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Expert Review of Gastroenterology &... 2016While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute... (Review)
Review
While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute DILI seems slow by comparison. In general, the key to treating suspected DILI is to stop using the drug prior to developing irreversible liver failure. However, predicting when to stop is an inexact science, and commonly used ALT monitoring is an ineffective strategy outside of clinical trials. The only specific antidote for acute DILI remains N-acetylcysteine (NAC) for acetaminophen poisoning, although NAC is proving to be beneficial in some cases of non-acetaminophen DILI in adults. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. Ursodeoxycholic acid, silymarin and glycyrrhizin have been used to treat DILI for decades, but success remains anecdotal. Bile acid washout regimens using cholestyramine appear to be more evidenced based, in particular for leflunomide toxicity. For drug-induced acute liver failure, the use of liver support systems is still investigational in the United States and emergency liver transplant remains limited by its availability. Primary prevention appears to be the key to avoiding DILI and the need for acute treatment. Pharmacogenomics, including human leukocyte antigen genotyping and the discovery of specific DILI biomarkers offers significant promise for the future. This article describes and summarizes the numerous and diverse treatment and prevention modalities that are currently available to manage DILI.
Topics: Acetylcysteine; Adrenal Cortex Hormones; Antidotes; Antioxidants; Chelating Agents; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Genetic Predisposition to Disease; Humans; Liver Transplantation; Liver, Artificial; Patient Selection; Pharmacogenomic Testing; Phenotype; Precision Medicine; Risk Factors; Therapeutic Irrigation; Treatment Outcome
PubMed: 26633044
DOI: 10.1586/17474124.2016.1127756 -
Drug Discovery Today Sep 2014Target-specific oral anticoagulants (TSOACs) provide safe and effective anticoagulation for the prevention and treatment of thrombosis in a variety of clinical settings... (Comparative Study)
Comparative Study Review
Target-specific oral anticoagulants (TSOACs) provide safe and effective anticoagulation for the prevention and treatment of thrombosis in a variety of clinical settings by interfering with the activity of thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban, betrixaban). Although TSOACs have practical advantages over vitamin K antagonists (VKAs), there are currently no antidotes to reverse their anticoagulant effect. Herein we summarize the available evidence for TSOAC reversal using nonspecific and specific reversal agents. We discuss important limitations of existing evidence, which is derived from studies in human volunteers, animal models and in vitro experiments. Studies evaluating the safety and efficacy of reversal agents on clinical outcomes such as bleeding and mortality in patients with TSOAC-associated bleeding are needed.
Topics: Administration, Oral; Animals; Anticoagulants; Antidotes; Antithrombins; Disease Models, Animal; Factor Xa Inhibitors; Hemorrhage; Humans
PubMed: 24880102
DOI: 10.1016/j.drudis.2014.05.013 -
Biomolecules Aug 2021Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a... (Review)
Review
Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently with respect to past years. Novel scientific evidence leads to advances concerning physiopathological mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the important aspects of this field.
Topics: Animals; Antidotes; Diabetes Mellitus; Glucagon; Homeostasis; Humans; Hypoglycemia; Insulin
PubMed: 34572493
DOI: 10.3390/biom11091281 -
Proceedings of the National Academy of... Feb 2023Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an...
Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an injectable antidote against CO and cyanide (CN) mixed poisoning. The solution contains four compounds: iron(III)porphyrin (FeTPPS, F), two methyl-β-cyclodextrin (CD) dimers linked by pyridine (Py3CD, P) and imidazole (Im3CD, I), and a reducing agent (NaSO, S). When these compounds are dissolved in saline, the solution contains two synthetic heme models including a complex of F with P (hemoCD-P) and another one of F with I (hemoCD-I), both in their iron(II) state. hemoCD-P is stable in its iron(II) state and captures CO more strongly than native hemoproteins, while hemoCD-I is readily autoxidized to its iron(III) state to scavenge CN once injected into blood circulation. The mixed solution (hemoCD-Twins) exhibited remarkable protective effects against acute CO and CN mixed poisoning in mice (~85% survival vs. 0% controls). In a model using rats, exposure to CO and CN resulted in a significant decrease in heart rate and blood pressure, which were restored by hemoCD-Twins in association with decreased CO and CN levels in blood. Pharmacokinetic data revealed a fast urinary excretion of hemoCD-Twins with an elimination half-life of 47 min. Finally, to simulate a fire accident and translate our findings to a real-life scenario, we confirmed that combustion gas from acrylic cloth caused severe toxicity to mice and that injection of hemoCD-Twins significantly improved the survival rate, leading to a rapid recovery from the physical incapacitation.
