The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CHNOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by tert-butyl groups: CH=NOtBu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH2OCH2 → CH2CH2CH2) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD50 values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only in vivo. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes * chemical synthesis chemistry pharmacology therapeutic use MeSH
- Atropine therapeutic use pharmacology MeSH
- Cholinesterase Inhibitors toxicity MeSH
- Mice MeSH
- Nerve Agents * toxicity MeSH
- Organophosphorus Compounds * toxicity MeSH
- Oximes chemistry MeSH
- Pyridinium Compounds * chemical synthesis chemistry therapeutic use pharmacology MeSH
- Soman toxicity MeSH
- Trimedoxime chemistry chemical synthesis pharmacology therapeutic use MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Sdělení z praxe pojednává o případu těžké methemoglobinemie u kojence způsobeném alimentární otravou dusičnany, jejichž zdrojem byla červená řepa uvařená ve vodě z domácí studny. Klinicky se manifestovala těžkou poruchou vědomí s potřebou umělé plicní ventilace, tachykardií, šedomodrým zbarvením kůže a tmavě modrou barvou sliznic. Laboratorním nálezem byla metabolická acidóza s vysokým laktátem, normální vypočtená saturace kyslíkem při nízké saturaci kyslíkem měřenou pulzním oxymetrem. Diagnóza byla definitivně potvrzena stanovením frakce methemoglobinu, která činila 67 %. Podání antidota (methylenová modř) vedlo k promptnímu zlepšení stavu s rychlou normalizací frakce methemoglobinu.
We present a case report of severe methemoglobinemia in infant caused by poisoning of nitrates from the beetroot cooked in water from private well. It was manifestated by unconsciousness, tachycardia, grey-bluish discoloration of the skin and mucous membranes. The arteficial ventilation was needed. There was metabolic lactate acidosis, normal counted oxygen saturation in blood gases analysis, but low measured oxygen saturation by pulse oxymeter. Diagnosis of methemoglobinemia was clear after confirmation of hight level of methemoglobin in blood (67 %). The child was treated by methylen blue, which had very prompt effect on clinical condition, the level of methemoglobin gradually normalized. We still have to think of the possibility of rare, but easily development of nitrate food poisoning from water and food served to infants.
- MeSH
- Antidotes pharmacology therapeutic use MeSH
- Beta vulgaris adverse effects MeSH
- Cucurbita adverse effects MeSH
- Nitrates * poisoning MeSH
- Nitrites poisoning MeSH
- Infant MeSH
- Humans MeSH
- Methemoglobinemia * diagnosis etiology therapy MeSH
- Methylene Blue pharmacology therapeutic use MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Antidotes classification therapeutic use MeSH
- Benzodiazepines poisoning MeSH
- Alcoholic Intoxication diagnosis drug therapy classification MeSH
- Mushroom Poisoning diagnosis drug therapy classification MeSH
- Poisoning * diagnosis etiology drug therapy classification nursing MeSH
- Acetaminophen poisoning MeSH
- Snake Bites drug therapy classification MeSH
- Publication type
- Review MeSH
The castor plant (Ricinus communis) is primarily known for its seeds, which contain a unique fatty acid called ricinoleic acid with several industrial and commercial applications. Castor seeds also contain ricin, a toxin considered a chemical and biological warfare agent. Despite years of investigation, there is still no effective antidote or vaccine available. However, some progress has been made, and the development of an effective treatment may be on the horizon. To provide an updated overview of this issue, we have conducted a comprehensive review of the literature on the current state of research in the fight against ricin. This review is based on the reported research and aims to address the challenges faced by researchers, as well as highlight the most successful cases achieved thus far. Our goal is to encourage the scientific community to continue their efforts in this critical search.
- MeSH
- Antidotes * chemistry pharmacology MeSH
- Chemical Warfare Agents chemistry MeSH
- Humans MeSH
- Ricin * antagonists & inhibitors chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
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
- Acetylcholinesterase metabolism MeSH
- Antidotes chemistry pharmacology MeSH
- Butyrylcholinesterase * metabolism chemistry MeSH
- Cholinesterase Inhibitors chemistry pharmacology MeSH
- Kinetics MeSH
- Humans MeSH
- Organophosphorus Compounds chemistry MeSH
- Organophosphate Poisoning * drug therapy MeSH
- Oximes * chemistry pharmacology MeSH
- Cholinesterase Reactivators * chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 μM and HssBChE IC50 = 0.036 ± 0.002 μM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.
- MeSH
- Acetylcholinesterase MeSH
- Antidotes pharmacology MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors toxicity MeSH
- Phosphorus MeSH
- Rats MeSH
- Oxygen MeSH
- Humans MeSH
- Oximes pharmacology MeSH
- Pralidoxime Compounds * MeSH
- Pyridinium Compounds pharmacology MeSH
- Cholinesterase Reactivators * pharmacology MeSH
- Taurine analogs & derivatives MeSH
- Trimedoxime pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Oxime reactivators of acetylcholinesterase (AChE) are used as causal antidotes for intended and unintended poisoning by organophosphate nerve agents and pesticides. Despite all efforts to develop new AChE reactivators, none of these drug candidates replaced conventional clinically used oximes. In addition to the therapeutic efficacy, determining the safety profile is crucial in preclinical drug evaluation. The exact mechanism of oxime toxicity and the structure-toxicity relationship are subjects of ongoing research, with oxidative stress proposed as a possible mechanism. In the present study, we investigated four promising bispyridinium oxime AChE reactivators, K048, K074, K075, and K203, and their ability to induce oxidative stress in vitro. Cultured human hepatoma cells were exposed to oximes at concentrations corresponding to their IC50 values determined by the MTT assay after 24 h. Their potency to generate reactive oxygen species, interfere with the thiol antioxidant system, and induce lipid peroxidation was evaluated at 1, 4, and 24 h of exposure. Reactivators without a double bond in the four-carbon linker, K048 and K074, showed a greater potential to induce oxidative stress compared with K075 and K203, which contain a double bond. Unlike oximes with a three-carbon-long linker, the number of aldoxime groups attached to the pyridinium moieties does not determine the oxidative stress induction for K048, K074, K075, and K203 oximes. In conclusion, our results emphasize that the structure of oximes plays a critical role in inducing oxidative stress, and this relationship does not correlate with their cytotoxicity expressed as the IC50 value. However, it is important to note that oxidative stress cannot be disregarded as a potential contributor to the side effects associated with oximes.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes pharmacology MeSH
- Hep G2 Cells MeSH
- Cholinesterase Inhibitors toxicity MeSH
- Humans MeSH
- Organophosphates toxicity MeSH
- Oxidative Stress MeSH
- Oximes pharmacology chemistry MeSH
- Pyridinium Compounds pharmacology chemistry MeSH
- Cholinesterase Reactivators * pharmacology chemistry MeSH
- Carbon MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Idarucizumab, fragment monoklonální protilátky schopný vázat molekuly dabigatranu v ekvimolárním množství, je specifickým antidotem pro dabigatran. Dávka idarucizumabu byla odhadnuta na základě pozorovaných plazmatických koncentrací dabigatranu tak, aby vedla k okamžitému, úplnému a trvalému zvrácení antikoagulačního účinku dabigatranu. Aktuálně je doporučeno jednorázové podání 5 g intravenózně. Za určitých situací ale může dojít k vyčerpání kapacity idarucizumabu a k opětovnému nárůstu plazmatických koncentrací dabigatranu v řádu několika hodin po iniciálním podání. Jednu z takových situací ilustrujeme případem pacientky s akutním renálním selháním, kdy ani navzdory podání druhé dávky idarucizumabu nedošlo k trvalé reverzi účinku dabigatranu. Dostupnost specifického antidota je nespornou výhodou dabigatranu oproti ostatním přímým antikoagulanciím. Jeho použití je s ohledem na limitace jeho účinnosti třeba kriticky zhodnotit. A to především u pacientů s akutním renálním selháním či s velmi vysokými plazmatickými koncentracemi dabigatranu.
