The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota chemie   farmakologie   MeSH
• butyrylcholinesterasa * metabolismus   chemie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• organofosforové sloučeniny chemie   MeSH
• otrava organofosfáty * farmakoterapie   MeSH
• oximy * chemie   farmakologie   MeSH
• reaktivátory cholinesterasy * chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABAAR by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• lidé MeSH
• neurotoxické syndromy * etiologie   prevence a kontrola   MeSH
• neurozánětlivé nemoci MeSH
• organofosfáty MeSH
• otrava organofosfáty * farmakoterapie   prevence a kontrola   MeSH
• reaktivní formy kyslíku MeSH
• záchvaty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• dítě MeSH
• dřevěné a živočišné uhlí aplikace a dávkování   MeSH
• insekticidy otrava   MeSH
• kyseliny otrava   MeSH
• lidé MeSH
• louh otrava   MeSH
• mykotoxikóza klasifikace   terapie   MeSH
• nežádoucí účinky léčiv prevence a kontrola   terapie   MeSH
• otrava organofosfáty terapie   MeSH
• otrava rostlinami klasifikace   prevence a kontrola   terapie   MeSH
• otrava * epidemiologie   etiologie   klasifikace   prevence a kontrola   terapie   MeSH
• toxické účinky MeSH
• výrobky pro domácnost otrava   MeSH
• zneužívání léčiv prevence a kontrola   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

The problem of the efficient treatment of acute organophosphorus (OP) poisoning needs more efforts in the development of a versatile antidote, applicable for treatment of the injuries of both peripheral and central nervous systems. A series of N-H, N-methyl, N-butyl, and N-phenyl derivatives of benzhydroxamic (1a-1d), 3-methoxybenzhydroxamic (2a-2d), 4-methoxybenzhydroxamic (3a-3d) acids, and corresponding salycilhydroxamates (4a-4d) was prepared. Their predicted hydrophobicity (log P) was evaluated as regards to ВВВ score by the open access cheminformatics tools; prediction of the passive transport across the BBB was found by means on the parallel artificial membrane permeability assay (PAMPA). The data on reactivation capacity of human acetylcholinesterase (HssAChE) inhibited by GB, VX, and paraoxon was supported by molecular docking study on binding to the active site of the AChE, viability study against mammalian cells (Chinese hamster ovary CHO-K1), and biodegradability (Closed Bottle test OECD 301D). Among the studied compounds, N-butyl derivatives have better balanced combination of properties; among them, N-butylsalicylhydroxamic acid is most promising. The studied compounds demonstrate modest reactivation capacity; change of N-H by N-Me ensures the reactivation capacity in studied concentrations on all studied OP substrates; among N-butyl derivatives, the N-butylsalicylhydroxamic acid demonstrates most promising results within the series. The found regularities may lead to selection of perspective structures to complement current formulations for medical countermeasures against poisoning by organophosphorus toxicants.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• CHO buňky MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• Cricetulus MeSH
• křečci praví MeSH
• lidé MeSH
• otrava organofosfáty * MeSH
• oximy chemie   MeSH
• reaktivátory cholinesterasy * chemie   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

High lethality, fast action, and simple synthesis make nerve agents (NAs) the most dreaded chemical weapons (CWs) of mass destruction in the world. Disturbances of the autonomic nervous system and neuromuscular junction (NMJ) by NAs and organophosphorus (OP) insecticides lead to cholinergic crisis and skeletal muscle paralysis. Current medical intervention has remained mostly unchanged since their first discovery in the 1950s. Within this overview, we have followed their development, clinical successes, and failures and discuss the major demerits of available antidotes. In current times, with precision medicine becoming increasingly relevant in various fields of medicine, the antidotal approach should be broadened to better cope with individual cases of NA intoxication. When possible, countermeasures could be targeted directly to achieve a better patient prognosis. As the threat of NA misuse and accidental cases of OP insecticide intoxication are still omnipresent, advancement of intervention expertise and further research in this field should be supported.

• MeSH
• antidota terapeutické užití   MeSH
• lidé MeSH
• otrava organofosfáty * farmakoterapie   MeSH
• oximy MeSH
• reaktivátory cholinesterasy * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Otrava organofosfáty (OP) tedy inaktivace acetylcholinesterasy (AChE) v nervových zakončeních a svalech, je toxický mechanismus společný pro nervově paralytické látky (NPL) a pesticidy. Standardní protiopatření proti otravě OP zahrnuje inhibici muskarinových receptorů a využití reaktivátoru AChE ( oximu). Použití posledně jmenovaného je však limitováno (ne)univerzálností reaktivátorů vůči různým OP a jejich nízká penetrace do mozku. Cílem tohoto projektu je vývoj oximů s lepší penetrací přes hematoencefalickou bariéru, (HEB). Konkrétně se jedná o monokvarterní oximy s vyváženými fyz.-chem vlastnostmi obsahující vytipovaný nuklofil zajišťující reaktivaci a ligand periferního anionického místa zajišťující vazbu na enzym. Budou připraveny unikátních monokvarterní reaktivátory, u kterých lze očekávat výrazně lepší permeaci přes HEB v porovnání s běžně používanými biskvarterními reaktivátory. Kombinací in vitro a in vivo technik zajistíme hodnocení účinnosti, popíšeme vlastnosti nových oximů a; Inactivation of acetylcholinestarse (AChE) in nerve and muscle by organophosphates is the toxic mechanism common to both nerve agents and pesticides. Standard countermeasures against OP poisoning involves muscarinic inhibition and the use of oxime a reactivator. The latter, however, is limited by a versatility ox oximes and by the low penetration of reactivators into the brain. The aim of this project is to develop oxime reactivators with better penetration of the blood brain barrier (BBB). Namely, monoquaternary oximes with balanced physico-chemical properties containing selected nuclophile capable of AChE reactivation and a ligand of peripherial anionic site ensuring the binding to the enzyme. Unique reactivators will be prepared and by application of series of in vitro and in vivo tests compounds will be evaluated and described. The best candidate of the preclinical development and with practical potential will be indentified

• MeSH
• antidota chemická syntéza   terapeutické užití   MeSH
• enzymové reaktivátory terapeutické užití   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• intravitální mikroskopie MeSH
• lidé MeSH
• otrava organofosfáty farmakoterapie   MeSH
• oximy terapeutické užití   MeSH
• techniky in vitro MeSH
• vyvíjení léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• hodnotící studie MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• veřejné zdravotnictví
• toxikologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic study.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory aplikace a dávkování   toxicita   MeSH
• enzymatické testy MeSH
• hematoencefalická bariéra metabolismus   MeSH
• hmotnostní spektrometrie MeSH
• hydrofobní a hydrofilní interakce MeSH
• imidazoly chemie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• otrava organofosfáty farmakoterapie   MeSH
• oximy aplikace a dávkování   farmakokinetika   MeSH
• plocha pod křivkou MeSH
• přemostěné cyklické sloučeniny chemie   MeSH
• pyridinové sloučeniny aplikace a dávkování   farmakokinetika   MeSH
• reaktivátory cholinesterasy aplikace a dávkování   farmakokinetika   MeSH
• sarin aplikace a dávkování   toxicita   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD50 values of nerve agents over 24 h following poisoning without or with a single administration of antidotal treatment. In this study, LD50 values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated poisoning were evaluated in mice for two experimental end points - 6 h and 24 h. While the efficacy of atropine or oxime-based antidotal treatment was the same regardless of the experimental end point, the therapeutic efficacy of all three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) was mostly slightly higher at the 6 h end point compared to the 24 h end point, although the therapeutic efficacy of MB compounds was not superior to oxime-based antidotal treatment. These results contrast with a study in guinea-pigs using a structurally-related compound, MB327, which showed a striking increase in protection at 6 h compared to 24 h. It is suggested that the disparity may be due to pharmacokinetic differences between the two animal species.

• MeSH
• antidota farmakologie   MeSH
• časové faktory MeSH
• chemické bojové látky toxicita   MeSH
• LD50 MeSH
• myši MeSH
• nikotinoví antagonisté farmakologie   MeSH
• organofosfáty toxicita   MeSH
• organofosforové sloučeniny toxicita   MeSH
• otrava organofosfáty farmakoterapie   etiologie   MeSH
• oximy farmakologie   MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• sarin toxicita   MeSH
• soman toxicita   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

BACKGROUND: Oximes are used in addition to atropine to treat organophosphate poisoning. However, the efficiency of oximes is still a matter of debate. In vitro experiments suggested than new oximes are more potent than the commercial oximes. However, the antidotal activity of new oximes has not been assessed in vivo. METHODS: The aim of this work was to assess the safety and efficiency of new oximes compared to pralidoxime in a rat model of diethyl paraoxon-induced non-lethal respiratory toxicity. RESULTS: Safety study of oximes showed no adverse effects on ventilation in rats. KO-33, KO-48, KO-74 oximes did not exhibit significant antidotal effect in vivo. In contrast, KO-27 and BI-6 showed evidence of antidotal activity by normalization of respiratory frequency and respiratory times. KO-27 became inefficient only during the last 30 min of the study. In contrast, pralidoxime demonstrated to be inefficient at 30 min post injection. Inversely, the antidotal activity of BI-6 occurred lately, within the last 90 min post injection. CONCLUSION: This study showed respiratory safety of new oximes. Regarding, the efficiency, KO-27 revealed to be a rapid acting antidote toward diethylparaoxon-induced respiratory toxicity, meanwhile BI-6 was a late-acting antidote. Simultaneous administration of these two oximes might result in a complete and prolonged antidotal efficiency.

• MeSH
• antidota farmakologie   MeSH
• bezpečnost MeSH
• cholinesterasové inhibitory toxicita   MeSH
• dýchání účinky léků   MeSH
• krysa rodu rattus MeSH
• otrava organofosfáty farmakoterapie   etiologie   MeSH
• oximy farmakologie   MeSH
• paraoxon toxicita   MeSH
• potkani Sprague-Dawley MeSH
• větrání metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• acetylcholinesterasa MeSH
• antidota farmakologie   terapeutické užití   MeSH
• nervová bojová látka otrava   MeSH
• obidoxim chlorid MeSH
• organofosfáty toxicita   MeSH
• otrava organofosfáty farmakoterapie   MeSH
• oximy terapeutické užití   MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• simulace molekulového dockingu MeSH
• trimedoxim MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH