The influence of three newly developed bispyridinium antinicotinic compounds (the non-oximes MB408, MB442 and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with an oxime) of acute poisoning by the organophosphorus nerve agents tabun and soman was studied in mice. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-oximes was evaluated by determination of the LD50 values of the nerve agents and measurement of the survival time after supralethal poisoning. Addition of all the tested non-oximes increased significantly the therapeutic efficacy of atropine in combination with an oxime against tabun poisoning. They also positively influenced the number of surviving mice 6 hr after supralethal poisoning with tabun. However, they were only slightly effective for the treatment of soman poisoning. The benefit of the tested bispyridinium non-oximes was dose-dependent. To conclude, the addition of bispyridinium non-oximes to the standard antidotal treatment of acute poisoning with tabun was beneficial regardless of the chosen non-oxime, but only slightly beneficial in the case of soman poisoning.

• MeSH
• antidota chemická syntéza   farmakologie   terapeutické užití   MeSH
• atropin farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• LD50 MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nervová bojová látka otrava   MeSH
• nikotinoví agonisté chemická syntéza   farmakologie   MeSH
• organofosfáty toxicita   MeSH
• otrava organofosfáty farmakoterapie   etiologie   MeSH
• oximy farmakologie   MeSH
• preklinické hodnocení léčiv MeSH
• pyridinové sloučeniny chemická syntéza   farmakologie   terapeutické užití   MeSH
• soman otrava   MeSH
• synergismus léků MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

AIM: The influence of the dose on the ability of promising newly prepared reversible inhibitor of acetylcholinesterase (6-chlorotacrine) to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. METHODS: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probit-logarithmical analysis of death occurring within 24 hrs after administration of soman. RESULTS: The dose of 6-chlorotacrine significantly influences the prophylactic efficacy of 6-chlorotacrine. Its highest dose was only able to significantly protect mice against acute toxicity of soman and increase the efficacy of antidotal treatment (atropine in combination with the oxime HI-6) of soman-poisoned mice. In addition, the highest dose of 6-chlorotacrine was significantly more effective to protect mice from soman poisoning than its lowest dose. CONCLUSION: These findings demonstrate the important influence of the dose of 6-chlorotacine on its prophylactic efficacy in the case of pharmacological pretreatment of soman poisoning in mice.

• MeSH
• antidota farmakologie   MeSH
• chemicky indukované poruchy prevence a kontrola   MeSH
• cholinesterasové inhibitory otrava   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• preexpoziční profylaxe metody   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• soman otrava   MeSH
• takrin analogy a deriváty   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

AIM: The ability of four newly prepared reversible inhibitors of acetylcholinesterase (6-chlorotacrine, 7-phenoxytacrine, compounds 1 and 2) and currently used carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. METHODS: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman. RESULTS: 6-chlorotacrine was only able to markedly protect mice against acute toxicity of soman. In addition, the pharmacological pretreatment with 6-chlorotacrine or compound 2 was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. The other newly prepared reversible inhibitors of acetylcholinesterase (7-phenoxytacrine, compound 1) as well as commonly used pyridostigmine did not influence the efficacy of antidotal treatment. CONCLUSION: These findings demonstrate that pharmacological pretreatment of somanpoisoned mice can be promising and useful in the case of administration of 6-chlorotacrine and partly compound 2.

• MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• isochinoliny MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• myši MeSH
• pyridinové sloučeniny aplikace a dávkování   farmakologie   MeSH
• pyridostigmin-bromid farmakologie   MeSH
• soman otrava   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The ability of four newly developed reversible inhibitors of acetylcholinesterase (PC-37, PC-48, JaKo 39, JaKo 40) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated and compared. No reversible inhibitor of acetylcholinesterase studied was able to decrease the LD50 value of soman in mice. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of acetylcholinesterase was not able to significantly protect mice against soman-induced lethal acute toxicity. In addition, neither pyridostigmine nor new reversible inhibitors of acetylcholinesterase was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of acetylcholinesterase is not promising.

• MeSH
• antidota terapeutické užití   MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• LD50 MeSH
• myši MeSH
• piperaziny terapeutické užití   MeSH
• pyridostigmin-bromid terapeutické užití   MeSH
• soman antagonisté a inhibitory   otrava   MeSH
• takrin analogy a deriváty   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

The ability of three newly developed reversible inhibitors of acetylcholinesterase (AChE) (K298, K344 and K474) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was compared. Neither pyridostigmine nor new reversible inhibitors of AChE were able to increase the LD(50) value of soman. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of AChE was not able to protect mice against soman-induced lethal acute toxicity. The pharmacological pre-treatment with pyridostigmine alone or with K474 was able to slightly increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice, but the increase in the efficacy of antidotal treatment was not significant. The other newly developed reversible inhibitors of AChF (K298, K344) were completely ineffective. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of AChF is not promising.

• MeSH
• antidota aplikace a dávkování   farmakologie   MeSH
• atropin aplikace a dávkování   farmakologie   MeSH
• chemické bojové látky otrava   MeSH
• cholinesterasové inhibitory aplikace a dávkování   farmakologie   MeSH
• isochinoliny aplikace a dávkování   farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• LD50 MeSH
• myši MeSH
• oximy aplikace a dávkování   farmakologie   MeSH
• pyridinové sloučeniny aplikace a dávkování   farmakologie   MeSH
• pyridostigmin-bromid aplikace a dávkování   farmakologie   MeSH
• reaktivátory cholinesterasy aplikace a dávkování   farmakologie   MeSH
• soman aplikace a dávkování   otrava   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

The purpose of our study was to examine an early activation of JNK and p38 mitogen activated protein kinases (MAPK) and their substrate c-Myc after soman poisoning in order to enlighten the pathogenetic mechanism of nerve agent-induced non-specific effects. Male Wistar rats were intramuscularly poisoned by soman (60 μg.kg-1 - 70% LD50). Samples were taken 4, 24, and 72 hours after poisoning, immunohistochemically stained and phospho-JNKThr-183/Tyr-185, phospho-p38Thr180/Tyr182, and phospho-c- MycThr58/Ser62 expressions were measured using a computer Image analysis in apical and cryptal enterocytes of the colon transversum. We observed decreased phospho-JNK in apical enterocytes 4 and 24 h after poisoning and increased phospho-JNK in cryptal and apical enterocytes 72 h after intoxication. Phosphop38 dropped significantly in the apical compartment 72 h after soman poisoning. An activation of c-Myc decreased in both apical and cryptal compartment 4 and 24 h after soman intoxication, while increased in both compartments 72 h after poisoning. Soman poisoning seems to temporarily suppress promitotic pathways of proliferating cryptal cells and causes delayed activation of JNK stress signaling pathway.

• MeSH
• časové faktory MeSH
• colon transversum chemie   MeSH
• enterocyty chemie   MeSH
• experimenty na zvířatech MeSH
• financování organizované MeSH
• JNK mitogenem aktivované proteinkinasy chemie   MeSH
• kontrolní skupiny MeSH
• MAP kinasový signální systém fyziologie   MeSH
• mitogenem aktivované proteinkinasy p38 chemie   MeSH
• potkani Wistar MeSH
• protoonkogenní proteiny c-myc chemie   MeSH
• soman otrava   toxicita   MeSH
• výzkumný projekt MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH

The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 μg/kg intramuscularly, i.m.; 80% of LD₅₀ value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime.

• MeSH
• chování zvířat účinky léků   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• molekulární struktura MeSH
• neuroprotektivní látky aplikace a dávkování   chemie   terapeutické užití   MeSH
• neurotoxické syndromy etiologie   patofyziologie   prevence a kontrola   MeSH
• oximy aplikace a dávkování   chemie   terapeutické užití   MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   chemie   terapeutické užití   MeSH
• soman otrava   MeSH
• trimedoxim aplikace a dávkování   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: The present experiment is based on biochemical assessment of nerve agent soman intoxication and atropine, respectively atropine and HI-6, trimedoxime or K203 treatment in rats. BACKGROUND: Nerve agents are toxic substances irreversibly inhibiting enzyme acetylcholinesterase (AChE). Treatment is typically based on application of atropine and oxime reactivator. Atropine is able to protect overstimulation of muscarinic acetylcholine receptors. Application of oxime reactivator enable return of AChE activity and full suppression of intoxication. METHODS: In a total, fifteen biochemical markers were assayed in plasma or blood of intoxicated animals. 42 rats were divided into 7 groups each 6 individuals. The first group was exposed to atropine; the second group was exposed to one LD50 of soman and atropine. The groups 3-5 were exposed in a same way as the second group and were treated with oxime reactivators: HI-6 (group 3), trimedoxime (4) and K203 (5). The sixth group was control treated with saline solution only. The last (seventh) group was intoxicated with soman only. RESULTS: The most striking shifts were found for blood acetylcholinesterase and plasma creatinine, glucose, inorganic phosphate as well as uric acid. Lactate dehydrogenase and aspartate aminotransferase assays were useless due to soman interference. CONCLUSION: It was demonstrated that treatment was able to protect poisoned animals from metabolic disorder represented by hyperglycemia and nephropathy represented by hyperuricemia and elevated creatinine. Soman exposure and treatment with the oxime reactivators and/or atropine contains quite complex and still not well understood side mechanisms (Tab. 2, Fig. 1, Ref. 25).

