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Current Pharmaceutical Biotechnology Aug 2012
Topics: Antidotes; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Emergency Treatment; Humans; Poisoning
PubMed: 22352725
DOI: 10.2174/138920112802273164 -
Current Drug Metabolism 2014Protein engineering holds the potential to transform the metabolic drug landscape through the development of smart, stimulusresponsive drug systems. Protein therapeutics... (Review)
Review
Protein engineering holds the potential to transform the metabolic drug landscape through the development of smart, stimulusresponsive drug systems. Protein therapeutics are a rapidly expanding segment of Food and Drug Administration approved drugs that will improve clinical outcomes over the long run. Engineering of protein therapeutics is still in its infancy, but recent general advances in protein engineering capabilities are being leveraged to yield improved control over both pharmacokinetics and pharmacodynamics. Stimulus- responsive protein therapeutics are drugs which have been designed to be metabolized under targeted conditions. Protein engineering is being utilized to develop tailored smart therapeutics with biochemical logic. This review focuses on applications of targeted drug neutralization, stimulus-responsive engineered protein prodrugs, and emerging multicomponent smart drug systems (e.g., antibody-drug conjugates, responsive engineered zymogens, prospective biochemical logic smart drug systems, drug buffers, and network medicine applications).
Topics: Animals; Antidotes; Biological Products; Humans; Prodrugs; Protein Engineering
PubMed: 25495737
DOI: 10.2174/1389200216666141208151524 -
Clinical Toxicology (Philadelphia, Pa.) May 2022Methyl mercaptan (CHSH) is a colorless, toxic gas with potential for occupational exposure and used as a weapon of mass destruction. Inhalation at high concentrations...
CONTEXT
Methyl mercaptan (CHSH) is a colorless, toxic gas with potential for occupational exposure and used as a weapon of mass destruction. Inhalation at high concentrations can result in dyspnea, hypoventilation, seizures, and death. No specific methyl mercaptan antidote exists, highlighting a critical need for such an agent. Here, we investigated the mechanism of CHSH toxicity, and rescue from CHSH poisoning by the vitamin B analog cobinamide, in mammalian cells. We also developed lethal CHSH inhalation models in mice and rabbits, and tested the efficacy of intramuscular injection of cobinamide as a CHSH antidote.
RESULTS
We found that cobinamide binds to CHSH ( = 84 µM), and improved growth of cells exposed to CHSH. CHSH reduced cellular oxygen consumption and intracellular ATP content and activated the stress protein c-Jun N-terminal kinase (JNK); cobinamide reversed these changes. A single intramuscular injection of cobinamide (20 mg/kg) rescued 6 of 6 mice exposed to a lethal dose of CHSH gas, while all six saline-treated mice died ( = 0.0013). In rabbits exposed to CHSH gas, 11 of 12 animals (92%) treated with two intramuscular injections of cobinamide (50 mg/kg each) survived, while only 2 of 12 animals (17%) treated with saline survived ( = 0.001).
CONCLUSION
We conclude that cobinamide could potentially serve as a CHSH antidote.
Topics: Animals; Antidotes; Chlorocebus aethiops; Cobamides; Humans; Mice; Rabbits; Sulfhydryl Compounds; Vitamin B 12
PubMed: 34989638
DOI: 10.1080/15563650.2021.2017949 -
Critical Care (London, England) Feb 2023Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically,...
Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included supportive care, correction of acid-base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong ("we recommend") or weak/conditional ("we suggest"), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on 446 patients, in whom overall mortality was 18.7%. In the subgroup of patients with a glycolate concentration ≤ 12 mmol/L (or anion gap ≤ 28 mmol/L), mortality was 3.6%; in this subgroup, outcomes in patients receiving ECTR were not better than in those who did not receive ECTR. The EXTRIP workgroup made the following recommendations for the use of ECTR in addition to supportive care over supportive care alone in the management of EG poisoning (very low quality of evidence for all recommendations): i) Suggest ECTR if fomepizole is used and EG concentration > 50 mmol/L OR osmol gap > 50; or ii) Recommend ECTR if ethanol is used and EG concentration > 50 mmol/L OR osmol gap > 50; or iii) Recommend ECTR if glycolate concentration is > 12 mmol/L or anion gap > 27 mmol/L; or iv) Suggest ECTR if glycolate concentration 8-12 mmol/L or anion gap 23-27 mmol/L; or v) Recommend ECTR if there are severe clinical features (coma, seizures, or AKI). In most settings, the workgroup recommends using intermittent hemodialysis over other ECTRs. If intermittent hemodialysis is not available, CKRT is recommended over other types of ECTR. Cessation of ECTR is recommended once the anion gap is < 18 mmol/L or suggested if EG concentration is < 4 mmol/L. The dosage of antidotes (fomepizole or ethanol) needs to be adjusted during ECTR.
Topics: Humans; Antidotes; Fomepizole; Ethanol; Renal Dialysis; Glycolates; Ethylene Glycol; Poisoning
PubMed: 36765419
DOI: 10.1186/s13054-022-04227-2 -
Deutsches Arzteblatt International Oct 2013In 2011, German hospitals treated approximately 205 000 patients suffering from acute poisoning. Change is seen over time both in the types of poisoning that occur and... (Review)
Review
BACKGROUND
In 2011, German hospitals treated approximately 205 000 patients suffering from acute poisoning. Change is seen over time both in the types of poisoning that occur and in the indications for specific treatment.
METHODS
This article is based on a selective review of the literature, with special attention to the health reports of the German federal government, the annual reports of the GIZ-Nord Poisons Center (the poison information center for the four northwestern states of Germany, i.e. Bremen, Hamburg, Lower Saxony and Schleswig-Holstein), and the recommendations of international medical associations.
RESULTS
From 1996 to 2011, the GIZ-Nord Poisons Center answered more than 450 000 inquiries, most of which involved exposures to medical drugs, chemicals, plants, foods, or cosmetics. Poisoning was clinically manifest in only a fraction of these cases. Ethanol intoxication is the commonest type of acute poisoning and suicide by medical drug overdose is the commonest type of suicide by poisoning. Death from acute poisoning is most commonly the result of either smoke inhalation or illegal drug use. Severe poisoning is only rarely due to the ingestion of chemicals (particularly detergents and cleaning products), cosmetics, or plant matter. Medical procedures that are intended to reduce the absorption of a poison or enhance its elimination are now only rarely indicated. Antidotes (e.g., atropine, 4-dimethylaminophenol, naloxone, toluidine blue) are available for only a few kinds of poisoning. Randomized clinical trials of treatment have been carried out for only a few substances.
CONCLUSION
Most exposures to poisons can be treated with general emergency care and, if necessary, with symptomatic intensive-care measures. Poison information centers help ensure that cases of poisoning are dealt with efficiently. The data they collect are a useful aid to toxicological assessment and can serve as a point of departure for research projects.
Topics: Antidotes; Critical Care; Emergency Medical Services; Humans; Poisoning; Toxicity Tests
PubMed: 24194796
DOI: 10.3238/arztebl.2013.0690 -
ELife Oct 2023Selfish genetic elements can promote their transmission at the expense of individual survival, creating conflict between the element and the rest of the genome....
Selfish genetic elements can promote their transmission at the expense of individual survival, creating conflict between the element and the rest of the genome. Recently, a large number of toxin-antidote (TA) post-segregation distorters have been identified in non-obligate outcrossing nematodes. Their origin and the evolutionary forces that keep them at intermediate population frequencies are poorly understood. Here, we study a TA element in called . Two major haplotypes of this locus, with and without the selfish element, segregate in . We evaluate the fitness consequences of the element outside of its role in gene drive in non-outcrossing animals and demonstrate that loss of the toxin decreased fitness of hermaphrodites and resulted in reductions in fecundity and body size. These findings suggest a biological role for beyond toxin lethality. This work demonstrates that a TA element can provide a fitness benefit to its hosts either during their initial evolution or by being co-opted by the animals following their selfish spread. These findings guide our understanding on how TA elements can remain in a population where gene drive is minimized, helping resolve the mystery of prevalent TA elements in selfing animals.
Topics: Animals; Caenorhabditis elegans; Antidotes; Repetitive Sequences, Nucleic Acid; Fertility; Gene Frequency; Toxins, Biological; Caenorhabditis elegans Proteins
PubMed: 37874324
DOI: 10.7554/eLife.81640 -
Journal of Occupational Health Jan 2005Exposure to toxic metals remains a widespread occupational and environmental problem in world. There have been a number of reports in the recent past suggesting an... (Review)
Review
Exposure to toxic metals remains a widespread occupational and environmental problem in world. There have been a number of reports in the recent past suggesting an incidence of childhood lead poisoning and chronic arsenic poisoning due to contaminated drinking water in many areas of West Bengal in India and Bangladesh has become a national calamity. Low level metal exposure in humans is caused by air, food and water intake. Lead and arsenic generally interferes with a number of body functions such as the central nervous system (CNS), the haematopoietic system, liver and kidneys. Over the past few decades there has been growing awareness and concern that the toxic biochemical and functional effects are occurring at a lower level of metal exposure than those that produce overt clinical and pathological signs and symptoms. Despite many years of research, we are still far from an effective treatment of chronic plumbism and arsenicosis. Medical treatment of acute and chronic lead and arsenic toxicity is furnished by chelating agents. Chelating agents are organic compounds capable of linking together metal ions to form complex ring-like structures called chelates. They have been used clinically as antidotes for acute and chronic poisoning. 2, 3-dimercaprol (BAL) has long been the mainstay of chelation therapy for lead or arsenic poisoning. Meso 2, 3, -dimercaptosuccinic acid (DMSA) has been tried successfully in animals as well as in a few cases of human lead and arsenic poisoning. DMSA could be a safe and effective method for treating lead or arsenic poisoning, but one of the major disadvantages of chelation with DMSA has been its inability to remove lead from the intracellular sites because of its lipophobic nature. Further, it does not provide protection in terms of clinical/ biochemical recovery. A new trend in chelation therapy is to use combined treatment. This includes the use of structurally different chelators or a combination of an adjuvant and a chelator to provide better clinical/biochemical recovery in addition to lead mobilization. The present review article attempts to provide update information about the current strategies being adopted for a safe, effective and specific treatment for two major toxic metals or metalloid.
Topics: Animals; Antidotes; Arsenic Poisoning; Bangladesh; Chelating Agents; Humans; India; Lead Poisoning; Male; Mice
PubMed: 15703449
DOI: 10.1539/joh.47.1 -
Frontiers in Bioscience (Scholar... Jan 2010Organophosphorus (OP) pesticide poisoning causes significant morbidity and mortality, particularly in the developing world, with upwards of 3 million people poisoned... (Review)
Review
Organophosphorus (OP) pesticide poisoning causes significant morbidity and mortality, particularly in the developing world, with upwards of 3 million people poisoned each year. Although OP poisoning is not common in developed countries, recently greater attention has been given to these chemicals because of their similarity to chemical warfare agents. Despite the agricultural use of OP pesticides for roughly 60 years, no new therapies have been developed since the 1960s. A promising field of novel antidotes for OP poisoning, OP hydrolases, has recently garnered increased support. These bacterial enzymes have demonstrated tremendous prophylactic and antidotal efficacy against a few different OP classes in animal models. These studies, as well as the limitations and challenges of therapeutic development of these enzymes, are discussed.
Topics: Antidotes; Catalysis; Glutathione Transferase; Humans; Organophosphate Poisoning; Pesticides; Phosphoric Monoester Hydrolases; Phosphoric Triester Hydrolases; Poisoning
PubMed: 20036941
DOI: 10.2741/s58 -
Genetics Jul 2022The principles of heredity state that the two alleles carried by a heterozygote are equally transmitted to the progeny. However, genomic regions that escape this rule...
The principles of heredity state that the two alleles carried by a heterozygote are equally transmitted to the progeny. However, genomic regions that escape this rule have been reported in many organisms. It is notably the case of genetic loci referred to as gamete killers, where one allele enhances its transmission by causing the death of the gametes that do not carry it. Gamete killers are of great interest, particularly to understand mechanisms of evolution and speciation. Although being common in plants, only a few, all in rice, have so far been deciphered to the causal genes. Here, we studied a pollen killer found in hybrids between two accessions of Arabidopsis thaliana. Exploring natural variation, we observed this pollen killer in many crosses within the species. Genetic analyses revealed that three genetically linked elements are necessary for pollen killer activity. Using mutants, we showed that this pollen killer works according to a poison-antidote model, where the poison kills pollen grains not producing the antidote. We identified the gene encoding the antidote, a chimeric protein addressed to mitochondria. De novo genomic sequencing in 12 natural variants with different behaviors regarding the pollen killer revealed a hyper variable locus, with important structural variations particularly in killer genotypes, where the antidote gene recently underwent duplications. Our results strongly suggest that the gene has newly evolved within A. thaliana. Finally, we identified in the protein sequence polymorphisms related to its antidote activity.
Topics: Alleles; Antidotes; Arabidopsis; Poisons; Pollen
PubMed: 35666201
DOI: 10.1093/genetics/iyac089 -
The American Journal of Medicine Nov 2016The direct oral anticoagulants (DOACs) provide a number of clinical advantages over vitamin K antagonists for the treatment of thromboembolism, including improved... (Review)
Review
The direct oral anticoagulants (DOACs) provide a number of clinical advantages over vitamin K antagonists for the treatment of thromboembolism, including improved efficacy and safety, as well as no need for regular monitoring of anticoagulant effect. However, as with all anticoagulants, bleeding complications may occur, and anticoagulant reversal may be required in specific clinical situations, such as in patients experiencing spontaneous or traumatic bleeds, or in anticoagulated patients requiring emergency surgery or other invasive procedures. Therefore, several reversal agents for the DOACs are in development. This includes the specific reversal agent idarucizumab, which has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for use in patients treated with dabigatran when urgent reversal of its anticoagulant effects is needed. Idarucizumab is a humanized monoclonal antibody fragment that binds with high affinity to free and thrombin-bound dabigatran, resulting in an almost irreversibly bound idarucizumab-dabigatran complex and thereby neutralizing dabigatran's anticoagulant activity. The reversal of the anticoagulant effects of dabigatran by idarucizumab has been demonstrated in animal bleeding models, in healthy volunteers with a range of ages and renal function, and in anticoagulated patients. In the phase 1 trials, at doses of 2 g or greater, idarucizumab resulted in immediate and complete reversal of the dabigatran anticoagulant effects and was well tolerated. In the absence of dabigatran, idarucizumab showed no effect on coagulation parameters or thrombin formation. These findings provide initial evidence that idarucizumab could provide a safe and effective means of reversing anticoagulant activity in patients treated with dabigatran in need of emergency surgery or in emergency bleeding situations.
Topics: Antibodies, Monoclonal, Humanized; Antidotes; Antithrombins; Clinical Trials, Phase I as Topic; Dabigatran; Hemorrhage; Humans; Renal Insufficiency, Chronic; Treatment Outcome
PubMed: 27569674
DOI: 10.1016/j.amjmed.2016.06.007