs poisoning after fulfillment of inclusion and exclusion criteria. RESULTS Total 100 patients were studied and majority were in the age group of 21-30 years. On Arterial Blood Gas Study,88% had acid base imbalance and 12% had normal acid base balance. Majority of the patient had respiratory alkalosis (49%), followed by respiratory acidosis (16%),metabolic acidosis (15%),metabolic alkalosis (8%).The overall mortality in our study was 19%.The mortality rate in metabolic acidosis group was 46.66%, respiratory acidosis group was 37.5%, metabolic alkalosis group was 12.5 % and respiratory alkalosis group was 10.2 %. CONCLUSION Acid -base imbalances are present in majority of the patients presenting with acute OPC poisoning. The assessment of the initial acid base status can help in determining the prognosis of the patients, help to intensify management and reduce the overall mortality in patients with acute OPC poisoning.

Serum creatine phosphokinase as a marker of severity and prognosis in organophosphorus compound poisoning

Background: Various newer biomarkers for organophosphorus (OP) compound poisoning are being looked at from diagnostic and prognostic perspectives. The present study was conducted to observe if serum creatine phosphokinase (CPK) can be used as a marker to assess the severity and monitor prognosis in patients of OP compound poisoning. Methods: In this hospital based prospective, observational study, 100 duly screened patients presenting with OP compound were classified as per severity grade according to POP scale. Serum cholinesterase and serum CPK levels were assessed twice, on day 1 and on day 4; apart from requirements as per standard management protocol; and the levels were compared across severity grades of OP compound poisoning. Outcomes such as intermediate syndrome and need of intubation and chances of mortality were studied for correlation. Results: There was statistically significant positive correlation between serum CPK level on day 1 as well as on day 4 with the severity of poisoning. The day 1 mean serum cholinesterase level also increased with the increase in severity of poisoning, but not the day 4 level. Significantly positive correlation was observed between serum CPK levels and development of intermediate syndrome, need of intubation and chances of mortality amongst cases. Conclusions: Serum CPK can be used as an efficient marker of severity in the patients of OP compound poisoning and will be useful to predict prognosis and outcome.

Profile of Organophosphorus Poisoning at Hitech Medical College and Hospital in Bhubaneswar, Odisha

Organophosphorus Compound Poisoning is one of the most common toxicological emergencies encountered particularly in rural agricultural patients presenting to the emergency department of Hitech Medical College and Hospital in Bhubaneswar, Odisha. Atotal 372 cases of organophosphorus compound poisoning were analyzed during the three-year period from January 2017 to December 2020. The basic demographic data such as age, sex, socioeconomic status, occupation along with specific data such as motive of poisoning, types of compound consumed with its quantity, distance from referral place and the final prognosis. The commonest patients were Young Male agricultural workers. Suicidal intent mainly due to financial crisis was seen to be the commonest among both males and females with Dichlorovos being the most used poison. Of all the cases there were three cases of respiratory failure resulting in multi organ failure.

Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes.

Chitosan-decorated liposomes were proposed for the first time for the intranasal delivery of acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) to the brain as a therapy for organophosphorus compounds (OPs) poisoning. Firstly, the chitosome composition based on phospholipids, cholesterol, chitosans (Cs) of different molecular weights, and its arginine derivative was developed and optimized. The use of the polymer modification led to an increase in the encapsulation efficiency toward rhodamine B (RhB; ~85%) and 2-PAM (~60%) by 20% compared to conventional liposomes. The formation of monodispersed and stable nanosized particles with a hydrodynamic diameter of up to 130 nm was shown using dynamic light scattering. The addition of the polymers recharged the liposome surface (from -15 mV to +20 mV), which demonstrates the successful deposition of Cs on the vesicles. In vitro spectrophotometric analysis showed a slow release of substrates (RhB and 2-PAM) from the nanocontainers, while the concentration and Cs type did not significantly affect the chitosome permeability. Flow cytometry and fluorescence microscopy qualitatively and quantitatively demonstrated the penetration of the developed chitosomes into normal Chang liver and M-HeLa cervical cancer cells. At the final stage, the ability of the formulated 2-PAM to reactivate brain AChE was assessed in a model of paraoxon-induced poisoning in an in vivo test. Intranasal administration of 2-PAM-containing chitosomes allows it to reach the degree of enzyme reactivation up to 35 ± 4%.

Case report on impending respiratory failure due to allerged organophosphorus compound poisoning (CHLORPYRIFOS)

In many parts of the world, particularly in impoverished nations, organophosphate compounds in few incidences operate as suicide agents, are frequently employed as pesticides which are strong inhibitors of the acetylcholinesterase enzyme. A 43year-old male, was admitted to an emergency department at 9:00am, with a two-hour history of nausea and elevated secretions of salivation via the mouth. He had no previous history of psychiatric or neurological disorders but with extreme causes of Respiratory Failure due to COVID-19. On three days before his admission, he quarrelled with his wife, became extremely depressed, and decided to commit suicide. He had a two-hour history of nausea and intermittent vomiting, diarrhoea and a one-hour history of persistent increased vomiting, increased salivation secretions through the mouth, chills, progressive sweating, difficulty breathing, and dizziness. Upon admission, his neurological examination in the emergency department revealed a Glasgow Coma Scale score of 9/15. On admission, he was placed on two litres per minute of intranasal oxygen via the nasal cannula. On the same day, Hewas treated by gastric lavage and administered atropine 0.15 mg intravenously, and the dose was doubled every 10 minutes until atropinisationwas achieved, and a bolus dose of 500ml of 0.9% of normal saline was initiated immediately.

Human HepaRG liver spheroids: cold storage protocol and study on pyridinium oxime-induced hepatotoxicity in vitro

Oximes play an essential role in the therapy of organophosphorus compound (OP) poisoning by reactivating inhibited acetylcholinesterase. Impairment of liver function was observed in OP poisoning and associated with obidoxime treatment by some reports. In this study human three-dimensional HepaRG spheroids were used as complex in vitro model to investigate oxime-induced liver toxicity. In this context, cold storage of liver spheroids at 4 °C in standard culture medium and in optimized tissue preservation solutions of up to 72 h was assessed. Cold storage in standard culture medium resulted in a complete loss of viability whereas an optimized tissue preservation solution preserved viability. Separately from that liver spheroids were exposed to the four oximes pralidoxime, obidoxime, HI-6, MMB-4 and cytotoxicity (effective concentration, EC50) was determined with an ATP-based assay at several time points. The release of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin secretion was measured in supernatants. The same parameters were assessed with diclofenac as positive hepatotoxic control and with the OP pesticides malathion and malaoxon alone or in the presence of obidoxime. All individual tested oximes and OP showed a low cytotoxicity with effective concentrations mostly >2,000 μM. In contrast, the exposure to malaoxon in the presence of 1,000 μM obidoxime resulted in a marked decrease of viability and an increased release of AST indicating risk of liver injury only if oxime antidotes are strongly overdosed.

Dual-Modal Nanoscavenger for Detoxification of Organophosphorus Compounds

Organophosphorus compounds (OPs) pose great military and civilian hazards. However, therapeutic and prophylactic antidotes against OP poisoning remain challenging. In this study, we first developed a novel nanoscavenger (rOPH/ZIF-8@E-Lipo) against methyl paraoxon (MP) poisoning using enzyme immobilization and erythrocyte-liposome hybrid membrane camouflage techniques. Then, we evaluated the physicochemical characterization, stability, and biocompatibility of the nanoscavengers. Afterward, we examined acetylcholinesterase (AChE) activity, cell viability, and intracellular reactive oxygen species (ROS) to indicate the protective effects of the nanoscavengers in vitro. Following the pharmacokinetic and biodistribution studies, we further evaluated the therapeutic and prophylactic detoxification efficacy of the nanoscavengers against MP in various poisoning settings. Finally, we explored the penetration capacity of the nanoscavengers across the blood-brain barrier (BBB). The present study validated the successful construction of a novel nanoscavenger with excellent stability and biocompatibility. In vitro, the resulting nanoscavenger exhibited a significant protection against MP-induced AChE inactivation, oxidative stress, and cytotoxicity. In vivo, apart from the positive therapeutic effects, the nanoscavengers also exerted significant prophylactic detoxification efficacy against single lethal MP exposure, repeated lethal MP challenges, and sublethal MP poisoning. These excellent detoxification effects of the nanoscavengers against OPs may originate from a dual-mode mechanism of inner recombinant organophosphorus hydrolase (rOPH) and outer erythrocyte membrane-anchored AChE. Finally, in vitro and in vivo studies jointly demonstrated that monosialoganglioside (GM1)-modified rOPH/ZIF-8@E-Lipo could penetrate the BBB with high efficiency. In conclusion, a stable and safe dual-modal nanoscavenger was developed with BBB penetration capability, providing a promising strategy for the treatment and prevention of OP poisoning.

Synthesis, Molecular Docking, BSA, and In Vitro Reactivation Study of Imidazopyridine Oximes Against Paraoxon Inhibited Acetylcholinesterase.

To synthesize and evaluate the fused heterocyclic imidazo[1,2-a]pyridine based oxime as a reactivator against paraoxon inhibited acetylcholinesterase. Organophosphorus compounds (OPs) include parathion, malathion, chlorpyrifos, monocrotophos, and diazinon, which are commonly used in agriculture for enhancing agricultural productivity via killing crop-damaging pests. However, people may get exposed to OPs pesticides unintentionally/intentionally via ingestion, inhalation, or dermal. The current treatment regimen includes reactivator such as mono or bis-pyridinium oximes along with anticholinergic and anticonvulsant drugs that are recommended for the treatment of OP poisoning. Unfortunately, the drawback of the existing reactivator is the permanent charge present on the pyridinium, making them inefficient to cross the blood-brain barrier (BBB) and reactivate OP-inhibited central nervous system (CNS) acetylcholinesterase. Therefore, there is a need of a reactivator that could cross the BBB and reactivate the OP inhibited acetylcholinesterase. The objectives of the study were synthesis, molecular docking, BSA binding, and in-vitro estimation of oximes of various substituted imidazo [1,2-a]pyridine against paraoxon inhibited acetylcholinesterase. The reactivators were synthesized in three steps and characterized using various spectroscopic techniques. The molecular docking study was performed on 2WHP and 3ZLV PDB using the Glide-XP software. The acid dissociation constant (pKa) of oximes was calculated experimentally, and the drug-likeness properties of the oximes were calculated in silico using Molinspiration and Swiss ADME software. The binding of oximes with bovine serum albumin (BSA) was also investigated using a Fluorescence spectrophotometer. The reactivation potential of the oximes was determined by in vitro enzymatic assay. The In-silico study inferred that the synthesized molecules fulfilled the parameters required for a successful CNS drug candidate. Furthermore, in-vitro enzymatic assay indicated reasonable reactivation potential of the oximes against paraoxon-inhibited AChE. The binding of oximes with bovine serum albumin (BSA) revealed that there was a static quenching of intrinsic fluorescence of BSA by the oxime. The binding constant value and number of binding sites were found to be 0.24 x 104 mol-1 and 1, respectively. The results of the study concluded that this scaffold could be used for further designing of more efficient uncharged reactivators.

Magnesium sulfate in organophosphorus compound poisoning: A prospective open-label clinician-initiated intervention trial with historical controls.

Background:The addition of magnesium sulfate (MgSO4) to standard treatment has improved mortality and morbidity associated with organophosphorus compound (OPC) poisoning. We aimed to assess the effectiveness of adjunctive intravenous MgSO4 (IV MgSO4) in poisoning from OPCs.Methods:Forty-seven cases and 72 controls were recruited to this prospective open-label clinician-initiated intervention trial after admitting OPC poisoning. All patients received standard treatment for anticholinesterase poisoning, and oximes were not used. Cases were divided into two groups. Group A (22 patients) received IV MgSO4 at 4 g/day in four divided doses (1 g every 6 h) on day 1. Group B (25 patients) received the same daily dose of IV MgSO4 throughout the hospital stay. Group C (72 patients) represents historical controls who did not receive IV MgSO4. The primary outcome was inhospital mortality. The secondary outcomes included the development of intermediate syndrome (IMS), the requirement of mechanical ventilation (MV), duration of MV, and length of hospital stay.Results:Baseline parameters in both groups were comparable. There is no statistically significant difference in mortality among three groups (Group A: 2/22, 9.1%; Group B: 5/25, 20% and Group C: 6/72, 8.3%). Results were similar for the development of IMS, the requirement of MV, length of MV, and duration of hospital stay.Conclusion:IV MgSO4 did not result in better outcomes compared with standard care alone in OPC poisoning.