• MeSH
• antidota terapeutické užití   MeSH
• atropin terapeutické užití   MeSH
• biologické markery krev   MeSH
• chemické bojové látky otrava   MeSH
• cholinesterasové inhibitory otrava   MeSH
• krysa rodu rattus MeSH
• oximy terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• reaktivátory cholinesterasy terapeutické užití   MeSH
• soman otrava   MeSH
• trimedoxim terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of the study was to evaluate the expression of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and MAPK-activated transcription factors elk-1, c-jun and c-myc in rat cerebellar Purkinje cells after soman poisoning to investigate the pathogenetic mechanism of non-specific long-term adverse effects of nerve agents. Male Wistar rats were poisoned by intramuscular administration of soman at a dose 60 microg kg(-1) (80% LD(50)), while control animals were administered physiological saline. Samples were taken 1, 7 and 14 days after poisoning, immunohistochemically stained and p-p38MAPK, p-c-jun, p-c-myc, and p-elk-1 expressions were measured using computer image analysis. An increased expression of phosphorylated p38 MAPK and c-myc 14 days after soman poisoning was found, while both activated elk-1 and c-jun expression remained unchanged 1, 7 and 14 days after intoxication. Late activation of p38 MAPK and their targets might be the underlying mechanism of chronic neurophysiological adverse effects.

• MeSH
• cholinesterasové inhibitory otrava   MeSH
• fosforylace MeSH
• imunohistochemie MeSH
• krysa rodu rattus MeSH
• mitogenem aktivované proteinkinasy p38 biosyntéza   fyziologie   genetika   MeSH
• mozeček cytologie   patologie   účinky léků   MeSH
• počítačové zpracování obrazu MeSH
• potkani Wistar MeSH
• proteiny nervové tkáně biosyntéza   MeSH
• Purkyňovy buňky patologie   účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• soman otrava   MeSH
• transkripční faktory genetika   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

The influence of the combination of oximes on the reactivating and therapeutic efficacy of antidotal treatment of acute soman poisoning was evaluated. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate soman-inhibited acetylcholinesterase and reduce acute toxicity of soman was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo model. Studies determining percent of reactivation of soman-inhibited blood and diaphragm acetylcholinesterase in poisoned rats showed that the reactivating efficacy of both combinations of oximes is slightly greater than the reactivating efficacy of the most effective individual oxime, but the difference among them is not significant. Both combinations of oximes were found to be as effective in the reduction of acute lethal toxic effects in soman-poisoned mice as the antidotal treatment involving the most efficacious individual oxime. Thus, the efficacy of oximes is comparative in rats vs mice. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the newly developed oxime K203 is approximately as effective as commonly used trimedoxime; nevertheless, their reactivating and therapeutic efficacy is markedly lower compared to the oxime HI-6. Based on the obtained data, one can conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the potency of the most effective individual oxime (HI-6) to reactivate soman-inhibited rat acetylcholinesterase and to reduce acute toxicity of soman.

• MeSH
• antidota chemie   terapeutické užití   MeSH
• chemické bojové látky otrava   MeSH
• cholinesterasové inhibitory otrava   MeSH
• fixní kombinace léků MeSH
• krysa rodu rattus MeSH
• myši MeSH
• oximy chemie   terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny chemie   terapeutické užití   MeSH
• reaktivátory cholinesterasy chemie   terapeutické užití   MeSH
• soman otrava   MeSH
• trimedoxim chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH