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Annales de Biologie Clinique Feb 2019Many neutralizing agents of anticoagulant effect of factor Xa or thrombin inhibitors (xabans and dabigatran, respectively) have been developed since the... (Review)
Review
Many neutralizing agents of anticoagulant effect of factor Xa or thrombin inhibitors (xabans and dabigatran, respectively) have been developed since the commercialization of direct oral anticoagulants (DOAC) in 2008. Idarucizumab is a specific antidote of dabigatran commercialised since 2016. An antidote of xabans, andexanet-α, was very recently approved by the Food and Drug Administration (FDA). Other antidotes of DOAC are under pre-clinical or clinical development; the most advanced being the aripazine in addition to γ-thrombine S195A and GDFXa-αM complex. Prothrombin complex concentrates activated or not, are part of the pro-hemostatic agents suggested for DOAC handling in case of haemorrhage or preceeding urgent surgery or invasive procedures. Other pro-hemostatic agents (FXa, FX (a)-C, FVa) are in pre-clinical stage. The efficacy of these different agents in DOAC reversal and mortality reduction is still controversal in the light of the sparse results of in vitro, ex vivo, pre-clinical and clinical studies.
Topics: Administration, Oral; Anticoagulants; Antidotes; Antithrombins; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Recombinant Proteins; Rivaroxaban
PubMed: 30591426
DOI: 10.1684/abc.2018.1400 -
Der Anaesthesist Sep 2017The introduction of nonvitamin K antagonistic, direct oral anticoagulants (DOAC) made thromboembolic prophylaxis easier for patients. For many physicians, however,... (Review)
Review
The introduction of nonvitamin K antagonistic, direct oral anticoagulants (DOAC) made thromboembolic prophylaxis easier for patients. For many physicians, however, there is still uncertainty about monitoring, preoperative discontinuation, and restarting of DOAC therapy. Guidelines for the management of bleeding are provided, but require specific therapeutic skills in the management of diagnostics and therapy of acute hemorrhage. Small clinical studies and case reports indicate that unspecific therapy with prothrombin complex concentrates (PCC) and activated PCC (aPCC) concentrate may reverse DOAC-induced anticoagulation. However, PCC or aPCC at higher doses potentially provoke thromboembolic complications. However, idarucizumab, a specific, fast-acting, antidote for dabigatran, provides immediate and sustained reversal with no intrinsic or prohemostatic activity. This review article provides an overview of the pharmacology and potential risk of DOAC and the management in the perioperative period with a focus of current concepts in the treatment of DOAC-associated bleeding.
Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Dabigatran; Hemorrhage; Humans; Prothrombin; Thromboembolism
PubMed: 28455651
DOI: 10.1007/s00101-017-0313-5 -
Current Biology : CB Mar 2021Toxin-antidote elements (TAs) are selfish genetic dyads that spread in populations by selectively killing non-carriers. TAs are common in prokaryotes, but very few...
Toxin-antidote elements (TAs) are selfish genetic dyads that spread in populations by selectively killing non-carriers. TAs are common in prokaryotes, but very few examples are known in animals. Here, we report the discovery of maternal-effect TAs in both C. tropicalis and C. briggsae, two distant relatives of C. elegans. In C. tropicalis, multiple TAs combine to cause a striking degree of intraspecific incompatibility: five elements reduce the fitness of >70% of the F hybrid progeny of two Caribbean isolates. We identified the genes underlying one of the novel TAs, slow-1/grow-1, and found that its toxin, slow-1, is homologous to nuclear hormone receptors. Remarkably, although previously known TAs act during embryonic development, maternal loading of slow-1 in oocytes specifically slows down larval development, delaying the onset of reproduction by several days. Finally, we found that balancing selection acting on linked, conflicting TAs hampers their ability to spread in populations, leading to more stable genetic incompatibilities. Our findings indicate that TAs are widespread in Caenorhabditis species and target a wide range of developmental processes and that antagonism between them may cause lasting incompatibilities in natural populations. We expect that similar phenomena exist in other animal species.
Topics: Animals; Antidotes; Caenorhabditis; Female; Male; Repetitive Sequences, Nucleic Acid; Toxins, Biological
PubMed: 33417886
DOI: 10.1016/j.cub.2020.12.013 -
Journal of Ethnopharmacology Jun 2022Traditional healers have used medicinal plants to treat snakebite envenomation worldwide; however, mostly without scientific validation. There have been many studies on... (Review)
Review
ETHNOPHARMACOLOGICAL RELEVANCE
Traditional healers have used medicinal plants to treat snakebite envenomation worldwide; however, mostly without scientific validation. There have been many studies on the therapeutic potential of the natural products against snake envenomation.
AIM OF THE STUDY
This review has highlighted snake venom inhibitory activity of bioactive compounds and peptides from plants that have found a traditional use in treating snakebite envenomation. We have systematically reviewed the scenario of different phases of natural snake venom inhibitors characterization covering a period from 1994 until the present and critically analysed the lacuna of the studies if any, and further scope for their translation from bench to bedside.
MATERIALS AND METHODS
The medicinal plant-derived compounds used against snakebite therapy were reviewed from the available literature in public databases (Scopus, MEDLINE) from 1994 till 2020. The search words used were 'natural inhibitors against snakebite,' 'natural products as therapeutics against snakebite,' 'natural products as antidote against snake envenomation,' ' snake venom toxin natural inhibitors,' 'snake venom herbal inhibitors'. However, the scope of this review does not include computational (in silico) predictions without any wet laboratory validation and snake venom inhibitory activity of the crude plant extracts. In addition, we have also predicted the ADMET properties of the identified snake venom inhibitors to highlight their valuable pharmacokinetics for future clinical studies.
RESULTS
The therapeutic application of plant-derived natural inhibitors to treat snakebite envenomation as an auxiliary to antivenom therapy has been gaining significant momentum. Pharmacological reassessment of the natural compounds derived from traditional medicinal plants has demonstrated inhibition of the principal toxic enzymes of snake venoms at various extents to curb the lethal and/or deleterious effects of venomous snakebite. Nevertheless, such molecules are yet to be commercialized for clinical application in the treatment of snakebite. There are many obstacles in the marketability of the plant-derived natural products as snake envenomation antidote and strategies must be explored for the translation of these compounds from drug candidates to their clinical application.
CONCLUSION
In order to minimize the adverse implications of snake envenomation, strategies must be developed for the smooth transition of these plant-derived small molecule inhibitors from bench to bedside. In this article we have presented an inclusive review and have critically analysed natural products for their therapeutic potential against snake envenomation, and have proposed a road map for use of natural products as antidote against snakebite.
Topics: Antidotes; Antivenins; Biological Products; Plants, Medicinal; Snake Bites; Snake Venoms
PubMed: 35314419
DOI: 10.1016/j.jep.2022.115208 -
Disaster Medicine and Public Health... Feb 2023Nerve agent attacks pose a serious threat worldwide and ensuring optimal readiness is essential to management. We review a mass casualty incident (MCI) drill in a busy... (Review)
Review
OBJECTIVE
Nerve agent attacks pose a serious threat worldwide and ensuring optimal readiness is essential to management. We review a mass casualty incident (MCI) drill in a busy urban New York City Emergency Department incorporating an antidote-dosing tool.
METHODS
Emergency Management and Preparedness planned an MCI drill involving a nerve agent exposure and engaged the pharmacy department to participate on a more comprehensive level. The clinical pharmacist prepared a treatment tool with antidote dosing recommendations to distribute to team members participating in the drill.
RESULTS
During the launch of the exercise, all clinicians involved reviewed the antidote-dosing tool with the pharmacy team members. Because of the ease of use, limited time was necessary to review the dosing tool before the start of the exercise. After the exercise, feedback regarding the use of the tool was very positive and participants appreciated the tool for use in a theoretical emergency that they have had limited experience managing.
CONCLUSIONS
Optimizing team preparedness with accessible and practical dosing tools may be a helpful addition to emergency preparedness for chemical and biological events with the potential for many casualties.
Topics: Humans; Civil Defense; Mass Casualty Incidents; Antidotes; Nerve Agents; Disaster Planning; Emergency Service, Hospital
PubMed: 36847261
DOI: 10.1017/dmp.2023.5 -
Medizinische Klinik, Intensivmedizin... Sep 2021Severe bleeding under antithrombotic therapy is common and challenging in intensive care medicine; on the one hand, rapid bleeding control must be achieved and, on the... (Review)
Review
BACKGROUND
Severe bleeding under antithrombotic therapy is common and challenging in intensive care medicine; on the one hand, rapid bleeding control must be achieved and, on the other hand, thromboembolic complications must be avoided.
AIMS
The paper will provide a brief overview of direct oral anticoagulants, therapeutic options and precise instructions for dealing with severe bleeding.
RESULTS
In addition to general measures in direct oral anticoagulant (DOAC)-associated major bleeding, prothrombin complex concentrate (PCC), idarucizumab and andexanet alfa are available as specific antidote therapy. In case of bleeding under heparin therapy, protamine sulfate is available as a possible antidote.
CONCLUSIONS
In particular, the importance of andexanet alfa in the treatment of factor Xa inhibitor-associated bleeding requires further investigation.
Topics: Administration, Oral; Anticoagulants; Antidotes; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Recombinant Proteins
PubMed: 34463792
DOI: 10.1007/s00063-021-00848-7 -
Current Opinion in Anaesthesiology Apr 2024The advent of direct oral anticoagulants (DOACs) marks a significant milestone in anticoagulant treatment. However, DOACs can exacerbate bleeding, which is challenging... (Review)
Review
PURPOSE OF REVIEW
The advent of direct oral anticoagulants (DOACs) marks a significant milestone in anticoagulant treatment. However, DOACs can exacerbate bleeding, which is challenging for the treating clinician, especially when combined with traumatic injury.
