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1.
Int J Mol Sci ; 25(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38891812

RESUMO

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals' resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood-brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.


Assuntos
Acetilcolinesterase , Modelos Animais de Doenças , Intoxicação por Organofosfatos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais , Camundongos , Humanos , Acetilcolinesterase/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Atropina/farmacologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Camundongos Knockout , Inibidores da Colinesterase , Acetilcolina/metabolismo
2.
Hum Exp Toxicol ; 43: 9603271241260655, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38861017

RESUMO

Organophosphorus (OP) poisoning is a significant cause of morbidity and mortality worldwide. Recent research has explored new approaches to improving treatment options, which present several challenges. This study aimed to evaluate the role of fresh frozen plasma (FFP) as an adjunctive therapy for acute OP intoxication. A prospective single-blinded randomized clinical trial was conducted on patients of both sexes admitted to the Intensive Care Unit (ICU) of the Poison Control Center at Ain Shams University Hospital (PCC-ASUH) with acute OP toxicity during the period from the beginning of August 2022 to the end of July 2023. According to the Peradeniya score, Group I consisted of 48 patients (52%) with moderate OP poisoning, and Group II consisted of 44 patients (48%) with severe OP poisoning. Patients in the moderate group were assigned to receive either standard treatment (Group Ia, n = 24) or standard treatment plus FFP (Group Ib, n = 24). In addition, patients in the severe group were assigned to receive either standard treatment (Group IIa, n = 22) or standard treatment plus FFP (Group IIb, n = 22). A total of 46 patients received FFP transfusion. The authors demonstrated that the early use of a total of nine packs of FFP (250 mL each) over three consecutive days significantly reduced the total doses of atropine and oximes, the total hospitalization period, and the requirement for mechanical ventilation in patients with OP poisoning, both in the moderate and severe groups.


Assuntos
Intoxicação por Organofosfatos , Plasma , Humanos , Feminino , Masculino , Intoxicação por Organofosfatos/terapia , Adulto , Pessoa de Meia-Idade , Método Simples-Cego , Estudos Prospectivos , Transfusão de Componentes Sanguíneos , Adulto Jovem , Antídotos/uso terapêutico
3.
J Pharm Biomed Anal ; 247: 116237, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38838441

RESUMO

Organophosphorus (OP) compounds are the most extensively used pesticides' class worldwide; cause most self­poisoning deaths especially in India. Thus, it is utmost important for early identification and aggressive management of OP poisoning from the clinical perspective to prevent serious complications by using sophisticated LC-MS/MS approach. This was a prospective study involving 103 patients of OP cases admitted to Karnataka Institute of Medical Sciences from June 2022 to May 2023, based on the inclusion and exclusion criteria patients were subjected to study. On admission, venous blood was collected from patient with Malathion and Profenofos OP poisoning history and subjected to serum biomarker and to LC-MS/MS analysis. Out of the 103 patients, 68 patients consumed Profenofos (66%) and 35 patients consumed Malathion (34%). Pseudocholinesterase levels among the of OP cases revealed that the 33 patients had mild toxicity, 40 patients had moderate toxicity and 30 patients had severe toxicity of OP poisoning. Subsequently LC-MS/MS analysis showed that the results obtained are not in correlation with indirect serum marker pseudocholinesterase levels. On the other side, LC-MS/MS results are in correlation with the clinical outcome of the patients with respect to morbidity and mortality. Thus, LC-MS/MS approach to assess the OP levels in patients could be used as potential diagnostic and prognostic marker for the absolute quantification of OP compounds compared to indirect OP levels estimation.


Assuntos
Biomarcadores , Intoxicação por Organofosfatos , Compostos Organofosforados , Espectrometria de Massas em Tandem , Humanos , Intoxicação por Organofosfatos/sangue , Intoxicação por Organofosfatos/tratamento farmacológico , Intoxicação por Organofosfatos/diagnóstico , Biomarcadores/sangue , Espectrometria de Massas em Tandem/métodos , Estudos Prospectivos , Masculino , Feminino , Adulto , Compostos Organofosforados/sangue , Pessoa de Meia-Idade , Cromatografia Líquida/métodos , Índice de Gravidade de Doença , Malation/sangue , Adulto Jovem , Índia , Praguicidas/intoxicação , Praguicidas/sangue , Idoso , Butirilcolinesterase/sangue , Adolescente
4.
BMJ Paediatr Open ; 8(1)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38754895

RESUMO

INTRODUCTION: Background: Childhood poisoning, characterised by exposure to toxic substances, poses a global health concern with variations across regions. Despite the importance of having current information about childhood acute poisoning in our region, there is a noticeable gap in such research in our local context. Regularly reviewing the agents responsible for poisoning in our locale is essential for devising prevention strategies and treatment approaches. This study aimed to examine the patterns and outcomes of childhood poisoning at the Children's Emergency Department of the Federal Medical Centre, Yenagoa, Bayelsa State, Nigeria. METHODS: A retrospective cross-sectional study was conducted, analysing cases of childhood poisoning in the Children's Emergency Ward, presenting from January 2013 to December 2022. Sociodemographic data, types of poisoning agents, home interventions, clinical features and outcomes were extracted from medical records. RESULTS: Of 9389 admissions, 81 (0.8%) cases were admitted for childhood poisoning, but only 69 cases were analysed (total n=69). Children aged under 5 years (52.2%) and who were males (59.4%) were mostly involved. Organophosphates (21.7%) and kerosene (20.3%) were common poisoning agents, often accidental (72.5%) and occurring at home (94.2%). Delayed hospital presentation (>2 hours) was common (68.1%). Vomiting (72.5%) and drooling saliva (56.5%) were prevalent symptoms. Hydration (60.9%) was the main hospital intervention, while antidotes were infrequently used (15.9%). Mortality was 8.7%, predominantly due to kerosene ingestion in young children. CONCLUSION: Organophosphate and kerosene poisoning are the most common in this facility. Enforcement challenges persist, emphasising the importance of safe storage practices and improved poison control measures. Addressing resource constraints for antidote availability and increasing awareness are vital for effective management and prevention.


Assuntos
Serviço Hospitalar de Emergência , Intoxicação , Humanos , Nigéria/epidemiologia , Estudos Retrospectivos , Feminino , Masculino , Pré-Escolar , Estudos Transversais , Intoxicação/epidemiologia , Intoxicação/terapia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Criança , Lactente , Querosene/intoxicação , Intoxicação por Organofosfatos
5.
Clin Toxicol (Phila) ; 62(4): 219-228, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38738692

RESUMO

INTRODUCTION: Intermediate syndrome is an important cause of respiratory failure following acute organophosphorus pesticide poisoning. The objective of this study was to examine the pathophysiology of this syndrome by analysis of sequential repetitive nerve stimulation studies in patients with acute organophosphorus pesticide poisoning. METHODS: Thirty-four consenting symptomatic patients with acute organophosphorus pesticide poisoning with intermediate syndrome (n = 10) or a milder forme fruste intermediate syndrome (n = 24) were assessed prospectively with daily physical examination and repetitive nerve stimulation done on the right and left median and ulnar nerves. The compound muscle action potential at 1, 3, 10, 15, 20 and 30 Hertz was measured with a train of ten stimuli. The amplitudes of the resulting stimuli were normalized to the first stimulus (100 per cent) and plotted against time. The decrease in the area under the curve of all the second stimulus compound muscle action potentials in the first 0.3 seconds was measured as a means of quantifying the refractory block. The decrease in the area under the curve under the 10, 15, 20 and 30 Hertz compound muscle action potentials relative to this pooled second stimulus compound muscle action potentials-area under the curve indicated the extent of additional rate-dependent block (decreasing compound muscle action potential-area under the curve over the first 0.3 seconds after the first stimulus with increasing Hertz). RESULTS: These new measurements strongly correlated with the severity of weakness. Refractory block was seen in most patients but was more severe in those with intermediate syndrome than those with forme fruste (partial) intermediate syndrome (median 55 per cent versus 16 per cent, P = 0.0001). Similar large differences were found for rate-dependent block (30 per cent versus 7 per cent, P = 0.001), which was uncommon in forme fruste intermediate syndrome but found in nine out of 10 patients with intermediate syndrome. Rate dependent block was generally only observed after 24 hours. The simplest strong predictor was total block at 30 Hertz repetitive nerve stimulation (89 per cent [interquartile range 73 to 94 per cent] versus 21 per cent [4 to 55 per cent]; P < 0.0001), which was very similar to total block calculated by summing other calculations. DISCUSSION: These findings likely represent depolarization and desensitization block from prolonged excessive cholinergic stimulation but it is not clear if these are from pre- or post-synaptic pathology. An animal model of intermediate syndrome with repetitive nerve stimulation studies might enable a better pathophysiological understanding of the two types of block. LIMITATIONS: The limited number of repetitive nerve stimulation studies performed were sufficient to demonstrate proof-of-concept, but further studies with more patients are needed to better define the correlates, clinical relevance and possible diagnostic/prognostic roles for the use of this technique. CONCLUSION: There are two easily distinguishable pathophysiological abnormalities in the neuromuscular block in intermediate syndrome. While they often coincide, both may be observed in isolation. The total and rate-dependent block at 30 Hertz are strongly associated with more severe weakness.


Assuntos
Potenciais de Ação , Estimulação Elétrica , Junção Neuromuscular , Intoxicação por Organofosfatos , Humanos , Intoxicação por Organofosfatos/fisiopatologia , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Potenciais de Ação/efeitos dos fármacos , Junção Neuromuscular/fisiopatologia , Junção Neuromuscular/efeitos dos fármacos , Estudos Prospectivos , Adulto Jovem , Nervo Mediano/fisiopatologia , Nervo Ulnar/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/etiologia , Idoso
6.
Toxicol Lett ; 397: 42-47, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38723915

RESUMO

Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2'-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR.


Assuntos
Diafragma , Agentes Neurotóxicos , Compostos de Piridínio , Animais , Diafragma/efeitos dos fármacos , Diafragma/inervação , Agentes Neurotóxicos/toxicidade , Masculino , Compostos de Piridínio/farmacologia , Compostos de Piridínio/química , Transmissão Sináptica/efeitos dos fármacos , Relação Estrutura-Atividade , Junção Neuromuscular/efeitos dos fármacos , Ratos , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Ratos Wistar , Intoxicação por Organofosfatos/tratamento farmacológico , Oximas/farmacologia , Oximas/química , Ratos Sprague-Dawley , Estrutura Molecular
7.
Toxicol Lett ; 397: 151-162, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38759939

RESUMO

Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising MB327 analogs with a 4-aminopyridinium ion partial structure (PTM0056, PTM0062, and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new analogs of the aforementioned compounds with a 4-aminopyridinium ion partial structure (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90-0012 and PTMD90-0015) designed to substitute entropically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research.


Assuntos
Receptores Nicotínicos , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Animais , Masculino , Agentes Neurotóxicos/toxicidade , Ratos Wistar , Ratos , Intoxicação por Organofosfatos/tratamento farmacológico , Diafragma/efeitos dos fármacos , Diafragma/metabolismo , Relação Estrutura-Atividade , Compostos de Piridínio/farmacologia , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Contração Muscular/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Sítios de Ligação
8.
Chem Res Toxicol ; 37(4): 643-657, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38556765

RESUMO

Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro, achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 µM, a 4-fold increase from our 2018 report. The best QMP (1b), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.


Assuntos
Reativadores da Colinesterase , Indolquinonas , Intoxicação por Organofosfatos , Soman , Humanos , Idoso , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Compostos Organofosforados/farmacologia , Compostos Organofosforados/metabolismo , Serina , Oximas , Reativadores da Colinesterase/química
9.
Mymensingh Med J ; 33(2): 509-515, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38557534

RESUMO

Organophosphorus compound (OPC) poisoning is common in Bangladesh. The toxicity of the agent and paucity of appropriate medical services has resulted in high mortality rates. To find out the clinical profile and outcome of OPC poisoning patients is the main aim of my study. This descriptive cross-sectional study was conducted in the Department of Medicine, Mymensingh Medical College Hospital, Bangladesh from September 2016 to November 2018. In this study, mean age of the study subjects was 25.90±11.24 years. Males (70.8%) were predominant than female (29.2%). In this study, most of the poisoning was done by ingestion (98.3%) and only two (1.7%) by inhalation. Regarding features, most muscarinic effect was constricted pupil and bronchospasm (65.0%). Common nicotinic effect was fasciculation (25.0%) and central effect was headache (61.67%). Mean amount of OPC ingestion was 26.30±17.24 ml in this study. Regarding circumstances of poisoning, familial disharmony (38.3%) and quarrel with other family members (37.5%) were the major reason followed by failure of personal affairs (15.0%) and other reasons (9.2%). Regarding complications, aspiration pneumonia was found in 6.7% cases, cardiac arrhythmia was in 6.7% cases and intermediate syndrome was in 1.7% cases. Most of the study subjects (95.0%) recovered fully. Most of the patients were from rural area. Suicidal was the common motive and familial disharmony and quarrel with other family members are the common circumstances of poisoning. Mortality rate was 5.0%.


Assuntos
Intoxicação por Organofosfatos , Intoxicação , Masculino , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Intoxicação por Organofosfatos/epidemiologia , Intoxicação por Organofosfatos/terapia , Centros de Atenção Terciária , Estudos Transversais , Compostos Organofosforados , Bangladesh/epidemiologia , Intoxicação/epidemiologia , Intoxicação/terapia , Intoxicação/complicações
10.
J Infect Dev Ctries ; 18(2): 277-284, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38484356

RESUMO

INTRODUCTION: The aim of this study was to determine the clinical predictors of staphylococcal ventilator-associated pneumonia (VAP) and to compare the outcomes of staphylococcal VAP with non-staphylococcal VAP. METHODOLOGY: A retrospective observational study was conducted among adult patients admitted to the medical intensive care unit (MICU) in a tertiary care hospital in India from January 2017 to December 2019. The patients were grouped based on their diagnosis into staphylococcal and non-staphylococcal VAP, and the baseline characteristics, clinical parameters, co-morbidities, and outcome parameters were compared. RESULTS: Out of 2129 MICU admissions, 456 patients with microbiologically confirmed VAP were included, of which 69 (15.1%) had staphylococcal VAP, and the remaining 387 (84.9%) had non-staphylococcal VAP. Organophosphorus (OP) poisoning was identified as an independent predictor of staphylococcal VAP (odds ratio: 2.57; 95% CI: 1.4 to 4.73). The median duration of mechanical ventilation before VAP diagnosis was less in the staphylococcal VAP group (4 vs. 5 days; p = 0.004). The staphylococcal group also showed a better in-hospital outcome. CONCLUSIONS: OP poisoning was an independent predictor of staphylococcal VAP. Staphylococcal VAP was diagnosed earlier in patients than non-staphylococcal VAP. Screening for nasal carriage for Staphylococcus, especially in patients with OP poisoning at the time of MICU admission, may help guide antibiotic therapy.


Assuntos
Intoxicação por Organofosfatos , Pneumonia Associada à Ventilação Mecânica , Adulto , Humanos , Pneumonia Associada à Ventilação Mecânica/microbiologia , Estudos Retrospectivos , Respiração Artificial , Staphylococcus , Unidades de Terapia Intensiva
11.
Neuropharmacology ; 249: 109895, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38437913

RESUMO

Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.


Assuntos
Lesões Encefálicas , Intoxicação por Organofosfatos , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Isoflurofato/toxicidade , Organofosfatos , Inibidores da Colinesterase/farmacologia , Intoxicação por Organofosfatos/tratamento farmacológico , Intoxicação por Organofosfatos/patologia , Lesões Encefálicas/induzido quimicamente , Encéfalo , Midazolam/farmacologia
12.
Arh Hig Rada Toksikol ; 75(1): 81-84, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38548379

RESUMO

Organophosphorus poisoning is a critical condition that can cause central nervous system depression, respiratory failure, and death early on. As its clinical manifestations closely resemble those of carbamate pesticide poisoning, the aim of this case study is to present a case of misdiagnosis, initially identifying carbofuran poisoning as organophosphate in a patient suspect of a heatstroke. We also present a case of intentional self-poisoning with organophosphate dichlorvos to underline the likelihood of pesticide poisoning in patients exhibiting acute cholinergic symptoms when the ingested substance is not known. In such cases, empirical treatment with atropine and oxime can be started pending timely differential diagnosis to adjust treatment as necessary.


Assuntos
Inseticidas , Intoxicação por Organofosfatos , Praguicidas , Intoxicação , Humanos , Carbamatos/uso terapêutico , Intoxicação por Organofosfatos/diagnóstico , Intoxicação por Organofosfatos/tratamento farmacológico , Diclorvós/uso terapêutico , Intoxicação/terapia
13.
Chem Biol Interact ; 394: 110941, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38493910

RESUMO

The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.


Assuntos
Butirilcolinesterase , Reativadores da Colinesterase , Intoxicação por Organofosfatos , Oximas , Oximas/química , Oximas/farmacologia , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Humanos , Intoxicação por Organofosfatos/tratamento farmacológico , Acetilcolinesterase/metabolismo , Antídotos/química , Antídotos/farmacologia , Cinética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Animais , Compostos Organofosforados/química
14.
Toxicology ; 503: 153741, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38311098

RESUMO

Organophosphate (OP) poisoning is currently treated with atropine, oximes and benzodiazepines. The nicotinic signs, i.e., respiratory impairment, can only be targeted indirectly via the use of oximes as reactivators of OP-inhibited acetylcholinesterase. Hence, compounds selectively targeting nicotinic acetylcholine receptors (nAChRs) might fundamentally improve current treatment options. The bispyridinium compound MB327 has previously shown some therapeutic effect against nerve agents in vitro and in vivo. Nevertheless, compound optimization was deemed necessary, due to limitations (e.g., toxicity and efficacy). The current study investigated a series of 4-tert-butyl bispyridinium compounds and of corresponding bispyridinium compounds without substituents in a rat diaphragm model using an indirect field stimulation technique. The length of the respective linker influenced the ability of the bispyridinium compounds to restore muscle function in rat hemidiaphragms. The current data show structure-activity relationships for a series of bispyridinium compounds and provide insight for future structure-based molecular modeling.


Assuntos
Reativadores da Colinesterase , Agentes Neurotóxicos , Intoxicação por Organofosfatos , Ratos , Animais , Oximas/farmacologia , Oximas/uso terapêutico , Agentes Neurotóxicos/toxicidade , Diafragma , Acetilcolinesterase/metabolismo , Compostos de Piridínio/farmacologia , Compostos de Piridínio/uso terapêutico , Relação Estrutura-Atividade , Intoxicação por Organofosfatos/tratamento farmacológico , Reativadores da Colinesterase/farmacologia , Inibidores da Colinesterase/farmacologia
15.
Disaster Med Public Health Prep ; 18: e32, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38384185

RESUMO

Pralidoxime is the only oxime antidote to organophosphate poisoning stocked in the United Kingdom, produced by rational drug design in the 1950s. Typically, it is used alongside atropine, to reverse the effects of acetylcholinesterase inhibition. However, its efficacy has been questioned by recent meta-analyses of use treating attempted suicides in less economically developed countries, where organophosphate poisoning is more common. This policy analysis assesses the likely efficacy of pralidoxime in the United Kingdom, in scenarios largely different from those evaluated in meta-analyses. In all scenarios, the UK delay in antidote administration poses a major problem, as pralidoxime acts in a time-critical reactivation mechanism before "ageing" of acetylcholinesterase occurs. Additionally, changes in the organophosphates used today versus those pralidoxime was rationally designed to reverse, have reduced efficacy since the 1950s. Finally, the current dosage regimen may be insufficient. Therefore, one must re-evaluate our preparedness and approach to organophosphate poisoning in the United Kingdom.


Assuntos
Reativadores da Colinesterase , Intoxicação por Organofosfatos , Compostos de Pralidoxima , Humanos , Antídotos/uso terapêutico , Intoxicação por Organofosfatos/tratamento farmacológico , Acetilcolinesterase/uso terapêutico , Reativadores da Colinesterase/uso terapêutico , Reativadores da Colinesterase/farmacologia
16.
BMJ Case Rep ; 17(2)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383128

RESUMO

Organophosphate poisoning is a common, under-reported cause of attempted and completed suicide worldwide. Following the resolution of the acute cholinergic syndrome, patients may develop respiratory muscle and proximal limb weakness, known as intermediate syndrome. A young man was brought to our rural hospital unconscious, in extremis, due to organophosphate pesticide poisoning. He developed atypical intermediate syndrome with global paralysis, persistent fasciculations and prolonged cholinergic symptoms, differing from the recognised presentation. He was intubated for fifteen days in our newly developed intensive care unit. Limited treatment options and the absence of blood gases, electrolyte testing, ECGs, invasive monitoring and imaging, in conjunction with regular disruptions to electricity and oxygen, and complications including seizures and pneumonia, all made this prolonged intubation an ambitious and challenging endeavour. We offer learning points for the acute physician and rural intensivist, and a summary of our reflections and hints for best care when adapting to a resource-limited setting.


Assuntos
Inseticidas , Intoxicação por Organofosfatos , Masculino , Humanos , Intoxicação por Organofosfatos/terapia , Zâmbia , Unidades de Terapia Intensiva , Colinérgicos
17.
Arch Toxicol ; 98(4): 1177-1189, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38305864

RESUMO

Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.


Assuntos
Midazolam , Intoxicação por Organofosfatos , Humanos , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Midazolam/farmacologia , Midazolam/uso terapêutico , Pregnanolona/farmacologia , Isoflurofato/farmacologia , Organofosfatos , Encéfalo , Intoxicação por Organofosfatos/tratamento farmacológico
18.
Toxicol Lett ; 394: 23-31, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387764

RESUMO

Intoxications with organophosphorus compounds (OPCs) effect a severe impairment of cholinergic neurotransmission that, as a result of overstimulation may lead to desensitization of nicotinic acetylcholine receptors (nAChRs) and finally to death due to respiratory paralysis. So far, therapeutics, that are capable to address and revert desensitized neuromuscular nAChRs into their resting, i.e. functional state are still missing. Still, among a class of compounds termed bispyridinium salts, which are characterized by the presence of two pyridinium subunits, constituents have been identified, that can counteract organophosphate poisoning by resensitizing desensitized nAChRs. According to comprehensive modeling studies this effect is mediated by an allosteric binding site at the nAChR termed MB327-PAM-1 site. For MB327, the most prominent representative of the bispyridinium salts and all other analogues studied so far, the affinity for the aforementioned binding site and the intrinsic activity measured in ex vivo and in in vivo experiments are distinctly too low, to meet the criteria to be fulfilled for therapeutic use. Hence, in order to identify new compounds with higher affinities for the MB327-PAM-1 binding site, as a basic requirement for an enhanced potency, two compound libraries, the ChemDiv library with 60 constituents and the Tocriscreen Plus library with 1280 members have been screened for hit compounds addressing the MB327-PAM-1 binding site, utilizing the [2H6]MB327 MS Binding Assay recently developed by us. This led to the identification of a set of 10 chemically diverse compounds, all of which exhibit an IC50 value of ≤ 10 µM (in the [2H6]MB327 MS Binding Assay), which had been defined as selection criteria. The three most affine ligands, which besides a quinazoline scaffold share similarities with regard to the substitution pattern and the nature of the substituents, are UNC0638, UNC0642 and UNC0646. With binding affinities expressed as pKi values of 6.01 ± 0.10, 5.97 ± 0.05 and 6.23 ± 0.02, respectively, these compounds exceed the binding affinity of MB327 by more than one log unit. This renders them promising starting points for the development of drugs for the treatment of organophosphorus poisoning by addressing the MB327-PAM-1 binding site of the nAChR.


Assuntos
Intoxicação por Organofosfatos , Compostos de Piridínio , Receptores Nicotínicos , Humanos , Receptores Nicotínicos/metabolismo , Sais/metabolismo , Sais/uso terapêutico , Relação Estrutura-Atividade , Sítios de Ligação , Intoxicação por Organofosfatos/tratamento farmacológico , Ligantes
19.
J Pharmacol Exp Ther ; 388(2): 386-398, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38050069

RESUMO

Nerve agents and organophosphates (OP) are neurotoxic chemicals that induce acute seizures, status epilepticus (SE), and mortality. Long-term neurologic and neurodegenerative effects manifest months to years after OP exposure. Current benzodiazepine anticonvulsants are ineffective in preventing such long-term neurobehavioral and neuropathological changes. New and effective anticonvulsants are needed for OP intoxication, especially for mitigating the long-term sequelae after acute exposure. We developed neurosteroids as novel anticonvulsants and neuroprotectants in OP exposure models. In this study, we evaluated the long-term efficacy of novel synthetic neurosteroids in preventing the development of chronic epilepsy and hyperexcitable ictal events in a rat OP model of SE. Rats were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP), and the experimental groups were treated with the synthetic neurosteroid valaxanolone (VX) or lysaxanolone (LX) 40 minutes post-exposure in conjunction with midazolam. Video-electroencephalography was monitored for two months to assess spontaneous recurrent seizures (SRS), epileptiform discharges, interictal spikes, and high-frequency oscillations (HFOs). Within 60 days of DFP exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. LX treatment was associated with a dose-dependent reduction of epilepsy occurrence and overall seizure burden with a significant decrease in SRS and epileptiform discharges. It also significantly reduced the occurrence of epileptic biomarkers of HFOs and interictal spikes, indicating potential disease-modifying activity. Similarly, the neurosteroid analog VX also significantly attenuated SRS, discharges, HFOs, and ictal events. These results demonstrate the long-term protective effects of synthetic neurosteroids in the OP-exposed post-SE model, indicating their disease-modifying potential to prevent epilepsy and ictal abnormalities. SIGNIFICANCE STATEMENT: The effects of nerve agents and organophosphate (OP) exposure are persistent, and survivors suffer from a number of devastating, chronic neurological dysfunctions. Currently, there is no specific therapy for preventing this disastrous impact of OP exposure. We propose synthetic neurosteroids that activate tonic inhibition provide viable options for preventing the long-term neurological effects of OP intoxication. The results from this study reveal the disease-modifying potential of two novel synthetic neurosteroids in preventing epileptogenesis and chronic epileptic seizures after OP-induced SE.


Assuntos
Epilepsia , Agentes Neurotóxicos , Neuroesteroides , Intoxicação por Organofosfatos , Compostos Organotiofosforados , Estado Epiléptico , Ratos , Animais , Neuroesteroides/uso terapêutico , Anticonvulsivantes/efeitos adversos , Organofosfatos/efeitos adversos , Agentes Neurotóxicos/efeitos adversos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Epilepsia/tratamento farmacológico , Eletroencefalografia , Biomarcadores
20.
J Pharmacol Exp Ther ; 388(2): 399-415, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38071567

RESUMO

Organophosphates (OPs) and nerve agents are potent neurotoxic compounds that cause seizures, status epilepticus (SE), brain injury, or death. There are persistent long-term neurologic and neurodegenerative effects that manifest months to years after the initial exposure. Current antidotes are ineffective in preventing these long-term neurobehavioral and neuropathological changes. Additionally, there are few effective neuroprotectants for mitigating the long-term effects of acute OP intoxication. We have pioneered neurosteroids as novel anticonvulsants and neuroprotectants for OP intoxication and seizures. In this study, we evaluated the efficacy of two novel synthetic, water-soluble neurosteroids, valaxanolone (VX) and lysaxanolone (LX), in combating the long-term behavioral and neuropathological impairments caused by acute OP intoxication and SE. Animals were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP) and were treated with VX or LX in addition to midazolam at 40 minutes postexposure. The extent of neurodegeneration, along with various behavioral and memory deficits, were assessed at 3 months postexposure. VX significantly reduced deficits of aggressive behavior, anxiety, memory, and depressive-like traits in control (DFP-exposed, midazolam-treated) animals; VX also significantly prevented the DFP-induced chronic loss of NeuN(+) principal neurons and PV(+) inhibitory neurons in the hippocampus and other regions. Additionally, VX-treated animals exhibited a reduced inflammatory response with decreased GFAP(+) astrogliosis and IBA1(+) microgliosis in the hippocampus, amygdala, and other regions. Similarly, LX showed significant improvement in behavioral and memory deficits, and reduced neurodegeneration and cellular neuroinflammation. Together, these results demonstrate the neuroprotectant effects of the novel synthetic neurosteroids in mitigating the long-term neurologic dysfunction and neurodegeneration associated with OP exposure. SIGNIFICANCE STATEMENT: Survivors of nerve agents and organophosphate (OP) exposures suffer from long-term neurological deficits. Currently, there is no specific drug therapy for mitigating the impact of OP exposure. However, novel synthetic neurosteroids that activate tonic inhibition provide a viable option for treating OP intoxication. The data from this study indicates the neuroprotective effects of synthetic, water-soluble neurosteroids for attenuation of long-term neurological deficits after OP intoxication. These findings establish valaxanolone and lysaxanolone as potent and efficacious neuroprotectants suitable for injectable dosing.


Assuntos
Agentes Neurotóxicos , Fármacos Neuroprotetores , Neuroesteroides , Intoxicação por Organofosfatos , Compostos Organotiofosforados , Estado Epiléptico , Ratos , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Neuroesteroides/uso terapêutico , Isoflurofato/farmacologia , Midazolam/farmacologia , Doenças Neuroinflamatórias , Encéfalo , Agentes Neurotóxicos/farmacologia , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Convulsões/tratamento farmacológico , Intoxicação por Organofosfatos/tratamento farmacológico , Organofosfatos/farmacologia , Transtornos da Memória/patologia
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