Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror (like in Syria). Oxime antidotes currently used in medical practice still fall short of their therapeutic purpose, as they fail to fully restore the activity of cholinesterases, the main target for OPs. As orphan drugs, these antidotes are tested too seldom for anybody’s benefit. Over the last few decades, search for improved reactivators has reached new levels, but the translation of data obtained in vitro to in vivo application is still a problem that hinders efficient therapy. In this study, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidotes reactivation efficiency from in vitro to in vivo application. Our results show that this extrapolation is possible with well-determined kinetic constants, but that it also largely depends on oxime circulation time and its tissue-specific distribution. This suggests that pharmacokinetic studies should be planned at the early stages of antidote development. Special attention should also be given to improving oxime distribution throughout the organism to overcome this major constraint in improving overall OP therapy.Iako su organofosforni živčani bojni otrovi potpuno zabranjeni za upotrebu, njihova je prisutnost i dalje velik problem, posebice kao kemijsko oružje u terorističkim napadima (poput nedavnih u Siriji). Oksimi koji se danas koriste kao protuotrovi u tretmanu nemaju dostatno djelovanje na reaktivaciju aktivnosti kolinesteraza, glavnih meta djelovanja organofosfornih spojeva. Valja napomenuti kako se klinička testiranja ovih protuotrova rijetko provode zbog svoje iznimne specifičnosti. Tijekom zadnjih desetljeća učinjen je napredak u istraživanju novih učinkovitijih protuotrova, međutim još je uvijek veliki nedostatak u poboljšavanju terapije translacija in vitro dobivenih rezultata u in vivo primjenu. Ovom studijom ispitali smo mogućnosti ekstrapolacije reaktivacijske učinkovitosti određene za oksimske protuotrove iz in vitro u in vivo sustav. Naši rezultati pokazuju kako je ova translacija moguća uz detaljno određene kinetičke parametre in vitro i uz poznavanje distribucije oksima i vremena cirkulacije u organizmu. Takav rezultat ističe važnost planiranja i farmakokinetičkih istraživanja već u samom početku razvoja protuotrova. Također, poseban naglasak u istraživanju trebalo bi staviti i na poboljšanje tkivo-specifične distribucije oksima u organizmu čime bi se poboljšala cjelokupna terapijska učinkovitost

The Evaluation of the Potency of Newly Developed Oximes (K727, K733) and Trimedoxime to Counteract Acute Neurotoxic Effects of Tabun in Rats

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

A Comparison of the Potency of Newly Developed Oximes (K347, K628) and Currently Available Oximes (Obidoxime, HI-6) to Counteract Acute Neurotoxic Effects of Tabun in Rats

The ability of newly developed oximes (K347, K628) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oximes (obidoxime, HI-6) using a functional observational battery. The neuroprotective effects of the oximes studied (K347, K628, obidoxime, HI-6) combined with atropine on rats poisoned with tabun at a sublethal dose (220 μg/kg i.m.; 80 % of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by a functional observational battery and automatic measurement of motor activity at 24 hours following tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive 24 hours following tabun challenge. Both newly developed oximes (K347, K628) combined with atropine are able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings but they do not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease the tabun-induced acute neurotoxicity is higher than that of the oxime HI-6 and it is slightly slower than the neuroprotective efficacy of obidoxime. As the neuroprotective potency of both newly developed oximes (K347, K628) is not as high as the potency of obidoxime, they are not a suitable replacement for obidoxime for the treatment of acute tabun poisonings

A Comparison of the Neuroprotective Efficacy of Newly Developed Oximes (K156, K203) and Currently Available Oximes (Obidoxime, HI-6) in Cyclosarin-poisoned Rats

The neuroprotective effects of newly developed oximes (K156, K203) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin-induced neurotoxicity was monitored using a functional observational battery 24 hours after cyclosarin challenge. The results indicate that a newly developed oxime K156 is able to counteract slightly cyclosarin-induced neurotoxicity while another newly developed oxime K203 is completely ineffective in reducing cyclosarin-induced neurotoxic signs and symptoms. The neuroprotective efficacy of K156 is comparable with commonly used obidoxime and oxime HI-6. Thus, none of the newly developed oximes achieves better neuroprotective efficacy than both commonly used oximes. They are therefore not suitable replacements for antidotal treatment of acute poisonings with cyclosarin

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror (like in Syria). Oxime antidotes currently used in medical practice still fall short of their therapeutic purpose, as they fail to fully restore the activity of cholinesterases, the main target for OPs. As orphan drugs, these antidotes are tested too seldom for anybody’s benefit. Over the last few decades, search for improved reactivators has reached new levels, but the translation of data obtained in vitro to in vivo application is still a problem that hinders efficient therapy. In this study, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidotes reactivation efficiency from in vitro to in vivo application. Our results show that this extrapolation is possible with well-determined kinetic constants, but that it also largely depends on oxime circulation time and its tissue-specific distribution. This suggests that pharmacokinetic studies should be planned at the early stages of antidote development. Special attention should also be given to improving oxime distribution throughout the organism to overcome this major constraint in improving overall OP therapy.Iako su organofosforni živčani bojni otrovi potpuno zabranjeni za upotrebu, njihova je prisutnost i dalje velik problem, posebice kao kemijsko oružje u terorističkim napadima (poput nedavnih u Siriji). Oksimi koji se danas koriste kao protuotrovi u tretmanu nemaju dostatno djelovanje na reaktivaciju aktivnosti kolinesteraza, glavnih meta djelovanja organofosfornih spojeva. Valja napomenuti kako se klinička testiranja ovih protuotrova rijetko provode zbog svoje iznimne specifičnosti. Tijekom zadnjih desetljeća učinjen je napredak u istraživanju novih učinkovitijih protuotrova, međutim još je uvijek veliki nedostatak u poboljšavanju terapije translacija in vitro dobivenih rezultata u in vivo primjenu. Ovom studijom ispitali smo mogućnosti ekstrapolacije reaktivacijske učinkovitosti određene za oksimske protuotrove iz in vitro u in vivo sustav. Naši rezultati pokazuju kako je ova translacija moguća uz detaljno određene kinetičke parametre in vitro i uz poznavanje distribucije oksima i vremena cirkulacije u organizmu. Takav rezultat ističe važnost planiranja i farmakokinetičkih istraživanja već u samom početku razvoja protuotrova. Također, poseban naglasak u istraživanju trebalo bi staviti i na poboljšanje tkivo-specifične distribucije oksima u organizmu čime bi se poboljšala cjelokupna terapijska učinkovitost