RECENT FINDINGS
In major bleeding associated with DOACs, rapid reversal of the anticoagulant effects is crucial. Recent observational and nonrandomized interventional trials have demonstrated the effectiveness of the specific antidotes andexanet alfa and idarucizumab as well as the unspecific prothrombin complex concentrates (PCCs) to counteract the anticoagulant effects of DOACs. The European Society of Anaesthesiology and Intensive Care guideline for severe perioperative bleeding and the European trauma guideline propose divergent recommendations for the use of andexanet alfa and PCC to obtain hemostasis in Factor Xa inhibitor-related bleeding. The conflicting recommendations are due to limited evidence from clinical studies and the potential increased risk of thromboembolic complications after the administration of andexanet. Regarding dabigatran-associated major bleeding, both guidelines recommend the specific reversal agent idarucizumab as first-line therapy.
SUMMARY
Current guidelines recommend specific antidots and PCCs in DOAC-related major bleeding. Prospective randomized trials comparing specific vs. nonspecific hemostatic agents in the perioperative setting are needed to evaluate the effectiveness and safety of the hemostatic agents.
Topics: Humans; Administration, Oral; Anticoagulants; Antidotes; Hemorrhage; Hemostatics; Prospective Studies; Wounds and Injuries
PubMed: 38390922
DOI: 10.1097/ACO.0000000000001349 -
ACS Nano Jun 2019The lack of pharmaceutical antidotes for deadly toxicants has motivated tremendous research interests in seeking synthetic nanoscavengers to absorb and neutralize...
The lack of pharmaceutical antidotes for deadly toxicants has motivated tremendous research interests in seeking synthetic nanoscavengers to absorb and neutralize harmful biological or chemical agents. Herein, we report a cell-membrane-cloaked oil nanosponge formulation capable of dual-modal detoxification. The biomimetic oil nanosponge consists of an olive oil nanodroplet wrapped by a red blood cell membrane. In such a construct, the oil core can nonspecifically soak up toxicants through physical partition and the cell membrane shell can specifically absorb and neutralize toxicants through biological binding. The dual-modal detoxification capability of the oil nanosponges was validated using three distinct organophosphates (OPs), including paraoxon, diisopropyl fluorophosphate, and dichlorvos. By inhibiting acetylcholinesterase, OPs cause the accumulation of acetylcholine, which leads to neuromuscular disorders and even death. In mouse models of OP poisoning, the oil nanosponges reduced clinical signs of OP intoxication, lowered OP concentration in tissues, and greatly enhanced mouse survival in both the therapeutic regimen and the prophylactic regimen. Overall, oil nanosponges combine the merits of both cell membrane and oil nanodroplets for safe and effective detoxification, which also serve as a prototype of multimodal detoxification platforms.
Topics: Absorption, Physicochemical; Acetylcholinesterase; Animals; Antidotes; Cell Membrane; Cholinesterase Inhibitors; Erythrocytes; Mice; Mice, Inbred ICR; Nanoparticles; Olive Oil; Organophosphate Poisoning; Organophosphates; Protein Binding
PubMed: 31117372
DOI: 10.1021/acsnano.9b02773 -
Molecules (Basel, Switzerland) Mar 2020Poisoning is the greatest source of avoidable death in the world and can result from industrial exhausts, incessant bush burning, drug overdose, accidental toxication or... (Meta-Analysis)
Meta-Analysis Review
Poisoning is the greatest source of avoidable death in the world and can result from industrial exhausts, incessant bush burning, drug overdose, accidental toxication or snake envenomation. Since the advent of Albert Calmette's cobra venom antidote, efforts have been geared towards antidotes development for various poisons to date. While there are resources and facilities to tackle poisoning in urban areas, rural areas and developing countries are challenged with poisoning management due to either the absence of or inadequate facilities and this has paved the way for phyto-antidotes, some of which have been scientifically validated. This review presents the scope of antidotes' effectiveness in different experimental models and biotechnological advancements in antidote research for future applications. While pockets of evidence of the effectiveness of antidotes exist and with ample biotechnological developments, the utilization of analytic assays on existing and newly developed antidotes that have surpassed the proof of concept stage, as well as the inclusion of antidote's short and long-term risk assessment report, will help in providing the required scientific evidence(s) prior to regulatory authorities' approval.
Topics: Animals; Antidotes; Biotechnology; Disease Models, Animal; Drug Development; Drug Evaluation, Preclinical; Humans; Phytochemicals; Poisoning; Treatment Outcome
PubMed: 32225103
DOI: 10.3390/molecules25071516 -
Journal of Applied Toxicology : JAT Aug 2018Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse... (Review)
Review
Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration.
Topics: Animals; Antidotes; Antioxidants; Atropine; Cholinesterase Reactivators; Diazepam; Humans; Organophosphate Poisoning; Oxidative Stress; Oximes
PubMed: 29516527
DOI: 10.1002/jat.3605