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1.
Int J Mol Sci ; 21(18)2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32899591

RESUMO

Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.


Assuntos
Reativadores da Colinesterase/química , Trimedoxima/farmacologia , Trimedoxima/uso terapêutico , Acetilcolinesterase/metabolismo , Animais , Antídotos/farmacologia , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/farmacologia , Biologia Computacional/métodos , Humanos , Camundongos , Agentes Neurotóxicos/química , Compostos Organofosforados/química , Oximas/química , Ratos
2.
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
3.
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
4.
Arch Toxicol ; 93(5): 1365-1384, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30729277

RESUMO

Exposure to the chemical warfare nerve agent VX is extremely toxic, causing severe cholinergic symptoms. If not appropriately treated, death ultimately ensues. Based on our previously described whole-body vapor exposure system, we characterized in detail the clinical outcome, including respiratory dynamics, typical of whole-body exposure to lethal doses of VX vapor in freely moving rats. We further evaluated the efficacy of two different antidotal regimens, one comprising a single and the other repeated administration of antidotes, in countering the toxic effects of the exposure. We show that a 15 min exposure to air VX concentrations of 2.34-2.42 mg/m3 induced a late (15-30 min) onset of obvious cholinergic signs, which exacerbated over time, albeit without convulsions. Marked eye pathology was observed, characterized by pupil constriction to pinpoint, excessive lacrimation with red tears (chromodacryorrhea) and corneal damage. Respiratory distress was also evident, characterized by a three-fourfold increase in Penh values, an estimate of lung resistance, and by lung and diaphragm histological damage. A single administration of TAB (the oxime TMB-4, atropine and the anticholinergic and antiglutamatergic benactyzine) at the onset of clinical signs afforded only limited protection (66% survival), with clinical deterioration including weight loss, chromodacryorrhea, corneal damage, increased airway resistance and late death. In contrast, a combined therapy of TAB at the onset of clinical signs and repeated administration of atropine and toxogonin (ATOX) every 3-5 h, a maximum of five i.m. injections, led to 100% survival and a prompt recovery, accompanied by neither the above-described signs of eye pathology, nor by bronchoconstriction and respiratory distress. The necessity of recurrent treatments for successful elimination of VX vapor toxicity strongly supports continuous penetration of VX following termination of VX vapor exposure, most likely from a VX reservoir formed in the skin due to the exposure. This, combined with the above-described eye and respiratory pathology and absence of convulsions, are unique features of whole-body VX vapor exposure as compared to whole-body vapor exposure to other nerve agents, and should accordingly be considered when devising optimal countermeasures and medical protocols for treatment of VX vapor exposure.


Assuntos
Antídotos/administração & dosagem , Atropina/administração & dosagem , Benactizina/administração & dosagem , Substâncias para a Guerra Química/toxicidade , Compostos Organotiofosforados/toxicidade , Trimedoxima/administração & dosagem , Animais , Antídotos/farmacologia , Atropina/farmacologia , Benactizina/farmacologia , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/toxicidade , Esquema de Medicação , Combinação de Medicamentos , Exposição Ambiental/efeitos adversos , Oftalmopatias/induzido quimicamente , Oftalmopatias/prevenção & controle , Masculino , Cloreto de Obidoxima/administração & dosagem , Compostos Organotiofosforados/administração & dosagem , Ratos , Ratos Sprague-Dawley , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/prevenção & controle , Trimedoxima/farmacologia
5.
Arch Toxicol ; 93(3): 673-691, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30564897