Idarucizumab, a monoclonal antibody fragment capable of binding dabigatran molecules in a 1 : 1 stoichiometric relationship, is a specific antidote for dabigatran. The dose of idarucizumab was estimated based on observed plasma concentrations of dabigatran to achieve immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran. Currently, a single dose of 5 g intravenously is recommended. However, in certain situations, the capacity of idarucizumab may be exhausted, and dabigatran plasma concentrations may rise again within hours of initial administration. We illustrate one such situation with a patient with acute renal failure, where despite the administration of the second dose of idarucizumab, there was no sustained reversal of the effect of dabigatran. The availability of a specific antidote is an indisputable advantage of dabigatran over other direct anticoagulants. Its use needs to be critically evaluated in view of the limitations of its efficacy. This is especially true in patients with acute renal failure or very high plasma concentrations of dabigatran.
- MeSH
- Acute Kidney Injury * MeSH
- Antidotes * pharmacology therapeutic use MeSH
- Dabigatran * pharmacology MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Humans MeSH
- Aged, 80 and over MeSH
- Check Tag
- Humans MeSH
- Aged, 80 and over MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Organophosphorus compounds (OP) make up an important class of inhibitors, mostly employed as pesticides, even as chemical weapons. These toxic substances act through the inhibition of the acetylcholinesterase (AChE) enzyme, which results in elevated synaptic acetylcholine (ACh) levels, leading to serious adverse effects under the cholinergic syndrome. Many reactivators have been developed to combat the toxic effects of these AChE inhibitors. In this line, the oximes highlight because of their good reactivating power of cholinesterase enzymes. To date, no universal antidotes can reactivate AChE inhibited by any OP agent. This review summarizes the intoxication process by neurotoxic OP agents, along with the development of reactivators capable of reversing their effects, approaching aspects like the therapeutic and toxicological profile of these antidotes. Computational methods and conscious in vitro studies, capable of significantly predicting the toxicological profile of these drug candidates, might support the process of development of these reactivators before entering in vivo studies in animals, and then clinical trials. These approaches can assist in the design of safer and more effective molecules, reducing related cost and time for the process.
- MeSH
- Acetylcholinesterase chemistry MeSH
- Antidotes * pharmacology therapeutic use chemistry MeSH
- Cholinesterase Inhibitors toxicity MeSH
- Organophosphorus Compounds MeSH
- Oximes therapeutic use toxicity MeSH
- Cholinesterase Reactivators * therapeutic use toxicity MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Idarucizumab, fragment monoklonální protilátky schopný vázat molekuly dabigatranu v ekvimolárním množství, je specifickým antidotem pro dabigatran. Dávka idarucizumabu byla odhadnuta na základě pozorovaných plazmatických koncentrací dabigatranu tak, aby vedla k okamžitému, úplnému a trvalému zvrácení antikoagulačního účinku dabigatranu. Aktuálně je doporučeno jednorázové podání 5 g intravenózně. Za určitých situací ale může dojít k vyčerpání kapacity idarucizumabu a k opětovnému nárůstu plazmatických koncentrací dabigatranu v řádu několika hodin po iniciálním podání. Jednu z takových situací ilustrujeme případem pacientky s akutním renálním selháním, kdy ani navzdory podání druhé dávky idarucizumabu nedošlo k trvalé reverzi účinku dabigatranu.
Idarucizumab, a monoclonal antibody fragment capable of binding dabigatran molecules in a 1 : 1 stoichiometric relationship, is a specific antidote for dabigatran. The dose of idarucizumab was estimated based on observed plasma concentrations of dabigatran to achieve immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran. Currently, a single dose of 5 g intravenously is recommended. However, in certain situations, the capacity of idarucizumab may be exhausted, and dabigatran plasma concentrations may rise again within hours of initial administration. We illustrate one such situation with a patient with acute renal failure, where despite the administration of the second dose of idarucizumab, there was no sustained reversal of the effect of dabigatran. The availability of a specific antidote is an indisputable advantage of dabigatran over other direct anticoagulants. Its use needs to be critically evaluated in view of the limitations of its efficacy. This is especially true in patients with acute renal failure or very high plasma concentrations of dabigatran.
- MeSH
- Acute Kidney Injury MeSH
- Antidotes * pharmacology therapeutic use MeSH
- Dabigatran * pharmacology MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Humans MeSH
- Aged, 80 and over MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Aged, 80 and over MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