Topics: Rats; Mice; Animals; Carbon Monoxide; Porphyrins; Antidotes; Oxygen; Ferric Compounds; Cyanides; Iron; Ferrous Compounds
PubMed: 36802431
DOI: 10.1073/pnas.2209924120 -
British Journal of Pharmacology Oct 2010The use of biological agents has generally been confined to military-led conflicts. However, there has been an increase in non-state-based terrorism, including the use... (Review)
Review
The use of biological agents has generally been confined to military-led conflicts. However, there has been an increase in non-state-based terrorism, including the use of asymmetric warfare, such as biological agents in the past few decades. Thus, it is becoming increasingly important to consider strategies for preventing and preparing for attacks by insurgents, such as the development of pre- and post-exposure medical countermeasures. There are a wide range of prophylactics and treatments being investigated to combat the effects of biological agents. These include antibiotics (for both conventional and unconventional use), antibodies, anti-virals, immunomodulators, nucleic acids (analogues, antisense, ribozymes and DNAzymes), bacteriophage therapy and micro-encapsulation. While vaccines are commercially available for the prevention of anthrax, cholera, plague, Q fever and smallpox, there are no licensed vaccines available for use in the case of botulinum toxins, viral encephalitis, melioidosis or ricin. Antibiotics are still recommended as the mainstay treatment following exposure to anthrax, plague, Q fever and melioidosis. Anti-toxin therapy and anti-virals may be used in the case of botulinum toxins or smallpox respectively. However, supportive care is the only, or mainstay, post-exposure treatment for cholera, viral encephalitis and ricin - a recommendation that has not changed in decades. Indeed, with the difficulty that antibiotic resistance poses, the development and further evaluation of techniques and atypical pharmaceuticals are fundamental to the development of prophylaxis and post-exposure treatment options. The aim of this review is to present an update on prophylaxis and post-exposure treatment recommendations and research initiatives for biological agents in the open literature from 2007 to 2009.
Topics: Animals; Anti-Bacterial Agents; Antidotes; Antiviral Agents; Biological Warfare; Bioterrorism; Humans; Post-Exposure Prophylaxis; Time Factors; Vaccines
PubMed: 20860656
DOI: 10.1111/j.1476-5381.2010.00939.x -
Emergency Medicine Journal : EMJ Sep 2003A short cut review was carried out to establish whether the addition of intravenous calcium folinate to standard (ethanol) therapy reduced the visual complications of... (Review)
Review
A short cut review was carried out to establish whether the addition of intravenous calcium folinate to standard (ethanol) therapy reduced the visual complications of antifreeze (methanol and ethyleny glycol). Altogether 12 papers were found using the reported search, of which one animal study presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper are tabulated. A clinical bottom line is stated.
Topics: Animals; Antidotes; Ethylene Glycols; Humans; Leucovorin; Male
PubMed: 12954693
DOI: 10.1136/emj.20.5.466 -
Acta Bio-medica : Atenei Parmensis Dec 2019Honey and its polyphenolic compounds are of main natural antioxidants that have been used in traditional medicine. The aim of this review was to identify the protective... (Review)
Review
OBJECTIVE
Honey and its polyphenolic compounds are of main natural antioxidants that have been used in traditional medicine. The aim of this review was to identify the protective effects of honey and chrysin (a polyphenol available in honey) against the chemical and natural toxic agents.
METHOD
The scientific databases such as MEDLINE, PubMed, Scopus, Web of Science and Google Scholar were searched to identify studies on the antidotal effects of honey and chrysin against toxic agents.
RESULTS
This study found that honey had protective activity against toxic agents-induced organ damages by modulating oxidative stress, inflammation, and apoptosis pathways. However, clinical trial studies are needed to confirm the efficacy of honey and chrysin as antidote agents in human intoxication.
CONCLUSION
Honey and chrysin may be effective against toxic agents. (www.actabiomedica.it).
Topics: Antidotes; Drug-Related Side Effects and Adverse Reactions; Flavonoids; Honey; Humans; Polyphenols; Protective Agents
PubMed: 31910181
DOI: 10.23750/abm.v90i4.7534 -
Journal of Thrombosis and Haemostasis :... May 2012The conversion of prothrombin to thrombin is one of two non-duplicated enzymatic reactions during coagulation. Thrombin has long been considered an optimal anticoagulant... (Comparative Study)
Comparative Study
BACKGROUND
The conversion of prothrombin to thrombin is one of two non-duplicated enzymatic reactions during coagulation. Thrombin has long been considered an optimal anticoagulant target because it plays a crucial role in fibrin clot formation by catalyzing the cleavage of fibrinogen, upstream coagulation cofactors and platelet receptors. Although a number of anti-thrombin therapeutics exist, it is challenging to use them clinically due to their propensity to induce bleeding. Previously, we isolated a modified RNA aptamer (R9D-14) that binds prothrombin with high affinity and is a potent anticoagulant in vitro.
OBJECTIVES
We sought to explore the structure of R9D-14 and elucidate its anticoagulant mechanism(s). In addition to designing an optimized aptamer (RNA(R9D-14T)), we also explored whether complementary antidote oligonucleotides can rapidly modulate the optimized aptamer's anticoagulant activity.
METHODS AND RESULTS
RNA(R9D-14T) binds prothrombin and thrombin pro/exosite I with high affinity and inhibits both thrombin generation and thrombin exosite I-mediated activity (i.e. fibrin clot formation, feedback activity and platelet activation). RNA(R9D-14T) significantly prolongs the aPTT, PT and TCT clotting assays, and is a more potent inhibitor than the thrombin exosite I DNA aptamer ARC-183. Moreover, a complementary oligonucleotide antidote can rapidly (< 2 min) and durably (>2 h) reverse RNA(R9D-14T) anticoagulation in vitro.
CONCLUSIONS
Powerful anticoagulation, in conjunction with antidote reversibility, suggests that RNA(R9D-14T) may be ideal for clinical anticoagulation in settings that require rapid and robust anticoagulation, such as cardiopulmonary bypass, deep vein thrombosis, stroke or percutaneous coronary intervention.
Topics: Animals; Anticoagulants; Antidotes; Aptamers, Nucleotide; Base Sequence; Binding, Competitive; Blood Coagulation; Catalytic Domain; Cattle; Dogs; Drug Stability; Enzyme Activation; Factor Va; Half-Life; Humans; Mice; Molecular Sequence Data; Nucleic Acid Conformation; Partial Thromboplastin Time; Platelet Activation; Protein Binding; Prothrombin; Prothrombin Time; Rabbits; Rats; Ribonucleases; SELEX Aptamer Technique; Sheep; Species Specificity; Structure-Activity Relationship; Swine; Thrombin; Thrombin Time
PubMed: 22385910
DOI: 10.1111/j.1538-7836.2012.04679.x -
Human & Experimental Toxicology 2022Gelsenicine, one of the most toxic alkaloids of Benth (), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no... (Comparative Study)
Comparative Study
BACKGROUND
Gelsenicine, one of the most toxic alkaloids of Benth (), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available.
OBJECTIVE
This study aimed to analyse the toxicity characteristics of gelsenicine.
METHODS
Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened.
RESULTS
In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood-brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice.
CONCLUSIONS
Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicinerelated poisoning and its toxicity mechanisms.
Topics: Animals; Antidotes; Disease Models, Animal; Gelsemium; Humans; Indole Alkaloids; Male; Neurotoxins; Plant Extracts; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Sex Factors
PubMed: 35018838
DOI: 10.1177/09603271211062857 -
BMJ (Clinical Research Ed.) Mar 2007
Review
Topics: Acute Disease; Antidotes; Humans; Medical Staff, Hospital; Occupational Diseases; Organophosphate Poisoning; Pesticides; Poisoning
PubMed: 17379909
DOI: 10.1136/bmj.39134.566979.BE