V léčbě nádorových onemocnění se objevují stále účinnější léčebné strategie, které však s sebou přinášejí i nové nežádoucí účinky. Průlomem je použití imuno­‐onkologické léčby, kam patří léčba inhibitory kontrolních bodů. Bohužel s touto léčbou se pojí řada imunitně zprostředkovaných nežádoucích účinků, které také mohou postihnout nervový systém. Nejčastěji se objevuje myastenie, Guillainův­‐Barrého syndrom, neuropatie, aseptická meningitida, mononeuritis multiplex, encefalitida a transverzální myelitida. Dalšími léčivy, která potenciálně mohou vést k postižení nervového systému, jsou inhibitory BRAF a MEK, jež se například používají v léčbě metastazujícího melanomu.

More effective treatment strategies have been appearing in the treatment of cancer, but they also bring new unpleasant side effects with them. A breakthrough is the use of immuno-oncology therapy, which includes checkpoint inhibitors. Unfortunately, this treatment relates to number of immune-mediated adverse effects, which may affect also the nervous system. Myasthenia gravis, Guillain-Barré syndrome, neuropathy, aseptic meningitis, mononeuritis multiplex, encephalitis and transverse myelitis are the most common neurotoxic side effects. Other drugs that can lead to damage to the nervous system are BRAF and MEK inhibitors, for example used in the treatment of metastatic melanoma. Knowledge of these immune-related side effects is necessary for prompt diagnosis and treatment. Immediate discontinuation of oncology therapy, administration of high doses of corticosteroids, intravenous immunoglobulins or exchange plasmapheresis is recommended.

• MeSH
• dospělí MeSH
• ganciklovir aplikace a dávkování   terapeutické užití   MeSH
• Guillainův-Barrého syndrom diagnóza   etiologie   terapie   MeSH
• hormony kůry nadledvin aplikace a dávkování   terapeutické užití   MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• MAP kinasy kinas (kinas) antagonisté a inhibitory   škodlivé účinky   MeSH
• melanom farmakoterapie   MeSH
• meningitida aseptická diagnóza   etiologie   terapie   MeSH
• meningoencefalitida diagnóza   etiologie   terapie   MeSH
• neurotoxické syndromy diagnóza   etiologie   farmakoterapie   MeSH
• protinádorové látky imunologicky aktivní * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• protoonkogenní proteiny B-raf antagonisté a inhibitory   škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Solasodine analogues containing a seven-membered F ring with a nitrogen atom placed at position 22a were prepared from diosgenin or tigogenin in a four-step synthesis comprising of the simultaneous opening of the F-ring and introduction of cyanide in position 22α, activation of the 26-hydroxyl group as mesylate, nitrile reduction, and N-cyclization. Solasodine, six obtained 22a(N)-homo analogues, as well as four 26a-homosolasodine derivatives and their open-chain precursors (13 in total) were tested as potential inhibitors of acetyl- and butyryl-cholinesterases and showed activity at micromolar concentrations. The structure-activity relationship study revealed that activities against studied esterases are affected by the structure of E/F rings and the substitution pattern of ring A. The most potent compound 8 acted as non-competitive inhibitors and exerted IC50 = 8.51 μM and 7.05 μM for eeAChE and eqBChE, respectively. Molecular docking studies revealed the hydrogen bond interaction of 8 with S293 of AChE; further rings are stabilized via hydrophobic interaction (ring A) or interaction with Y341 and W286 (rings B and C). Biological experiments showed no neurotoxicity of differentiated SH-SY5Y cells. More importantly, results from neuroprotective assay based on glutamate-induced cytotoxicity revealed that most derivatives had the ability to increase the viability of differentiated SH-SY5Y cells in comparison to galantamine and lipoic acid assayed as standards. The newly synthesized solasodine analogues are able to inhibit and to bind cholinesterases in noncompetitive mode of inhibition and exhibited neuroprotection potential of differentiated neuroblastoma cells after Glu-induced toxicity.

• MeSH
• alkaloidy Solanaceí chemická syntéza   chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• cholinesterasy chemie   účinky léků   MeSH
• diosgenin chemie   MeSH
• dusík chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• neurotoxické syndromy farmakoterapie   enzymologie   patologie   MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The aim of our study was to compare the ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) with atropine to counteract acute sarin-induced brain damage with the efficacy of antidotal treatment involving single oxime (HI-6) and atropin using in vivo methods. METHODS: Brain damage and neuroprotective effects of antidotal treatment were evaluated in rats poisoned with sarin at a sublethal dose (108 μg/kg i.m.; 90% LD50) using histopathological, Fluoro-Jade B and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis 24 h after sarin administration. RESULTS: Both combinations of oximes reduce the number of rats that died before the end of experiment compared to non-treated sarin poisoning and sarin poisoning treated with HI-6 and atropine. In the case of treatment of sarin poisoning with HI-6 in combination with K203, all rats survived till the end of experiment. HI-6 with atropine was able to reduce sarin-induced brain damage, however, both combinations were slightly more effective. CONCLUSIONS: The oxime HI-6 in combination with K203 and atropine seems to be the most effective. Thus, both tested oxime combinations bring a small benefit in elimination of acute sarin-induced brain damage compared to single oxime antidotal therapy.

