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Clinical Pharmacokinetics Oct 2019Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic... (Review)
Review
Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability. Apixaban exposure increases dose proportionally for oral doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentration occurring 3-4 h after oral administration, and has a half-life of approximately 12 h. Elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total apixaban clearance occurring via renal excretion. The pharmacokinetics of apixaban are consistent across a broad range of patients, and apixaban has limited clinically relevant interactions with most commonly prescribed medications, allowing for fixed dosages without the need for therapeutic drug monitoring. The pharmacodynamic effect of apixaban is closely correlated with apixaban plasma concentration. This review provides a summary of the pharmacokinetic, pharmacodynamic, biopharmaceutical, and drug-drug interaction profiles of apixaban. Additionally, the population-pharmacokinetic analyses of apixaban in both healthy subjects and in the target patient populations are discussed.
Topics: Animals; Anticoagulants; Antidotes; Drug Interactions; Humans; Pyrazoles; Pyridones
PubMed: 31089975
DOI: 10.1007/s40262-019-00775-z -
Toxins Aug 2020Botulinum neurotoxins (BoNTs) produced by species are the most potent identified natural toxins. Classically, the toxic neurological syndrome is characterized by an... (Review)
Review
Botulinum neurotoxins (BoNTs) produced by species are the most potent identified natural toxins. Classically, the toxic neurological syndrome is characterized by an (afebrile) acute symmetric descending flaccid paralysis. The most know typical clinical syndrome of botulism refers to the foodborne form. All different forms are characterized by the same symptoms, caused by toxin-induced neuromuscular paralysis. The diagnosis of botulism is essentially clinical, as well as the decision to apply the specific antidotal treatment. The role of the laboratory is mandatory to confirm the clinical suspicion in relation to regulatory agencies, to identify the BoNTs involved and the source of intoxication. The laboratory diagnosis of foodborne botulism is based on the detection of BoNTs in clinical specimens/food samples and the isolation of BoNT from stools. Foodborne botulism intoxication is often underdiagnosed; the initial symptoms can be confused with more common clinical conditions (i.e., stroke, myasthenia gravis, Guillain-Barré syndrome-Miller-Fisher variant, Eaton-Lambert syndrome, tick paralysis and shellfish or tetrodotoxin poisoning). The treatment includes procedures for decontamination, antidote administration and, when required, support of respiratory function; few differences are related to the different way of exposure.
Topics: Animals; Botulism; Diagnosis, Differential; Female; Food Contamination; History, 18th Century; History, 19th Century; Humans; Pregnancy
PubMed: 32784744
DOI: 10.3390/toxins12080509 -
Journal of Educational Evaluation For... 2020The purpose of these practice guidelines is to offer and share strategies for preventing extravasation and measures for handling drugs known to cause tissue necrosis,...
The purpose of these practice guidelines is to offer and share strategies for preventing extravasation and measures for handling drugs known to cause tissue necrosis, which may occur even with the most skilled experts at intravenous (IV) injection. Herein, general knowledge about extravasation is first described, including its definition, incidence, risk factors, diagnosis, differential diagnosis, and extravasation injuries. Management of extravasation includes nursing intervention and thermal application. At the first sign of extravasation, nursing intervention with following steps is recommended: stop administration of IV fluids immediately, disconnect the IV tube from the cannula, aspirate any remaining drug from the cannula, administer drug-specific antidote, and notify the physician. Local thermal treatments are used to decrease the site reaction and absorption of the infiltrate. Local cooling (ice packs) aids in vasoconstriction, theoretically limiting the drug dispersion. Although clear benefit has not been demonstrated with thermal applications, it remains a standard supportive care. The recommended application schedule for both warm and cold applications is 15 to 20 minutes, every 4 hours, for 24 to 48 hours. For prevention of extravasation, health professionals should be familiar with the extravasation management standard guidelines. They should regularly check the extravasation kit, assess patients’ sensory changes, tingling or burning, and always pay attention to patients’ words. The medical team’s continuous education on extravasation is essential. With the practical use of these guidelines, it is expected to reduce the occurrence rate of extravasation and contribute to patient care improvement.
Topics: Antineoplastic Agents; Extravasation of Diagnostic and Therapeutic Materials; Humans; Injections, Intravenous; Risk Factors
PubMed: 32668826
DOI: 10.3352/jeehp.2020.17.21 -
Toxicological Sciences : An Official... Apr 2020Liver injury and acute liver failure caused by acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) overdose is a significant clinical problem in most western... (Review)
Review
Liver injury and acute liver failure caused by acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) overdose is a significant clinical problem in most western countries. The only clinically approved antidote is N-acetylcysteine (NAC), which promotes the recovery of hepatic GSH. If administered during the metabolism phase, GSH scavenges the reactive metabolite N-acetyl-p-benzoquinone imine. More recently, it was shown that NAC can also reconstitute mitochondrial GSH levels and scavenge reactive oxygen/peroxynitrite and can support mitochondrial bioenergetics. However, NAC has side effects and may not be efficacious after high overdoses. Repurposing of additional drugs based on their alternate mechanisms of action could be a promising approach. 4-Methylpyrazole (4MP) was shown to be highly effective against APAP toxicity by inhibiting cytochrome P450 enzymes in mice and humans. In addition, 4MP is a potent c-Jun N-terminal kinase inhibitor expanding its therapeutic window. Calmangafodipir (CMFP) is a SOD mimetic, which is well tolerated in patients and has the potential to be effective after severe overdoses. Other drugs approved for humans such as metformin and methylene blue were shown to be protective in mice at high doses or at human therapeutic doses, respectively. Additional protective strategies such as enhancing antioxidant activities, Nrf2-dependent gene induction and autophagy activation by herbal medicine components are being evaluated. However, at this point, their mechanistic insight is limited, and the doses used are high. More rigorous mechanistic studies are needed to advance these herbal compounds. Nevertheless, based on recent studies, 4-methylpyrazole and calmangafodipir have realistic prospects to become complimentary or even alternative antidotes to NAC for APAP overdose.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Repositioning; Humans; Liver; Liver Failure, Acute; Protective Agents
PubMed: 31926003
DOI: 10.1093/toxsci/kfaa002 -
Archives of Toxicology Feb 2022Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose... (Comparative Study)
Comparative Study Review
Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.
Topics: Acetaminophen; Acetylcysteine; Analgesics, Non-Narcotic; Animals; Antidotes; Chemical and Drug Induced Liver Injury; Drug Overdose; Fomepizole; Hepatocytes; Humans; Mice
PubMed: 34978586
DOI: 10.1007/s00204-021-03211-z -
Annals of Intensive Care Nov 2020Poisoning is one of the leading causes of admission to the emergency department and intensive care unit. A large number of epidemiological changes have occurred over the... (Review)
Review
BACKGROUND
Poisoning is one of the leading causes of admission to the emergency department and intensive care unit. A large number of epidemiological changes have occurred over the last years such as the exponential growth of new synthetic psychoactive substances. Major progress has also been made in analytical screening and assays, enabling the clinicians to rapidly obtain a definite diagnosis.
METHODS
A committee composed of 30 experts from five scientific societies, the Société de Réanimation de Langue Française (SRLF), the Société Française de Médecine d'Urgence (SFMU), the Société de Toxicologie Clinique (STC), the Société Française de Toxicologie Analytique (SFTA) and the Groupe Francophone de Réanimation et d'Urgences Pédiatriques (GFRUP) evaluated eight fields: (1) severity assessment and initial triage; (2) diagnostic approach and role of toxicological analyses; (3) supportive care; (4) decontamination; (5) elimination enhancement; (6) place of antidotes; (7) specificities related to recreational drug poisoning; and (8) characteristics of cardiotoxicant poisoning. Population, Intervention, Comparison, and Outcome (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Analysis of the literature and formulation of recommendations were then conducted according to the GRADE methodology.
RESULTS
The SRLF-SFMU guideline panel provided 41 statements concerning the management of pharmaceutical and recreational drug poisoning. Ethanol and chemical poisoning were excluded from the scope of these recommendations. After two rounds of discussion and various amendments, a strong consensus was reached for all recommendations. Six of these recommendations had a high level of evidence (GRADE 1±) and six had a low level of evidence (GRADE 2±). Twenty-nine recommendations were in the form of expert opinion recommendations due to the low evidences in the literature.
CONCLUSIONS
The experts reached a substantial consensus for several strong recommendations for optimal management of pharmaceutical and recreational drug poisoning, mainly regarding the conditions and effectiveness of naloxone and N-acetylcystein as antidotes to treat opioid and acetaminophen poisoning, respectively.
PubMed: 33226502
DOI: 10.1186/s13613-020-00762-9 -
Biomolecules Feb 2020High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of... (Review)
Review
High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.
Topics: Animals; Antidotes; Arsenic; Arsenic Poisoning; Arsenicals; Chelating Agents; Dimercaprol; Drinking Water; Humans; Models, Molecular; Occupational Exposure; Oxidative Stress; Succimer; Unithiol; Water Pollutants, Chemical
PubMed: 32033229
DOI: 10.3390/biom10020235 -
Trends in Cardiovascular Medicine Feb 2020Oral anticoagulants, old and new, are effective therapies for prevention and treatment of venous thromboembolism and reduction of stroke risk in patients with atrial... (Review)
Review
Oral anticoagulants, old and new, are effective therapies for prevention and treatment of venous thromboembolism and reduction of stroke risk in patients with atrial fibrillation. However, blocking elements of the clotting cascade carries an inherent risk of bleeding. Also, anticoagulated patients sometimes require urgent surgery or invasive procedures. This has led to the emergence of a body of scientific literature on the reversal of anticoagulation in these two settings. Traditionally, vitamin K antagonists (VKAs), which indirectly inactivate clotting factors II, VII, IX and X (and natural anticoagulant proteins C and S), had been the mainstay of oral anticoagulation for half a century. Only a few years ago, the US Food and Drug Administration (FDA) approved a specific VKA reversal agent, 4-Factor Prothrombin Complex Concentrate (4F-PCC). The last decade has seen the rise of non-Vitamin K oral anticoagulants (NOACs), which target specific factors, i.e. Factors IIa and Xa. Investigators have rapidly developed reversal agents for these agents as well, idarucizumab for the Factor IIa inhibitor dabigatran (Pradaxa) and andexanet alfa for the entire class of Factor Xa inhibitors (FXaIs), currently four drugs: rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) and betrixaban (Bevyxxa). Clinicians still use off-label PCC for reversing FXaIs in some settings, and a universal reversal agent, ciraparantag, remains in development. This review summarizes the safety and efficacy of these reversal agents in the setting of anticoagulant-associated major bleeding and the need for urgent surgery.
Topics: Administration, Oral; Anticoagulants; Antidotes; Atrial Fibrillation; Blood Coagulation; Blood Loss, Surgical; Clinical Decision-Making; Coagulants; Drug Administration Schedule; Humans; Perioperative Care; Postoperative Hemorrhage; Risk Assessment; Risk Factors; Stroke; Treatment Outcome; Venous Thromboembolism
PubMed: 30952383
DOI: 10.1016/j.tcm.2019.03.004 -
Nature Aug 2022Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation, has a key role in organ injury, degenerative disease and vulnerability of...
Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K-a group of naphthoquinones that includes menaquinone and phylloquinone-confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.
Topics: Antidotes; Antioxidants; Carbon-Carbon Ligases; Coenzymes; Ferroptosis; Hydroquinones; Lipid Peroxidation; Oxidation-Reduction; S100 Calcium-Binding Protein A4; Vitamin K; Warfarin
PubMed: 35922516
DOI: 10.1038/s41586-022-05022-3