RESUMO
RATIONALE: Anesthetics are widely used for optimizing surgical conditions, postoperative pain management, and treating various chronic pain conditions. Tetracaine and decamethonium are representative drugs of local anesthetics and neuromuscular blocking agents, respectively. However, overdose and toxicity of the drugs always lead to serious adverse events. Thus, there is a strong demand for effective antidotes. METHODS: The binding interactions of amide naphthotubes with tetracaine and decamethonium were systematically studied using 1H NMR, ITC, and DFT calculations. The antidotal effects of amide naphthotube to tetracaine toxicity were assessed in vitro and in vivo, and the mechanism of detoxification was explored at a cellular level. Additionally, mouse models were established to evaluate the reversal activities of amide naphthotube on decamethonium-induced mortality and muscle relaxation, and the reversal mechanism was investigated through pharmacokinetic experiments. RESULTS: We have demonstrated that the anti-isomer of amide naphthotube exhibits significant binding affinities towards tetracaine (K a = 1.89×107 M-1) and decamethonium (K a = 1.01×107 M-1) in water. The host displayed good biocompatibility both in vitro and in vivo. The administration of amide naphthotube following tetracaine overdose in mouse models notably increased the overall survival rate, indicating its effective antidotal properties. The host could reverse the tetracaine-induced Na+ channels blockage at the cellular level. Moreover, the injection of amide naphthotube also reversed the mortality and paralysis induced by decamethonium in mouse models following a pharmacokinetic mechanism. CONCLUSION: An emerging artificial receptor, amide naphthotube, has strong binding affinities towards tetracaine and decamethonium. It functions as a supramolecular antidote for tetracaine poisoning and a reversal agent for decamethonium by selectively sequestering these compounds in vivo.
Assuntos
Antídotos , Tetracaína , Animais , Tetracaína/farmacologia , Tetracaína/química , Camundongos , Antídotos/farmacologia , Antídotos/química , Amidas/química , Amidas/farmacologia , Masculino , Anestésicos Locais/farmacologia , Anestésicos Locais/química , Humanos , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/farmacologiaRESUMO
ABSTRACT: The effects of the calcium sensitizer levosimendan on hemodynamics and survival in guinea pigs intoxicated with the calcium blockers verapamil or diltiazem were evaluated in a randomized controlled study. One hundred four animals were randomized to be intoxicated with either verapamil (2.0 mg/kg) or diltiazem (4.5 mg/kg) and thereafter further randomized into 6 groups which received either saline (control), 3 different regimes of levosimendan, calcium chloride, and levosimendan combined with calcium chloride. The hemodynamics and survival of the animals were followed for 60 minutes after intoxication.The negative inotropic effect of calcium blockers was seen as a decrease by over 70% of the positive derivative of the left ventricular pressure. This was reversed by levosimendan. Moreover, both verapamil and diltiazem-induced marked hypotension (-69% and -63% of the baseline value, respectively) which was also reversed by levosimendan. The combined levosimendan and calcium chloride treatment had a synergistic effect in reversing verapamil or diltiazem-induced deterioration in hemodynamics.Both verapamil and diltiazem intoxications decreased the survival rate of guinea pigs to 13%. Levosimendan addition improved survival dose-dependently up to a survival rate of 75% and 88% in the verapamil and diltiazem groups, respectively. Low dose of levosimendan combined with calcium chloride improved survival in verapamil and diltiazem group to 88% and 100%, respectively.In conclusion, the administration of levosimendan improved hemodynamics and survival in calcium channel blocker intoxicated guinea pigs. The synergistic effect of levosimendan and calcium chloride suggests that this combination could be an effective antidote in calcium channel blocker intoxications.
Assuntos
Antídotos , Bloqueadores dos Canais de Cálcio , Diltiazem , Hidrazonas , Piridazinas , Simendana , Verapamil , Animais , Simendana/farmacologia , Cobaias , Bloqueadores dos Canais de Cálcio/farmacologia , Hidrazonas/farmacologia , Piridazinas/farmacologia , Diltiazem/farmacologia , Verapamil/farmacologia , Antídotos/farmacologia , Masculino , Hemodinâmica/efeitos dos fármacos , Cloreto de Cálcio , Cardiotônicos/farmacologia , Sinergismo Farmacológico , Modelos Animais de Doenças , Quimioterapia Combinada , Taxa de SobrevidaAssuntos
Analgésicos Opioides , Humanos , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/farmacologia , Antídotos/farmacologia , Antídotos/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/prevenção & controleRESUMO
Aluminum phosphide (AlP) is the main component of rice tablets (a pesticide), which produces phosphine gas (PH3) when exposed to stomach acid. The most important symptoms of PH3 toxicity include, lethargy, tachycardia, hypotension, and cardiac shock. It was shown that Iodine can chemically react with PH3, and the purpose of this study is to investigate the protective effects of Lugol solution in poisoning with rice tablets. Five doses (12, 15, 21, 23, and 25 mg/kg) of AlP were selected, for calculating its lethal dose (LD50). Then, the rats were divided into 4 groups: AlP, Lugol, AlP + Lugol, and Almond oil (as a control). After 4 h, the blood pressure and electrocardiogram (ECG) were recorded, and blood samples were obtained for biochemical tests, then liver, lung, kidney, heart, and brain tissues were removed for histopathological examination. The results of the blood pressure showed no significant changes (P > 0.05). In ECG, the PR interval showed a significant decrease in the AlP + Lugol group (P < 0.05). In biochemical tests, LDH, Ca2+, Creatinine, ALP, Mg2+, and K+ represented significant decreases in AlP + Lugol compared to the AlP group (P < 0.05). Also, the administration of Lugol's solution to AlP-poisoned rats resulted in a significant decrease in malondialdehyde levels and a significant increase in catalase activity (P < 0.05). Histopathological evaluation indicates that Lugol improves changes in the lungs, kidneys, brain, and heart. Our results showed that the Lugol solution could reduce tissue damage and oxidative stress in AlP-poisoned rats. We assume that the positive effects of Lugol on pulmonary and cardiac tissues are due to its ability to react directly with PH3.
Assuntos
Compostos de Alumínio , Fosfinas , Ratos Wistar , Animais , Fosfinas/toxicidade , Compostos de Alumínio/toxicidade , Masculino , Estresse Oxidativo/efeitos dos fármacos , Biomarcadores/sangue , Modelos Animais de Doenças , Pressão Sanguínea/efeitos dos fármacos , Antídotos/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Eletrocardiografia , Intoxicação/prevenção & controle , Antioxidantes/farmacologia , Praguicidas/toxicidade , Comprimidos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Ratos , Dose Letal Mediana , Miocárdio/patologia , Miocárdio/metabolismo , IodetosRESUMO
The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.
Assuntos
Acetilcolinesterase , Substâncias para a Guerra Química , Inibidores da Colinesterase , Reativadores da Colinesterase , Agentes Neurotóxicos , Oximas , Compostos de Piridínio , Oximas/farmacologia , Acetilcolinesterase/metabolismo , Reativadores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Compostos de Piridínio/farmacologia , Substâncias para a Guerra Química/toxicidade , Agentes Neurotóxicos/toxicidade , Compostos de Pralidoxima/farmacologia , Compostos Organotiofosforados/toxicidade , Animais , Antídotos/farmacologiaRESUMO
Snakebites affect about 1.8 million people annually. The current standard of care involves antibody-based antivenoms, which can be difficult to access and are generally not effective against local tissue injury, the primary cause of morbidity. Here, we used a pooled whole-genome CRISPR knockout screen to define human genes that, when targeted, modify cell responses to spitting cobra venoms. A large portion of modifying genes that conferred resistance to venom cytotoxicity was found to control proteoglycan biosynthesis, including EXT1, B4GALT7, EXT2, EXTL3, XYLT2, NDST1, and SLC35B2, which we validated independently. This finding suggested heparinoids as possible inhibitors. Heparinoids prevented venom cytotoxicity through binding to three-finger cytotoxins, and the US Food and Drug Administration-approved heparinoid tinzaparin was found to reduce tissue damage in mice when given via a medically relevant route and dose. Overall, our systematic molecular dissection of cobra venom cytotoxicity provides insight into how we can better treat cobra snakebite envenoming.
Assuntos
Venenos Elapídicos , Mordeduras de Serpentes , Animais , Humanos , Mordeduras de Serpentes/tratamento farmacológico , Camundongos , Antídotos/farmacologiaRESUMO
Nerve agents are a class of lethal neurotoxic chemicals used in chemical warfare. In this review, we have discussed a brief history of chemical warfare, followed by an exploration of the historical context surrounding nerve agents. The article explores the classification of these agents, their contemporary uses, their toxicity mechanisms, and the disadvantages of the current treatment options for nerve agent poisoning. It then discusses the possible application of enzymes as prophylactics against nerve agent poisoning, outlining the benefits and drawbacks of paraoxonase- 1. Finally, the current studies on paraoxonase-1 are reviewed, highlighting that several challenges need to be addressed in the use of paraoxonase-1 in the actual field and that its potential as a prophylactic antidote against nerve agent poisoning needs to be evaluated. The literature used in this manuscript was searched using various electronic databases, such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent, and books using the keywords chemical warfare agent, butyrylcholinesterase, enzyme, nerve agent, prophylactic, and paraoxonase-1, with the time scale for the analysis of articles between 1960 to 2023. The study has suggested that concerted efforts by researchers and agencies must be made to develop effective countermeasures against NA poisoning and that paraoxonase-1 has suitable properties for the development of efficient prophylaxis against NA poisoning.
Assuntos
Arildialquilfosfatase , Substâncias para a Guerra Química , Agentes Neurotóxicos , Arildialquilfosfatase/metabolismo , Arildialquilfosfatase/uso terapêutico , Humanos , Substâncias para a Guerra Química/intoxicação , Substâncias para a Guerra Química/toxicidade , Agentes Neurotóxicos/intoxicação , Agentes Neurotóxicos/toxicidade , Animais , Antídotos/uso terapêutico , Antídotos/farmacologiaRESUMO
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood-brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10-30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.
Assuntos
Acetilcolinesterase , Butirilcolinesterase , Humanos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Ligantes , Oximas/química , Oximas/farmacologia , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Colestenonas/farmacologia , Colestenonas/química , Cinética , Sarina/química , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/antagonistas & inibidores , Antídotos/farmacologia , Antídotos/química , Colesterol/metabolismo , Colesterol/química , Compostos OrganofosforadosRESUMO
Numerous toxins threaten humans, but specific antidotes are unavailable for most of them. Although CRISPR screening has aided the discovery of the mechanisms of some toxins, developing targeted antidotes remains a significant challenge. Recently, we established a systematic framework to develop antidotes by combining the identification of novel drug targets by using a genome-wide CRISPR screen with a virtual screen of drugs approved by the US Food and Drug Administration. This approach allows for a comprehensive understanding of toxin mechanisms at the whole-genome level and facilitates the identification of promising antidote drugs targeting specific molecules. Here, we present step-by-step instructions for executing genome-scale CRISPR-Cas9 knockout screens of toxins in HAP1 cells. We also provide detailed guidance for conducting an in silico drug screen and an in vivo drug validation. By using this protocol, it takes ~4 weeks to perform the genome-scale screen, 4 weeks for sequencing and data analysis, 4 weeks to validate candidate genes, 1 week for the virtual screen and 2 weeks for in vitro drug validation. This framework has the potential to accelerate the development of antidotes for a wide range of toxins and can rapidly identify promising drug candidates that are already known to be safe and effective. This could lead to the development of new antidotes much more quickly than traditional methods, protecting lives from diverse toxins and advancing human health.
Assuntos
Antídotos , Sistemas CRISPR-Cas , Simulação por Computador , Antídotos/farmacologia , Humanos , Avaliação Pré-Clínica de Medicamentos/métodos , AnimaisRESUMO
Thrombosis leads to elevated mortality rates and substantial medical expenses worldwide. Human factor IXa (HFIXa) protease is pivotal in tissue factor (TF)-mediated thrombin generation, and represents a promising target for anticoagulant therapy. We herein isolated novel DNA aptamers that specifically bind to HFIXa through systematic evolution of ligands by exponential enrichment (SELEX) method. We identified two distinct aptamers, seq 5 and seq 11, which demonstrated high binding affinity to HFIXa (Kd = 74.07 ± 2.53 nM, and 4.93 ± 0.15 nM, respectively). Computer software was used for conformational simulation and kinetic analysis of DNA aptamers and HFIXa binding. These aptamers dose-dependently prolonged activated partial thromboplastin time (aPTT) in plasma. We further rationally optimized the aptamers by truncation and site-directed mutation, and generated the truncated forms (Seq 5-1t, Seq 11-1t) and truncated-mutated forms (Seq 5-2tm, Seq 11-2tm). They also showed good anticoagulant effects. The rationally and structurally designed antidotes (seq 5-2b and seq 11-2b) were competitively bound to the DNA aptamers and effectively reversed the anticoagulant effect. This strategy provides DNA aptamer drug-antidote pair with effective anticoagulation and rapid reversal, developing advanced therapies by safe, regulatable aptamer drug-antidote pair.
Assuntos
Antídotos , Aptâmeros de Nucleotídeos , Fator IXa , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Humanos , Fator IXa/antagonistas & inibidores , Fator IXa/metabolismo , Antídotos/farmacologia , Antídotos/química , Antídotos/síntese química , Relação Dose-Resposta a Droga , Anticoagulantes/farmacologia , Anticoagulantes/química , Relação Estrutura-Atividade , Estrutura Molecular , Técnica de Seleção de AptâmerosRESUMO
Rising global population and increased food demands have resulted in the increased use of organophosphate pesticides (OPs), leading to toxin accumulation and transmission to humans. Pralidoxime (2-PAM), an FDA-approved drug, serves as an antidote for OP therapy. However, the atomic-level detoxification mechanisms regarding the design of novel antidotes remain unclear. This is the first study to examine the binding and unbinding pathways of 2-PAM to human acetylcholinesterase (HuAChE) through three identified doors using an enhanced sampling method called ligand-binding parallel cascade selection molecular dynamics (LB-PaCS-MD). Remarkably, LB-PaCS-MD could identify a predominant in-line binding mechanism through the acyl door at 63.79% ± 6.83%, also implicating it in a potential unbinding route (90.14% ± 4.22%). Interestingly, crucial conformational shifts in key residues, W86, Y341, and Y449, and the Ω loop significantly affect door dynamics and ligand binding modes. The LB-PaCS-MD technique can study ligand-binding pathways, thereby contributing to the design of antidotes and covalent drugs.
Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Simulação de Dinâmica Molecular , Humanos , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Antídotos/química , Antídotos/farmacologia , Antídotos/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ligantes , Compostos de Pralidoxima/química , Compostos de Pralidoxima/metabolismo , Compostos de Pralidoxima/farmacologia , Ligação ProteicaRESUMO
Injectable anticoagulants are widely used in medical procedures to prevent unwanted blood clotting. However, many lack safe, effective reversal agents. Here, we present new data on a previously described RNA origami-based, direct thrombin inhibitor (HEX01). We describe a new, fast-acting, specific, single-molecule reversal agent (antidote) and present in vivo data for the first time, including efficacy, reversibility, preliminary safety, and initial biodistribution studies. HEX01 contains multiple thrombin-binding aptamers appended on an RNA origami. It exhibits excellent anticoagulation activity in vitro and in vivo. The new single-molecule, DNA antidote (HEX02) reverses anticoagulation activity of HEX01 in human plasma within 30 s in vitro and functions effectively in a murine liver laceration model. Biodistribution studies of HEX01 in whole mice using ex vivo imaging show accumulation mainly in the liver over 24 h and with 10-fold lower concentrations in the kidneys. Additionally, we show that the HEX01/HEX02 system is non-cytotoxic to epithelial cell lines and non-hemolytic in vitro. Furthermore, we found no serum cytokine response to HEX01/HEX02 in a murine model. HEX01 and HEX02 represent a safe and effective coagulation control system with a fast-acting, specific reversal agent showing promise for potential drug development.
Assuntos
Aptâmeros de Nucleotídeos , Trombina , Animais , Camundongos , Humanos , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/química , Trombina/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Distribuição Tecidual , RNA , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/efeitos dos fármacos , Anticoagulantes/farmacologia , Anticoagulantes/química , Antitrombinas/farmacologia , Antídotos/farmacologia , Antídotos/químicaRESUMO
The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.
Assuntos
Agentes Neurotóxicos , Compostos Organofosforados , Humanos , Agentes Neurotóxicos/toxicidade , Compostos Organofosforados/toxicidade , Animais , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/uso terapêutico , Reativadores da Colinesterase/química , Contramedidas Médicas , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Substâncias para a Guerra Química/toxicidade , Antídotos/farmacologia , Antídotos/uso terapêutico , Oximas/farmacologia , Oximas/uso terapêutico , Oximas/químicaRESUMO
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.
Assuntos
Butirilcolinesterase , Reativadores da Colinesterase , Intoxicação por Organofosfatos , Oximas , Oximas/química , Oximas/farmacologia , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Humanos , Intoxicação por Organofosfatos/tratamento farmacológico , Acetilcolinesterase/metabolismo , Antídotos/química , Antídotos/farmacologia , Cinética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Animais , Compostos Organofosforados/químicaRESUMO
Thrombosis, the formation of blood clots within a blood vessel, can lead to severe complications including pulmonary embolism, cardiac arrest, and stroke. The most widely administered class of anticoagulants is heparin-based anticoagulants such as unfractionated heparin, low-molecular weight heparins (LMWHs), and fondaparinux. Protamine is the only FDA-approved heparin antidote. Protamine has limited efficacy neutralizing LMWHs and no reversal activity against fondaparinux. The use of protamine can lead to complications, including excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic window. In this work, a new concept in the design of a universal heparin antidote: switchable protonation of cationic ligands, is presented. A library of macromolecular polyanion inhibitors (MPIs) is synthesized and screened to identify molecules that can neutralize all heparins with high selectivity and reduced toxicity. MPIs are developed by assembling cationic binding groups possessing switchable protonation states onto a polymer scaffold. By strategically selecting the identity and modulating the density of cationic binding groups on the polymer scaffold, a superior universal heparin reversal agent is developed with improved heparin-binding activity and increased hemocompatibility profiles leading to minimal effect on hemostasis. The activity of this heparin antidote is demonstrated using in vitro and in vivo studies.
Assuntos
Cátions , Heparina , Animais , Heparina/química , Heparina/farmacologia , Ligantes , Cátions/química , Antagonistas de Heparina/química , Antagonistas de Heparina/farmacologia , Humanos , Polieletrólitos/química , Polímeros/química , Antídotos/química , Antídotos/farmacologia , Anticoagulantes/química , Anticoagulantes/farmacologia , Camundongos , Protaminas/química , Protaminas/farmacologiaRESUMO
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.
Assuntos
Reativadores da Colinesterase , Compostos de Pralidoxima , Taurina/análogos & derivados , Ratos , Humanos , Animais , Reativadores da Colinesterase/farmacologia , Trimedoxima/farmacologia , Butirilcolinesterase , Acetilcolinesterase , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Antídotos/farmacologia , Inibidores da Colinesterase/toxicidade , Fósforo , OxigênioRESUMO
Liver injury and acute liver failure caused by an acetaminophen (APAP) overdose is a significant clinical problem in western countries. With the introduction of the mouse model of APAP hepatotoxicity in the 1970 s, fundamental mechanisms of cell death were discovered. This included the recognition that part of the APAP dose is metabolized by cytochrome P450 generating a reactive metabolite that is detoxified by glutathione. After the partial depletion of glutathione, the reactive metabolite will covalently bind to sulfhydryl groups of proteins, which is the initiating event of the toxicity. This insight led to the introduction of N-acetyl-L-cysteine, a glutathione precursor, as antidote against APAP overdose in the clinic. Despite substantial progress in our understanding of the pathomechanisms over the last decades viable new antidotes only emerged recently. This review will discuss the background, mechanisms of action, and the clinical prospects of the existing FDA-approved antidote N-acetylcysteine, of several new drug candidates under clinical development [4-methylpyrazole (fomepizole), calmangafodipir] and examples of additional therapeutic targets (Nrf2 activators) and regeneration promoting agents (thrombopoietin mimetics, adenosine A2B receptor agonists, Wharton's Jelly mesenchymal stem cells). Although there are clear limitations of certain therapeutic approaches, there is reason to be optimistic. The substantial progress in the understanding of the pathophysiology of APAP hepatotoxicity led to the consideration of several drugs for development as clinical antidotes against APAP overdose in recent years. Based on the currently available information, it is likely that this will result in additional drugs that could be used as adjunct treatment for N-acetylcysteine.
Assuntos
Acetaminofen , Antídotos , Doença Hepática Induzida por Substâncias e Drogas , Falência Hepática Aguda , Acetaminofen/toxicidade , Acetaminofen/efeitos adversos , Humanos , Animais , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Antídotos/uso terapêutico , Antídotos/farmacologia , Acetilcisteína/uso terapêutico , Acetilcisteína/farmacologia , Analgésicos não Narcóticos/toxicidade , Analgésicos não Narcóticos/efeitos adversosRESUMO
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.
Assuntos
Antídotos , Ricina , Ricina/antagonistas & inibidores , Ricina/química , Humanos , Antídotos/química , Antídotos/farmacologia , Substâncias para a Guerra Química/química , AnimaisRESUMO
Despite the international convention on the prohibition of chemical weapons ratified in 1997, the threat of conflicts and terrorist attacks involving such weapons still exists. Among these, organophosphorus-nerve agents (OPs) inhibit cholinesterases (ChE) causing cholinergic syndrome. The reactivation of these enzymes is therefore essential to protect the poisoned people. However, these reactivating molecules, mainly named oximes, have major drawbacks with limited efficacy against some OPs and a non-negligible ChE inhibitor potential if administered at an inadequate dose, an effect that they are precisely supposed to mitigate. As a result, this project focused on assessing therapeutic efficacy, in mice, up to the NOAEL dose, the maximum dose of oxime that does not induce any observable toxic effect. NOAEL doses of HI-6 DMS, a reference oxime, and JDS364. HCl, a candidate reactivator, were assessed using dual-chamber plethysmography, with respiratory ventilation impairment as a toxicity criterion. Time-course modeling parameters and pharmacodynamic profiles, reflecting the interaction between the oxime and circulating ChE, were evaluated for treatments at their NOAEL and higher doses. Finally, the therapeutic potential against OPs poisoning was determined through the assessment of protective indices. For JDS364. HCl, the NOAEL dose corresponds to the smallest dose inducing the most significant therapeutic effect without causing any abnormality in ChE activity. In contrast, for HI-6 DMS, its therapeutic benefit was observed at doses higher than its NOAEL, leading to alterations in respiratory function. These alterations could not be directly correlated with ChE inhibition and had no adverse effects on survival. They are potentially attributed to the stimulation of non-enzymatic cholinergic targets by HI-6 DMS. Thus, the NOAEL appears to be an optimal dose for evaluating the efficacy of oximes, particularly when it can be linked to respiratory alterations effectively resulting from ChE inhibition.
Assuntos
Substâncias para a Guerra Química , Reativadores da Colinesterase , Agentes Neurotóxicos , Humanos , Camundongos , Animais , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/uso terapêutico , Reativadores da Colinesterase/química , Agentes Neurotóxicos/toxicidade , Nível de Efeito Adverso não Observado , Substâncias para a Guerra Química/toxicidade , Oximas/farmacologia , Oximas/uso terapêutico , Oximas/química , Compostos de Piridínio/farmacologia , Inibidores da Colinesterase/toxicidade , Inibidores da Colinesterase/química , Colinesterases , Acetilcolinesterase , Antídotos/farmacologia , Antídotos/uso terapêuticoRESUMO
Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.