RESUMO

For over 60 years, researchers across the world have sought to deal with poisoning by nerve agents, the most toxic and lethal chemical weapons. To date, there is no efficient causal antidote with sufficient effect. Every trialed compound fails to fulfil one or more criteria (e.g. reactivation potency, broad reactivation profile). In this recent contribution, we focused our attention to one of the promising compounds, namely the bis-pyridinium reactivator K203. The oxime K203 is very often cited as the best reactivator against tabun poisoning. Herein, we provide all the available literature data in comprehensive and critical review to address whether K203 could be considered as a new drug candidate against organophosphorus poisoning with the stress on tabun. We describe its development from the historical point of view and review all available in vitro as well as in vivo data to date. K203 is easily accessible by a relatively simple two-step synthesis. It is well accommodated in the enzyme active gorge of acetylcholinesterase providing suitable interactions for reactivation, as shown by molecular docking simulations. According to a literature survey, in vitro data for tabun-inhibited AChE are extraordinary. However, in vivo efficiency remains unconvincing. The K203 toxicity profile did not show any perturbations compared to clinically used standards; on the other hand versatility of K203 does not exceed currently available oximes. In summary, K203 does not seem to address current issues associated with the organophosphorus poisoning, especially the broad profile against all nerve agents. However, its reviewed efficacy entitles K203 to be considered as a backup or tentative replacement for obidoxime and trimedoxime, currently only available anti-tabun drugs.


Assuntos
Antídotos/farmacologia , Agentes Neurotóxicos/envenenamento , Intoxicação por Organofosfatos/tratamento farmacológico , Organofosfatos/toxicidade , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Acetilcolinesterase , Antídotos/uso terapêutico , Simulação de Acoplamento Molecular , Cloreto de Obidoxima , Trimedoxima
6.
Neurotoxicology ; 65: 248-254, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29128314

RESUMO

The effect of sarin on the binding parameters (KD & Bmax) of M2 muscarinic acetylcholine receptor (mAChR) was studied 24h and 1 week post exposure. Male & female Sprague-Daweley rats were poisoned with 1XLD50 sarin (80µg/kg, im) followed by treatment of trimedoxime bromide and atropine (7.5:5mg/kg, im) 1min later. Brains were removed and analyzed for M2 mAChR binding, using [3H]AFDX384, an M2 selective antagonist. A significant increase in KD of M2 mAChR was found in the cortex 24h post poisoning, displaying elevation from 4.65±1.16 to 8.45±1.06nM and 5.24±0.93 to 9.29±1.56nM in male and female rats, respectively. A rise in KD was also noted 1 week following exposure from 5.04±1.20 to 11.75±2.78 and from 5.37±1.02 to 11.66±1.73nM, presenting an added increase of 51 and 40% (compared to 24h) in males and females, respectively. Analysis of M2 receptor density (Bmax) revealed a significant reduction of 68% in males and insignificant reduction of 22% in females, 24h after sarin exposure which was followed by 37% recovery in males and 100% recovery in females, 1 week later. These results indicate that sarin induces a long-term decreased affinity in M2 mAChR (elevated KDs) and a transient effect on the number of this receptor subtype (Bmax). We hypothesize that the reduced affinity of the M2 receptors (negative auto-regulatory receptors) may cause long-term brain deficits by impairing the normal regulation release of ACh into the synaptic cleft.


Assuntos
Córtex Cerebral/metabolismo , Receptor Muscarínico M2/metabolismo , Sarina/toxicidade , Animais , Atropina/farmacologia , Feminino , Masculino , Pirenzepina/análogos & derivados , Pirenzepina/metabolismo , Ensaio Radioligante , Ratos , Caracteres Sexuais , Fatores de Tempo , Trimedoxima/farmacologia , Trítio/metabolismo
7.
Arch Toxicol ; 92(2): 745-757, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29098328