• MeSH
• antidota terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• neurotoxické syndromy farmakoterapie   MeSH
• oximy terapeutické užití   MeSH
• potkani Wistar MeSH
• sarin otrava   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• atropin terapeutické užití   MeSH
• chemické bojové látky otrava   MeSH
• lidé MeSH
• mozek účinky léků   enzymologie   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• neurotoxické syndromy farmakoterapie   MeSH
• organofosfáty toxicita   MeSH
• otrava organofosfáty farmakoterapie   MeSH
• oximy terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• reaktivátory cholinesterázy terapeutické užití   MeSH
• trimedoxim terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

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.

• MeSH
• antagonisté muskarinových receptorů farmakologie   MeSH
• atropin farmakologie   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• krysa rodu rattus MeSH
• nervový systém účinky léků   MeSH
• neuroprotektivní látky farmakologie   MeSH
• neurotoxické syndromy farmakoterapie   etiologie   MeSH
• organofosfáty toxicita   MeSH
• otrava organofosfáty farmakoterapie   etiologie   MeSH
• oximy farmakologie   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterázy farmakologie   MeSH
• trimedoxim farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The ability of two newly developed oximes (K361, K378) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the oxime K203 and trimedoxime using a functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (310 μg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by functional observational battery at 2 h following 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 (K361, K378) 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 lower than that of trimedoxime and the oxime K203. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.

• MeSH
• antidota MeSH
• atropin aplikace a dávkování   terapeutické užití   MeSH
• chemické bojové látky * toxicita   MeSH
• cholinesterasové inhibitory * MeSH
• krysa rodu rattus MeSH
• neuroprotektivní látky MeSH
• neurotoxické syndromy farmakoterapie   MeSH
• neurotoxiny MeSH
• nitrily MeSH
• organofosfáty MeSH
• organofosforové sloučeniny * toxicita   MeSH
• oximy * aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• trimedoxim * aplikace a dávkování   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

• MeSH
• dolní končetina patologie   MeSH
• duktální karcinom prsu * diagnóza   etiologie   farmakoterapie   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neoadjuvantní terapie MeSH
• neurotoxické syndromy etiologie   farmakoterapie   terapie   MeSH
• paclitaxel * škodlivé účinky   terapeutické užití   MeSH
• polyneuropatie * etiologie   farmakoterapie   chemicky indukované   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 µg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.

• MeSH
• acetylcholinesterasa krev   chemie   metabolismus   MeSH
• antagonisté muskarinových receptorů terapeutické užití   MeSH
• antidota terapeutické užití   MeSH
• atropin terapeutické užití   MeSH
• bránice účinky léků   enzymologie   MeSH
• cholinesterasové inhibitory aplikace a dávkování   chemie   toxicita   MeSH
• kombinovaná farmakoterapie MeSH
• mozek účinky léků   enzymologie   MeSH
• myši MeSH
• neurony účinky léků   enzymologie   MeSH
• neurotoxické syndromy krev   farmakoterapie   etiologie   metabolismus   MeSH
• obidoxim chlorid terapeutické užití   MeSH
• outbrední kmeny zvířat MeSH
• oximy terapeutické užití   MeSH
• potkani Wistar MeSH
• proteiny nervové tkáně agonisté   antagonisté a inhibitory   metabolismus   MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• reaktivátory cholinesterázy terapeutické užití   MeSH
• sarin aplikace a dávkování   antagonisté a inhibitory   toxicita   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

• MeSH
• avitaminóza patofyziologie   terapie   MeSH
• lidé MeSH
• nemoci centrálního nervového systému MeSH
• nemoci periferního nervového systému MeSH
• nemoci z povolání MeSH
• neurotoxické syndromy * etiologie   farmakoterapie   klasifikace   MeSH
• nežádoucí účinky léčiv MeSH
• poranění z opakovaného přetěžování MeSH
• poruchy nervového systému vyvolané alkoholem MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The neuroprotective effects of a newly developed oxime K203 and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin-induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings.

• MeSH
• antagonisté muskarinových receptorů terapeutické užití   MeSH
• antidota škodlivé účinky   terapeutické užití   MeSH
• atropin terapeutické užití   MeSH
• autonomní nervový systém účinky léků   patofyziologie   MeSH
• chemické bojové látky chemie   toxicita   MeSH
• cholinesterasové inhibitory chemie   toxicita   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• LD50 MeSH
• neurony účinky léků   MeSH
• neurotoxické syndromy farmakoterapie   patofyziologie   MeSH
• obidoxim chlorid škodlivé účinky   terapeutické užití   MeSH
• oximy škodlivé účinky   terapeutické užití   MeSH
• potkani Wistar MeSH
• psychomotorický výkon účinky léků   MeSH
• pyridinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• reaktivátory cholinesterázy škodlivé účinky   terapeutické užití   MeSH
• sarin antagonisté a inhibitory   toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH