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1.
Toxicol Appl Pharmacol ; 484: 116870, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38395364

RESUMO

The development of refractory status epilepticus (SE) following sarin intoxication presents a therapeutic challenge. Here, we evaluated the efficacy of delayed combined double or triple treatment in reducing abnormal epileptiform seizure activity (ESA) and the ensuing long-term neuronal insult. SE was induced in rats by exposure to 1.2 LD50 sarin followed by treatment with atropine and TMB4 (TA) 1 min later. Double treatment with ketamine and midazolam or triple treatment with ketamine, midazolam and levetiracetam was administered 30 min post-exposure, and the results were compared to those of single treatment with midazolam alone or triple treatment with ketamine, midazolam, and valproate, which was previously shown to ameliorate this neurological insult. Toxicity and electrocorticogram activity were monitored during the first week, and behavioral evaluations were performed 2 weeks post-exposure, followed by biochemical and immunohistopathological analyses. Both double and triple treatment reduced mortality and enhanced weight recovery compared to TA-only treatment. Triple treatment and, to a lesser extent, double treatment significantly ameliorated the ESA duration. Compared to the TA-only or the TA+ midazolam treatment, both double and triple treatment reduced the sarin-induced increase in the neuroinflammatory marker PGE2 and the brain damage marker TSPO and decreased gliosis, astrocytosis and neuronal damage. Finally, both double and triple treatment prevented a change in behavior, as measured in the open field test. No significant difference was observed between the efficacies of the two triple treatments, and both triple combinations completely prevented brain injury (no differences from the naïve rats). Delayed double and, to a greater extent, triple treatment may serve as an efficacious delayed therapy, preventing brain insult propagation following sarin-induced refractory SE.


Assuntos
Lesões Encefálicas , Ketamina , Agentes Neurotóxicos , Estado Epiléptico , Ratos , Animais , Sarina/toxicidade , Agentes Neurotóxicos/toxicidade , Midazolam/farmacologia , Midazolam/uso terapêutico , Ratos Sprague-Dawley , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Colinérgicos/efeitos adversos , Lesões Encefálicas/induzido quimicamente
2.
Exp Eye Res ; 223: 109195, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35917998

RESUMO

Ocular injuries following sulfur mustard (SM) exposure are characterized by an acute phase expressed by corneal erosions and inflammation of the anterior segment that after a clinically silent period may be followed by irreversible corneal injuries. The latter includes epithelial defects, chronic inflammation and neovascularization (NV), and were defined in rabbits and in humans as Limbal Stem Cell Deficiency (LSCD), that derived from a delayed loss of corneal epithelial stem cells (ESC), due to secondary processes most likely in the epithelial stem cell (SC) niche. The present study expands our research on SM-induced ocular injury to rodents (rats and mice) following whole body vapor exposure, aiming to define whether the delayed development of LSCD is a general characteristic of SM ocular toxicity. Freely moving rats and mice were exposed to SM vapor (155 µg/l, 10 min). Clinical examination was carried out in rats and included a slit-lamp bio-microscopy, up to 6 months. Eyes were taken for histology at different time points following exposure and evaluation included hematoxylin and eosin (H&E) staining for general morphology, PAS for identification of goblet cells and p63 immunohistochemistry for progenitor epithelial cells. Whole body exposure to SM vapor in rats and mice resulted in acute ocular injury characterized by corneal erosions and ocular inflammation. Following a brief recovery period, 80-90% of the exposed eyes developed corneal NV associated with abnormal corneal epithelium, stromal inflammation and endothelial damage. The late injury was accompanied by migration of conjunctival goblet cells to the cornea and a loss of limbal epithelial progenitor cells, indicating LSCD. The long-term ocular injury shown hereby in rats and mice was consistent with the lesions described in rabbits and in human casualties and demonstrated the general phenomenon of limbal epithelial stem cells deficiency in SM ocular toxicity. The delayed manifestation of this pathology points towards a therapeutic window for the development of medical countermeasures in small animals following exposure in a real life scenario.


Assuntos
Doenças da Córnea , Lesões da Córnea , Epitélio Corneano , Limbo da Córnea , Gás de Mostarda , Animais , Doenças da Córnea/induzido quimicamente , Doenças da Córnea/patologia , Lesões da Córnea/induzido quimicamente , Lesões da Córnea/patologia , Modelos Animais de Doenças , Amarelo de Eosina-(YS)/efeitos adversos , Epitélio Corneano/patologia , Hematoxilina , Humanos , Inflamação/patologia , Limbo da Córnea/patologia , Camundongos , Gás de Mostarda/toxicidade , Coelhos , Ratos , Células-Tronco/patologia , Neuropatia Óptica Tóxica
3.
Toxicol Appl Pharmacol ; 419: 115519, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33823148

RESUMO

The development of refractory status epilepticus (SE) induced by sarin intoxication presents a therapeutic challenge. In our current research we evaluate the efficacy of a delayed combined triple treatment in ending the abnormal epileptiform seizure activity (ESA) and the ensuing of long-term neuronal insult. SE was induced in male Sprague-Dawley rats by exposure to 1.2LD50 sarin insufficiently treated by atropine and TMB4 (TA) 1 min later. Triple treatment of ketamine, midazolam and valproic acid was administered 30 min or 1 h post exposure and was compared to a delayed single treatment with midazolam alone. Toxicity and electrocorticogram activity were monitored during the first week and behavioral evaluation performed 3 weeks post exposure followed by brain biochemical and immunohistopathological analyses. The addition of both single and triple treatments reduced mortality and enhanced weight recovery compared to the TA-only treated group. The triple treatment also significantly minimized the duration of the ESA, reduced the sarin-induced increase in the neuroinflammatory marker PGE2, the brain damage marker TSPO, decreased the gliosis, astrocytosis and neuronal damage compared to the TA+ midazolam or only TA treated groups. Finally, the triple treatment eliminated the sarin exposed increased open field activity, as well as impairing recognition memory as seen in the other experimental groups. The delayed triple treatment may serve as an efficient therapy, which prevents brain insult propagation following sarin-induced refractory SE, even if treatment is postponed for up to 1 h.


Assuntos
Anticonvulsivantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Ketamina/administração & dosagem , Midazolam/administração & dosagem , Sarina , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Proteínas de Transporte/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Injeções Intramusculares , Injeções Intraperitoneais , Masculino , Teste de Campo Aberto/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia , Estado Epiléptico/fisiopatologia , Fatores de Tempo
4.
Arch Toxicol ; 95(7): 2403-2412, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34032868

RESUMO

Long-term retrospective monitoring of exposure to organophosphorus nerve agents is challenging. We recently developed two highly sensitive analytical methods for regenerated sarin (GB) nerve agent in blood and its primary metabolite, isopropyl-methylphosphonic acid (IMPA), in urine. These methods were implemented in a toxicokinetics study carried out with sarin injected (i.v.) to rabbits at doses corresponding to 0.1, 0.5 or 0.9 LD50. The time frame for monitoring regenerated sarin from blood was 70 days for 0.1 LD50 and 0.5 LD50 and 77 days for 0.9 LD50, where rapid elimination occurred in the first 8 days with an initial average half-life of 1.2 days, followed by a second, slower elimination, with a terminal average half-life of 8.4 days. The time frame for monitoring IMPA in urine was 7, 15 and 16 days for 0.1 LD50, 0.5 LD50 and 0.9 LD50 intoxications, respectively. Rapid elimination of IMPA in urine occurred after exposure, with an average half-life of ~ 0.8 days on days 2-6. For the first time, a slower elimination route for IMPA, with an average half-life of ~ 4 days from day 6 onwards, was revealed. Both IMPA and regenerated sarin pharmacokinetics exhibit linearity with dose. The overlaid pharmacokinetic profiles of regenerated sarin in blood along with IMPA in urine emphasize the dominance of IMPA with a rapid decay in urine in the first week and the slower long-term decay of protein-bound sarin later in blood. To our knowledge, the two new sensitive methods exhibit the longest monitoring time frame reported in biological samples.


Assuntos
Substâncias para a Guerra Química , Sarina , Animais , Substâncias para a Guerra Química/metabolismo , Compostos Organofosforados/metabolismo , Coelhos , Estudos Retrospectivos
5.
Toxicol Appl Pharmacol ; 395: 114963, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32209366

RESUMO

BACKGROUND: Sarin is an irreversible organophosphate cholinesterase inhibitor. Following toxic signs, an extensive long-term brain damage is often reported. Thus, we evaluated the efficacy of a novel anticonvulsant drug retigabine, a modulator of neuronal voltage gated K+ channels, as a neuroprotective agent following sarin exposure. METHODS: Rats were exposed to 1 LD50 or 1.2 LD50 sarin and treated at onset of convulsions with retigabine (5 mg/kg, i.p.) alone or in combination with 5 mg/kg atropine and 7.5 mg/kg TMB-4 (TA) respectively. Brain biochemical and immunohistopathological analyses were processed 24 h and 1 week following 1 LD50 sarin exposure and at 4 weeks following exposure to 1.2 LD50 sarin. EEG activity in freely moving rats was also monitored by telemetry during the first week following exposure to 1.2 LD50 and behavior in the Open Field was evaluated 3 weeks post exposure. RESULTS: Treatment with retigabine following 1 LD50 sarin exposure or in combination with TA following 1.2 LD50 exposure significantly reduced mortality rate compared to the non-treated groups. In both experiments, the retigabine treatment significantly reduced gliosis, astrocytosis and brain damage as measured by translocator protein (TSPO). Following sarin exposure the combined treatment (retigabine+ TA) significantly minimized epileptiform seizure activity. Finally, in the Open Field behavioral test the non-treated sarin group showed an increased mobility which was reversed by the combined treatment. CONCLUSIONS: The M current modulator retigabine has been shown to be an effective adjunct therapy following OP induced convulsion, minimizing epileptiform seizure activity and attenuating the ensuing brain damage.


Assuntos
Anticonvulsivantes/administração & dosagem , Encefalopatias/induzido quimicamente , Encefalopatias/prevenção & controle , Carbamatos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fenilenodiaminas/administração & dosagem , Sarina/toxicidade , Animais , Atropina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encefalopatias/patologia , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Masculino , Neuroglia/patologia , Neurônios/patologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Trimedoxima/administração & dosagem
6.
Arch Toxicol ; 94(1): 103-111, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31720697

RESUMO

The highly toxic nerve agent sarin (o-isopropyl methyl-phosphonofluoridate, GB) has been used in several armed conflicts and terror attacks in recent decades. Due to its inherent high sensitivity, liquid chromatography-mass spectrometry (LC-MS/MS) has the potential to detect ultratrace levels of fluoride-regenerated G and V agents after appropriate chemical derivatization. A new method for the retrospective determination of exposure to sarin was developed. The method is based on sarin regeneration from blood using the fluoride-induced technique followed by derivatization with 2-[(dimethylamino)methyl]phenol (2-DMAMP) and LC-ESI-MS/MS (MRM) analysis. The validated method presents good linear response in the concentration range of 5-1000 pg/mL with a limit of quantitation (LOQ) of 5 pg/mL, 13.8% accuracy, 16.7% precision and a total recovery of 62% ± 9%. This new analytical approach has several advantages over existing GC/GC-MS-based methods in terms of sensitivity, specificity and simplicity, in addition to a short LC-MS cycle time of 12 min. The method was successfully applied in an in vivo experiment for retrospective determination of sarin in a rabbit exposed to 0.1 LD50 sarin (1.5 µg/kg, i.v.). GB-2-DMAMP was easily determined in samples drawn up to 11 days after exposure. The high S/N ratio (500) observed for the GB-2-DMAMP signal in the 11day sample poses the potential for an extended time frame of months for analysis with this new method for the retrospective detection of sarin exposure. To the best of our knowledge, this is the first report on LC-MS/MS trace analysis of regenerated GB from biological matrices.


Assuntos
Cromatografia Líquida/métodos , Agentes Neurotóxicos/análise , Sarina/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Feminino , Fluoretos/química , Meia-Vida , Humanos , Limite de Detecção , Agentes Neurotóxicos/química , Agentes Neurotóxicos/farmacocinética , Coelhos , Sarina/química , Sarina/farmacocinética , Sensibilidade e Especificidade , Solventes/química
7.
Exp Eye Res ; 184: 201-212, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31022400

RESUMO

Exposure to sulfur mustard (SM) may result in severe ocular injuries. While some of the eyes show a clinical resolution of the injury (defined as clinically non-impaired), part of the eyes develop irreversible late ocular pathologies (defined as clinically impaired) that may lead to corneal blindness. Understanding the pathological mechanisms underlying the development of the late pathology may lead to improved treatment options. Therefore, this study aimed to investigate the mRNA expression profiles of corneas from clinically impaired, clinically non-impaired and naïve eyes. Rabbit eyes were exposed to SM vapor and a clinical follow-up was carried out up to 4 weeks using a slit lamp microscope. At this time point, corneal tissues from clinically impaired, clinically non-impaired and naïve eyes were processed for RNA sequencing (RNA-seq) and differential expression analyses. The differential expression profiles were further subjected to pathway enrichment analysis using Ingenuity Pathway Analysis (IPA). Real-time PCR was used for RNA-seq validation. The late pathology developed in 54%-80% of the eyes following ocular exposure to SM, clinically manifested by inflammation, corneal opacity and neovascularization. RNA-seq results showed significant differences in mRNA levels of hundreds of genes between clinically impaired, clinically non-impaired and naïve corneas. Pathway enrichment analysis showed common pathways that were activated in all of the exposed eyes, such as Th1 and Th2 activation pathway, in addition to pathways that were activated only in the clinically impaired eyes compared to the clinically non-impaired eyes, such as IL-6 and ERK5 signaling. Corneal mRNA expression profiles for the clinically impaired, clinically non-impaired and naïve eyes generated a comprehensive database that revealed new factors and pathways, which for the first time were shown to be involved in SM-induced late pathology. Our data may contribute to the research on both the pathological mechanisms that are involved in the development of the late pathology and the protective pathways that are activated in the clinically non-impaired eyes and may point out towards novel therapeutic strategies for this severe ocular injury.


Assuntos
Substâncias para a Guerra Química/efeitos adversos , Neovascularização da Córnea , Opacidade da Córnea , Gás de Mostarda/efeitos adversos , RNA Mensageiro/metabolismo , Animais , Córnea , Neovascularização da Córnea/induzido quimicamente , Neovascularização da Córnea/metabolismo , Opacidade da Córnea/induzido quimicamente , Opacidade da Córnea/metabolismo , Modelos Animais de Doenças , Coelhos
8.
Toxicol Appl Pharmacol ; 310: 87-97, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27639427

RESUMO

Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80µg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h. In all brain regions tested, bax mRNA decreased 1h post exposure followed by an increase 24h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous "first response" mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Sarina/toxicidade , Animais , Substâncias para a Guerra Química , Masculino , Ratos , Ratos Sprague-Dawley
9.
Arch Toxicol ; 87(2): 347-60, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23052190

RESUMO

Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 µg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic-clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.


Assuntos
Anticonvulsivantes/farmacologia , Antídotos/farmacologia , Substâncias para a Guerra Química/intoxicação , Sulfato de Magnésio/farmacologia , Sarina/intoxicação , Convulsões/tratamento farmacológico , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Ciclopentanos/farmacologia , Epilepsia Tônico-Clônica , Masculino , Midazolam/farmacologia , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Telemetria
10.
Neurotoxicology ; 74: 19-27, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31095963

RESUMO

A common consequence of exposure to organophosphate nerve agents is the centrally mediated seizure activity that appears even after conventional treatment with atropine and oximes. We have previously demonstrated a major inflammatory response with subsequent brain damage which was correlated with the duration of the sarin-induced seizures (Chapman et al., 2006). In the present work seizures were induced by the nerve agent sarin (1.2 LD50) insufficiently treated 1 min later by atropine and trimedoxime bromide (TA), with additional midazolam treatment either 5 or 30 min after continuous seizure activity. The efficacy of both steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other drugs that were reported as beneficial in neuroprotection, were evaluated for their contribution as adjunct treatment against sarin induced seizures and the ensuing inflammatory brain damage. Results show that both steroids and NSAIDs were harmful when administered during convulsions, and steroids were at best ineffective if administered at their termination. However, if administered at termination of convulsions, the NSAID ibuprofen, the selective COX 2 inhibitor nimesulide and the PLA2 inhibitor quinacrine were partially effective in reducing brain inflammatory markers. Administration of exogenous analogs of prostaglandins (PGE2) immediately following sarin-induced convulsions was found to have a beneficial effect in reducing brain inflammatory markers measured at 24 h and one week post sarin exposure. These findings support the hypothesis that elevated levels of PGE2 have a beneficial role immediately following sarin induced seizures, and that early inhibition of PGE2 production by both steroids and NSAID is contraindicative.


Assuntos
Anti-Inflamatórios/uso terapêutico , Encefalopatias/induzido quimicamente , Encefalopatias/prevenção & controle , Substâncias para a Guerra Química , Inibidores da Colinesterase/toxicidade , Encefalite/induzido quimicamente , Encefalite/prevenção & controle , Prostaglandinas/metabolismo , Sarina/toxicidade , Animais , Anticonvulsivantes/uso terapêutico , Atropina/uso terapêutico , Reativadores da Colinesterase/uso terapêutico , Dinoprostona/metabolismo , Masculino , Midazolam/uso terapêutico , Agentes Neurotóxicos , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Trimedoxima/uso terapêutico
11.
Toxicol Lett ; 314: 153-163, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408696

RESUMO

Eye exposure to organophosphate (OP) chemical warfare irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. In contrast to the well-documented miotic and ciliary muscle spasm observed following chemical warfare, OP ocular exposure, little is known regarding the ocular surface histopathological insult. The aim of the present study was to determine the degree of the ocular surface insult following sarin or VX ocular exposure and to evaluate potential anti-cholinergic treatments in counteracting this insult. Rats that were whole body exposed to various sarin concentrations (0.049-43 µg/L; 5 min exposure), showed a dose-dependent miotic response and light reflex impairment. Following whole body sarin exposure, a dose dependent ocular surface histopathological insult was developed. A week following exposure to a low concentration of 0.05 µg/L, conjunctival pathology was observed, while corneal insult was noticed only following exposure to a concentration of 0.5 µg/L and above. Both tissues presented poorer outcomes when exposed to higher sarin concentrations. In contrast, eyes topically exposed to 1 µg sarin demonstrated no ocular insult a week following exposure. On the contrary, topical exposure to 1 µg VX resulted in a significant corneal insult. Anticholinergic treatments such as 0.1% atropine or 2% homatropine, given shortly following VX exposure, counteracted this insult. The results of this study show that not only do anti-cholinergic treatments counteract the miotic response, but also prevent the histopathological insult observed when given shortly following OP exposure.


Assuntos
Antídotos/farmacologia , Piscadela/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Olho/efeitos dos fármacos , Miose/prevenção & controle , Antagonistas Muscarínicos/farmacologia , Compostos Organotiofosforados/toxicidade , Sarina/toxicidade , Acetilcolinesterase/metabolismo , Animais , Citoproteção , Relação Dose-Resposta a Droga , Olho/enzimologia , Olho/patologia , Olho/fisiopatologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Masculino , Miose/induzido quimicamente , Miose/patologia , Miose/fisiopatologia , Ratos Long-Evans , Fatores de Tempo
12.
Toxicol Sci ; 159(1): 50-63, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28903494

RESUMO

Eye exposure to organophosphate (OP) irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. The aim of this study was to find an anticholinergic antidote, which would counteract miosis and visual impairment induced by the nerve agents sarin and VX with minimal untoward side-effects. Rat pupil width and light reflex were evaluated from 15 min up to 2 weeks following topical OP exposure with or without topical ocular treatment of atropine or homatropine or with a combined intramuscular treatment of trimedoxime (TMB-4) and atropine (TA). Visual function following insult and treatment was assessed using a cued Morris water maze task. Topical VX exposure showed a dose-dependent miosis with a significant reduction in visual function similar to the effect seen following sarin exposure. Homatropine (2%; w/v) and atropine (0.1%; w/v) treatment ameliorated both sarin and VX-induced miosis and the resulting visual impairment. TA treatment was sufficient in ameliorating the sarin-induced ocular impairment while an additional ocular treatment with either 0.1% atropine or 2% homatropine was necessary following VX exposure. To conclude the use of 0.1% atropine or 2% homatropine was beneficial in ameliorating the ocular insult following VX or sarin ocular exposure and thus should be considered as universal treatments against this intoxication. The findings also emphasize the necessity of additional ocular treatment to the systemic treatment in visually impaired casualties following VX exposure.


Assuntos
Olho/efeitos dos fármacos , Agentes Neurotóxicos/toxicidade , Compostos Organotiofosforados/toxicidade , Sarina/toxicidade , Animais , Antídotos/administração & dosagem , Atropina/administração & dosagem , Olho/fisiopatologia , Masculino , Miose/tratamento farmacológico , Pupila/efeitos dos fármacos , Ratos , Ratos Long-Evans , Tropanos/administração & dosagem , Visão Ocular/efeitos dos fármacos
13.
Neurotoxicology ; 49: 132-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25976749

RESUMO

Sarin poisoned rats display a hyper-cholinergic activity including hypersalivation, tremors, seizures and death. Here we studied the time and dose effects of midazolam treatment following nerve agent exposure. Rats were exposed to sarin (1.2 LD50, 108 µg/kg, im), and treated 1 min later with TMB4 and atropine (TA 7.5 and 5 mg/kg, im, respectively). Midazolam was injected either at 1 min (1 mg/kg, im), or 1 h later (1 or 5 mg/kg i.m.). Cortical seizures were monitored by electrocorticogram (ECoG). At 5 weeks, rats were assessed in a water maze task, and then their brains were extracted for biochemical analysis and histological evaluation. Results revealed a time and dose dependent effects of midazolam treatment. Rats treated with TA only displayed acute signs of sarin intoxication, 29% died within 24h and the ECoG showed seizures for several hours. Animals that received midazolam within 1 min survived with only minor clinical signs but with no biochemical, behavioral, or histological sequel. Animals that lived to receive midazolam at 1h (87%) survived and the effects of the delayed administration were dose dependent. Midazolam 5 mg/kg significantly counteracted the acute signs of intoxication and the impaired behavioral performance, attenuated some of the inflammatory response with no effect on morphological damage. Midazolam 1mg/kg showed only a slight tendency to modulate the cognitive function. In addition, the delayed administration of both midazolam doses significantly attenuated ECoG compared to TA treatment only. These results suggest that following prolonged seizure, high dose midazolam is beneficial in counteracting adverse effects of sarin poisoning.


Assuntos
Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/tratamento farmacológico , Inibidores da Colinesterase/toxicidade , Hipnóticos e Sedativos/administração & dosagem , Midazolam/administração & dosagem , Sarina/toxicidade , Análise de Variância , Animais , Lesões Encefálicas/fisiopatologia , Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Esquema de Medicação , Eletroencefalografia , Ensaio de Imunoadsorção Enzimática , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Índice de Gravidade de Doença , Fatores de Tempo
14.
Toxicol Sci ; 126(2): 515-24, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22247005

RESUMO

Eye exposure to the organophosphorus (OP) irreversible acetylcholinesterase inhibitor sarin results in long-term miosis and reduction in visual function. Anticholinergic drugs, such as atropine or homatropine, which are used topically in order to counter these effects may produce mydriasis and partial cycloplegia, which may worsen visual performance. This study was aimed to test the efficacy of short-acting anticholinergic drugs against sarin-induced miosis and visual impairment, which will minimally insult vision. Long-Evans rats, exposed topically to various sarin doses from 0 to 10 µg, showed a dose-dependent miosis, which returned to pre-exposure levels within 24-48 h. Tropicamide treatment rapidly widened the miotic effect to a different extent depending on time following treatment and dosage given. Cyclopentolate, however, showed a delayed response that finally widened the pupils in a dose-dependent manner. Atropine treatment showed a rapid widening of the pinpoint pupils exceeding baseline level finally causing mydriasis. Light reflex test showed that the contraction ability of the iris following atropine treatment was impaired, as opposed to the use of tropicamide which facilitated the iris contraction, similar to control. Finally, tropicamide and atropine treatments ameliorated the visual impairment, as opposed to cyclopentolate, which worsened visual performance. Considering that tropicamide treatment against sarin exposure did not cause mydriasis nor did it impair the iris contraction flexibility as a response to light, the use of this drug should be taken into consideration as a first-choice topical treatment against OP intoxication.


Assuntos
Inibidores da Colinesterase/toxicidade , Miose/induzido quimicamente , Sarina/toxicidade , Transtornos da Visão/induzido quimicamente , Animais , Masculino , Miose/fisiopatologia , Ratos , Ratos Long-Evans , Transtornos da Visão/fisiopatologia
15.
Toxicol Appl Pharmacol ; 227(1): 155-62, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18320638

RESUMO

Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where caramiphen exibited some protection at the 20-min time point. Our results show that caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed.


Assuntos
Antídotos/uso terapêutico , Benactizina/uso terapêutico , Substâncias para a Guerra Química/intoxicação , Inibidores da Colinesterase/intoxicação , Ciclopentanos/uso terapêutico , Sarina/intoxicação , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
16.
Toxicol Appl Pharmacol ; 231(1): 17-23, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18485435

RESUMO

The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 microg/kg/day, 0.05 LD(50)) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition (approximately 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction (approximately 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.


Assuntos
Química Encefálica/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/psicologia , Compostos Organotiofosforados/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Contagem de Células Sanguíneas , Análise Química do Sangue , Western Blotting , Peso Corporal/efeitos dos fármacos , Encéfalo/patologia , Inibidores da Colinesterase/administração & dosagem , Colinesterases/sangue , Colinesterases/metabolismo , Doença Crônica , Implantes de Medicamento , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Síndromes Neurotóxicas/fisiopatologia , Compostos Organotiofosforados/administração & dosagem , Oxotremorina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/enzimologia
17.
Biopharm Drug Dispos ; 28(3): 145-50, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17315239

RESUMO

Immediate administration of antidotal treatment is crucial in severe organophosphate (OP) poisoning and the use of an open intravenous (i.v.) line might also be required. The state of casualties might prevent getting access to their veins. The bone injection gun (BIG) was established as a simple method for introducing an intraosseous (i.o.) line and could be applied while wearing a protective suit. The present study followed the pharmacokinetics of the anticonvulsive drug midazolam after i.o. administration in pigs compared with i.v. and the common intramuscular (i.m.) administration. A new method for monitoring midazolam concentrations in plasma was developed. Plasma concentrations following both i.v. and i.o. administrations peaked at 2 min post injection and only at 10 min following the i.m. route. In an antidotal treatment study against paraoxone poisoning, the anticonvulsive effect of midazolam appeared immediately following i.o. administration, while it took 5-10 min to exhibit a similar effect following i.m. administration. This study indicates that the use of i.o. administration after OP poisoning might provide the necessary fast response for rapid termination of convulsions. The BIG might offer a convenient method for treating casualties in the chemical arena by teams wearing full protective gear.


Assuntos
Anticonvulsivantes/uso terapêutico , Antídotos/uso terapêutico , Midazolam/uso terapêutico , Intoxicação por Organofosfatos , Paraoxon/intoxicação , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Antídotos/administração & dosagem , Antídotos/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Infusões Intraósseas/instrumentação , Injeções Intramusculares/instrumentação , Injeções Intravenosas , Midazolam/administração & dosagem , Midazolam/farmacocinética , Intoxicação/tratamento farmacológico , Convulsões/induzido quimicamente , Suínos
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