RESUMO

Beside the key inhibition of acetylcholinesterase (AChE), involvement of oxidative stress in organophosphate (OP)-induced toxicity has been supported by experimental and human studies. On the other hand, according to our best knowledge, possible antioxidant properties of oximes, the only causal antidotes to OP-inhibited AChE, have been examined only by a few studies. Thus, we have determined the effect of four conventional (obidoxime, trimedoxime, pralidoxime, asoxime) and two promising experimental oximes (K027, K203) on dichlorvos (DDVP)-induced oxidative changes in vivo. Wistar rats (5/group) were treated with oxime (5% LD50 i.m) immediately after DDVP challenge (75% LD50 s.c). Oxidative stress biomarkers were determined in plasma and brain 60 min after the treatment: prooxidative-superoxide anion (O2·-) and total oxidative status (TOS); antioxidative-superoxide dismutase (SOD), total thiol (SH) groups, total antioxidant status (TAS) and paraoxonase (PON1); tissue oxidative stress burden-prooxidative-antioxidative balance (PAB) and oxidative stress index (OSI); oxidative tissue damage-malondialdehyde (MDA) and advanced oxidation protein products (AOPP). All oximes were able to attenuate DDVP-induced oxidative stress in rat plasma and brain. Changes of determined parameters in brain were not as prominent as it was seen in plasma. Based on OSI, better abilities of oxime K027, K203 and obidoxime to maintain DDVP-induced oxidative stress in rat brain were shown as compared to trimedoxime, pralidoxime and asoxime. Oximes can influence the complex in vivo redox processes that might contribute to their overall therapeutic efficacy. Further research is needed to understand the underlying molecular mechanisms involved in this phenomenon.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Diclorvós/toxicidade , Intoxicação por Organofosfatos/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Oximas/farmacologia , Animais , Arildialquilfosfatase/sangue , Biomarcadores/sangue , Masculino , Malondialdeído/sangue , Cloreto de Obidoxima/farmacologia , Compostos de Pralidoxima , Compostos de Piridínio/farmacologia , Ratos , Superóxido Dismutase/sangue , Trimedoxima/farmacologia
8.
Molecules ; 22(7)2017 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-28696367

RESUMO

The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.


Assuntos
Substâncias para a Guerra Química/envenenamento , Reativadores da Colinesterase/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Intoxicação por Organofosfatos/tratamento farmacológico , Organofosfatos/toxicidade , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Acetilcolinesterase/metabolismo , Animais , Atropina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Humanos , Masculino , Síndromes Neurotóxicas/tratamento farmacológico , Ratos Wistar , Trimedoxima/uso terapêutico
9.
Toxicol Mech Methods ; 27(3): 236-243, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28043192

RESUMO

The ability of two newly developed bispyridinium oximes (K920, K923) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the oxime K203 and trimedoxime using a functional observational battery (FOB). The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (130 µg/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by FOB at 2 h after tabun administration. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment while one non-treated tabun-poisoned rat died within 2 h. Both newly developed oximes (K920, K923) combined with atropine were able to markedly decrease tabun-induced neurotoxicity in the case of sublethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity did not prevail the neuroprotective efficacy of trimedoxime and the oxime K203. Therefore, the newly developed oximes are not suitable for the replacement of currently available oximes (especially trimedoxime) in the treatment of acute tabun poisonings.


Assuntos
Reativadores da Colinesterase/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Organofosfatos/toxicidade , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Trimedoxima/uso terapêutico , Animais , Reativadores da Colinesterase/química , Masculino , Estrutura Molecular , Fármacos Neuroprotetores/química , Síndromes Neurotóxicas/etiologia , Oximas/química , Compostos de Piridínio/química , Ratos Wistar , Trimedoxima/química
10.
Am J Hosp Palliat Care ; 34(7): 603-610, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27122617

RESUMO

BACKGROUND: Hospice and Palliative Medicine (HPM) competencies are of growing importance in training general pediatricians and pediatric sub-specialists. The Accreditation Council for Graduate Medical Education (ACGME) emphasized pediatric trainees should understand the "impact of chronic disease, terminal conditions and death on patients and their families." Currently, very little is known regarding pediatric trainee education in HPM. METHODS: We surveyed all 486 ACGME-accredited pediatric training program directors (PDs) - 200 in general pediatrics (GP), 57 in cardiology (CARD), 64 in critical care medicine (CCM), 69 in hematology-oncology (ONC) and 96 in neonatology (NICU). We collected training program's demographics, PD's attitudes and educational practices regarding HPM. RESULTS: The complete response rate was 30% (148/486). Overall, 45% offer formal HPM curriculum and 39% offer a rotation in HPM for trainees. HPM teaching modalities commonly reported included conferences, consultations and bedside teaching. Eighty-one percent of all respondents felt that HPM curriculum would improve trainees' ability to care for patients. While most groups felt that a HPM rotation would enhance trainees' education [GP (96%), CARD (77%), CCM (82%) and ONC (95%)], NICU PDs were more divided (55%; p < 0.05 for all comparisons vs. NICU). CONCLUSION: While most programs report perceived benefit from HPM training, there remains a paucity of opportunities for pediatric trainees. Passive teaching methods are frequently utilized in HPM curricula with minimal diversity in methods utilized to teach HPM. Opportunities to further emphasize HPM in general pediatric and pediatric sub-specialty training remains.


Assuntos
Cuidados Paliativos na Terminalidade da Vida , Medicina Paliativa/educação , Pediatria/educação , Criança , Currículo , Humanos , Inquéritos e Questionários , Trimedoxima/análogos & derivados
11.
Acta Medica (Hradec Kralove) ; 58(4): 135-43, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26960827

RESUMO

AIM: The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. METHODS: The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 µg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. RESULTS: All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. CONCLUSION: The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.


Assuntos
Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacologia , Sistema Nervoso/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Organofosfatos/toxicidade , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Trimedoxima/farmacologia , Animais , Atropina/farmacologia , Masculino , Antagonistas Muscarínicos/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Intoxicação por Organofosfatos/tratamento farmacológico , Intoxicação por Organofosfatos/etiologia , Ratos , Ratos Wistar
12.
Basic Clin Pharmacol Toxicol ; 116(4): 367-71, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25225130

RESUMO

The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.


Assuntos
Antídotos/uso terapêutico , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/uso terapêutico , Organofosfatos/toxicidade , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Trimedoxima/uso terapêutico , Animais , Atropina/farmacologia , Injeções Intramusculares , Dose Letal Mediana , Masculino , Camundongos , Parassimpatolíticos/farmacologia , Ratos , Ratos Wistar
13.
Arch Toxicol ; 88(2): 381-90, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24065055

RESUMO

Oxime-assisted reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a crucial step in the post-inhibitory treatment of OP intoxication. The limited efficacy of oxime reactivators for all OP nerve agents and pesticides led to the development of various novel oximes and their thorough kinetic investigations. Hence, in the present investigation, we have tested 10 structurally different pyridinium oxime-based reactivators for their in vitro potency to reactivate paraoxon- and DFP-inhibited electric eel AChE. From structure activity relationship point of view, various oximes such as mono-quaternary (2-PAM, K100, K024) and bis-quaternary symmetric (obidoxime, TMB-4) and asymmetric (K027, K048, K203, K618, K628) oximes bearing different connecting linkers (oxybismethylene, trimethylene, propane, butane, butene, and xylene) have been studied. The observed kinetic data demonstrate that not only the position of oxime group is decisive for the increased reactivation ability of oximes, but the role of connecting linker is also significant. Oximes with aliphatic linkers are superior reactivators than the oximes with unsaturated and aromatic linkers. The optimal chain length for plausible reactivation ability for paraoxon- and DFP-inhibited AChE is 3 or 4 carbon-carbon connecting linker between prydinium rings.


Assuntos
Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Isoflurofato/toxicidade , Paraoxon/toxicidade , Compostos de Piridínio/farmacologia , Acetilcolinesterase/metabolismo , Alcenos/química , Animais , Butanos/química , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacocinética , Electrophorus , Cinética , Cloreto de Obidoxima/química , Cloreto de Obidoxima/farmacologia , Compostos de Piridínio/química , Relação Estrutura-Atividade , Trimedoxima/química , Trimedoxima/farmacologia
14.
Toxicol Mech Methods ; 24(3): 173-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24295433

RESUMO

The potency of two newly developed oximes (K361 and K378) to reactivate tabun-inhibited cholinesterase and to reduce acute toxicity of tabun was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm cholinesterase in poisoned rats showed that the reactivating efficacy of the oxime K378 is slightly lower than the reactivating potency of the oxime K203 and trimedoxime while the ability of the oxime K361 to reactivate tabun-inhibited cholinesterase is markedly lower compared with the oxime K203 and trimedoxime. In the brain, the potency of both newly developed oximes to reactivate tabun-inhibited cholinesterase was negligible. The therapeutic efficacy of both newly developed oximes roughly corresponds to their weak reactivating efficacy. Their potency to reduce acute toxicity of tabun was significantly lower compared with the oxime K203 as well as trimedoxime. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.


Assuntos
Inibidores da Colinesterase/envenenamento , Reativadores da Colinesterase/uso terapêutico , Organofosfatos/toxicidade , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Trimedoxima/uso terapêutico , Animais , Barreira Hematoencefálica , Masculino , Camundongos , Ratos Wistar , Relação Estrutura-Atividade
15.
Basic Clin Pharmacol Toxicol ; 113(3): 201-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23647829

RESUMO

The ability of two newly developed bispyridinium oximes (K456, K458) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with oxime K203 and trimedoxime using the functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (200 µg/kg i.m.; 85% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery and automatic measurement of motor activity at 2 hr after tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K456, K458) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity was slightly higher than that of trimedoxime and oxime K203, but the difference in neuroprotective efficacy among all oximes studied is not large enough to make a decision about replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.


Assuntos
Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Animais , Atropina/farmacologia , Substâncias para a Guerra Química/toxicidade , Masculino , Organofosfatos/toxicidade , Ratos , Ratos Wistar , Trimedoxima/farmacologia
16.
Eksp Klin Farmakol ; 76(1): 21-4, 2013.
Artigo em Russo | MEDLINE | ID: mdl-23461011

RESUMO

The kinetics of oxime-induced reactivation of malathion-inhibited cholinesterase has been experimentally studied in vitro. It is shown that oximes do not restore the activity of inhibited butyrylcholinesterase. Acetylcholinesterase reactivation peak (5-mins long) was found to take place upon introduction of dipyroxime (32.5%), pralidoxime (18%), carboxyme (16%) at a concentration of 2.5 x 10(-4) mol/l or toxogonine (26%) at a concentration of 5 x 10(-4) mol/l. Toxogonine demonstrated the maximum affinity to phosphorylated enzyme, while dipyroxime is characterized by a high reactivity with respect to oxime. Significant reactivating ability of these preparations (kR -2300 mol(-1) min(-1) makes them promising solution for the treatment of malathion intoxication.


Assuntos
Acetilcolinesterase/química , Antídotos/química , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Reativadores da Colinesterase/química , Malation/química , Animais , Ativação Enzimática , Eritrócitos/química , Eritrócitos/enzimologia , Cavalos , Cinética , Cloreto de Obidoxima/química , Compostos de Pralidoxima/química , Soluções , Torpedo , Trimedoxima/química
17.
Toxicol Mech Methods ; 23(2): 94-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22901042

RESUMO

The potency of three newly developed bispyridinium compounds (K454, K456, K458) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm and brain acetylcholinesterase in poisoned rats showed that the reactivating efficacy of all newly developed oximes is comparable with K203 but lower than the reactivating potency of trimedoxime in diaphragm. In the brain, their potency to reactivate tabun-inhibited acetylcholinesterase is lower compared with trimedoxime and the oxime K203. All three newly developed oximes were also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy is consistent with the therapeutic potency of the oxime K203. On the other hand, their potency to reduce acute toxicity of tabun is significantly lower compared with trimedoxime. In conclusion, the reactivating and therapeutic potency of all three newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.


Assuntos
Substâncias para a Guerra Química/envenenamento , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/toxicidade , Organofosfatos/toxicidade , Compostos de Piridínio/toxicidade , Trimedoxima/toxicidade , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Diafragma/efeitos dos fármacos , Diafragma/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Wistar
18.
J Appl Toxicol ; 33(1): 18-23, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21717485

RESUMO

K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-propane dibromide] is a promising new reactivator of organophosphate- or organophosphonate-inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 ± 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg(-1)) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed-phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R(2) > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1-100 µg ml(-1). Near-identical plasma profiles were obtained for both compounds. No differences were found in the mean ± SD values of C(max) (18.6 ± 2.5 vs 20.0 ± 6.3 µg ml(-1), P = 0.72) and AUC(0-180min) (2290 ± 304 vs 2269 ± 197 min µg ml(-1), P = 0.84). However, the percentage coefficient of variation of the first-order rate constant of absorption (k(a)) was 3-fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution.


Assuntos
Reativadores da Colinesterase/farmacocinética , Oximas/farmacocinética , Compostos de Piridínio/farmacocinética , Trimedoxima/farmacocinética , Animais , Reativadores da Colinesterase/sangue , Cromatografia Líquida de Alta Pressão , Injeções Intramusculares , Masculino , Oximas/sangue , Compostos de Piridínio/sangue , Ratos , Ratos Wistar , Espectrofotometria Ultravioleta/métodos , Distribuição Tecidual , Trimedoxima/sangue
19.
Acta Medica (Hradec Kralove) ; 55(1): 27-31, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22696932

RESUMO

The reactivating and therapeutic efficacy of two combinations ofoximes (HI-6 + trimedoxime and HI-6 + K203) was compared with the effectiveness of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of both combinations of oximes is slightly higher than the reactivating efficacy of the most effective individual oxime in blood, diaphragm as well as in brain. Moreover, both combinations of oximes were found to be slightly more efficacious in the reduction of acute lethal toxic effects in cyclosarin-poisoned mice than the antidotal treatment involving single oxime. Based on the obtained data, we can conclude that the antidotal treatment involving chosen combinations of oximes brings a beneficial effect for its ability to counteract the acute poisoning with cyclosarin.


Assuntos
Antídotos/uso terapêutico , Reativadores da Colinesterase/uso terapêutico , Compostos Organofosforados/toxicidade , Animais , Camundongos , Camundongos Endogâmicos , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Ratos , Ratos Wistar , Trimedoxima/uso terapêutico
20.
Toxicol Mech Methods ; 22(4): 260-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22149934

RESUMO

The potency of the oxime HI-6 and two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) to reduce sarin-induced acute neurotoxic signs and symptoms was evaluated in this study. Sarin-induced neurotoxicity and the neuroprotective effects of atropine alone or in combination with HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with sarin at a sublethal dose (108 µg/kg i.m.; 90% of LD(50) value) were monitored by a functional observatory battery (FOB) 24 h following sarin administration. The results indicate that both mixtures of oximes combined with atropine were able to survive sarin-poisoned rats 24 h following sarin administration while two non-treated sarin-poisoned rats and one sarin-poisoned rat treated with atropine alone or with atropine in combination with the oxime HI-6 died within 24 h following sarin poisoning. All types of antidotal treatment were able to decrease sarin-induced neurotoxic signs and symptoms but not completely. While atropine alone and atropine in combination with the oxime HI-6 were able to eliminate some sarin-induced neurotoxic signs and symptoms, the neuroprotective efficacy of both combinations of oximes with atropine was slightly higher. Thus, both tested combinations of oximes in combination with atropine bring a small benefit for the neuroprotective efficacy of antidotal treatment of acute sarin poisonings.


Assuntos
Fármacos Neuroprotetores/uso terapêutico , Oximas/uso terapêutico , Compostos de Piridínio/uso terapêutico , Sarina/envenenamento , Trimedoxima/uso terapêutico , Animais , Antídotos/administração & dosagem , Antídotos/uso terapêutico , Atropina/química , Substâncias para a Guerra Química/envenenamento , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/envenenamento , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/administração & dosagem , Reativadores da Colinesterase/uso terapêutico , Quimioterapia Combinada , Masculino , Estrutura Molecular , Oximas/administração & dosagem , Oximas/química , Compostos de Piridínio/administração & dosagem , Compostos de Piridínio/química , Ratos , Ratos Wistar , Sarina/toxicidade , Trimedoxima/administração & dosagem , Trimedoxima/química
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