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Toxicology Mechanisms and Methods May 2021Chlorine gas is one of the highly produced chemicals in the USA and around the world. Chlorine gas has several uses in water purification, sanitation, and industrial... (Review)
Review
Chlorine gas is one of the highly produced chemicals in the USA and around the world. Chlorine gas has several uses in water purification, sanitation, and industrial applications; however, it is a toxic inhalation hazard agent. Inhalation of chlorine gas, based on the concentration and duration of the exposure, causes a spectrum of symptoms, including but not limited to lacrimation, rhinorrhea, bronchospasm, cough, dyspnea, acute lung injury, death, and survivors develop signs of pulmonary fibrosis and reactive airway disease. Despite the use of chlorine gas as a chemical warfare agent since World War I and its known potential as an industrial hazard, there is no specific antidote. The resurgence of the use of chlorine gas as a chemical warfare agent in recent years has brought speculation of its use as weapons of mass destruction. Therefore, developing antidotes for chlorine gas-induced lung injuries remains the need of the hour. While some of the pre-clinical studies have made substantial progress in the understanding of chlorine gas-induced pulmonary pathophysiology and identifying potential medical countermeasure(s), yet none of the drug candidates are approved by the U.S. Food and Drug Administration (FDA). In this review, we summarized pathophysiology of chlorine gas-induced pulmonary injuries, pre-clinical animal models, development of a pipeline of potential medical countermeasures under FDA animal rule, and future directions for the development of antidotes for chlorine gas-induced lung injuries.
Topics: Acute Lung Injury; Animals; Antidotes; Chemical Warfare Agents; Chlorine; Lung
PubMed: 31532270
DOI: 10.1080/15376516.2019.1669244 -
European Journal of Hospital Pharmacy :... Jul 2021Previous audits of antidote stocking in UK hospitals have demonstrated variable but improving compliance with joint Royal College of Emergency Medicine and National...
BACKGROUND
Previous audits of antidote stocking in UK hospitals have demonstrated variable but improving compliance with joint Royal College of Emergency Medicine and National Poisons Information Service guidance on antidote availability in emergency departments. The guidance was updated in 2017.
AIM
To provide a current picture of compliance with the 2017 antidote guidance and compare this to previous audits.
METHODS
Questionnaires were distributed to all hospitals in the UK with an emergency department via medicines information and regional pharmacy procurement networks. Data were collected on availability and stock levels of category A (immediately available) and category B (available within 1 hour) antidotes. Additionally, data were collected on holdings of category C (held supra-regionally) antidotes and arrangements for sourcing these if not stocked locally.
RESULTS
233 hospitals were surveyed and 178 replies (76.4%) were received. There were 73 hospitals (41.7%) fully compliant with guidance for category A, 34 hospitals (19.1%) for category B and 18 hospitals (10.1%) for both categories A and B antidotes. Few hospitals stocked category C antidotes (1.1%-34.8%). Evidence of formalised regional holding arrangements for category C antidotes, as advised in the guidance, was noted in some areas but many regions remain without such agreements.
CONCLUSIONS
Most hospitals remain not fully compliant with stocking recommendations for categories A and B antidotes, with limited recent improvement. Category C antidotes are stocked by few hospitals although awareness of where these can be sourced appears to be increasing. Emergency departments should review their antidote stocking arrangements to ensure compliance with guidance. Formal arrangements for stocking of the more rarely used category C antidotes at a regional level are also required, where not already in existence, in order to assure their availability in an equitable way across the country.
Topics: Antidotes; Emergency Service, Hospital; Hospitals; Humans; Pharmacy Service, Hospital; United Kingdom
PubMed: 34162673
DOI: 10.1136/ejhpharm-2019-001988 -
Annals of the New York Academy of... Aug 2016Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and... (Review)
Review
Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and organophosphate (OP) pesticide intoxication. Catalytically inactive OP-AChE conjugates formed between the active-center serine and phosphorus of OPs can, in principle, be reactivated by nucleophilic oxime antidotes. Antidote efficacy is limited by the structural diversity of OP-AChE conjugates resulting from differences in the structure of the conjugated OP, the different active-center volumes they occupy when conjugated to the active-center serine of AChE, and the distinct chemical characteristics of both OPs and oximes documented in numerous X-ray structures of OP-conjugated AChEs. Efforts to improve oxime reactivation efficacy by AChE structure-based enhancement of oxime structure have yielded only limited success. We outline here the potential limitations of available AChE X-ray structures that preclude an accurate prediction of oxime structures, which are necessary for association in the OP-AChE gorge and nucleophilic attack of the OP-conjugated phosphorus.
Topics: Acetylcholinesterase; Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Crystallography, X-Ray; Drug Design; Humans; Organophosphate Poisoning; Oximes; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 27371941
DOI: 10.1111/nyas.13128 -
Metal Ions in Life Sciences Jan 2019Physiological metabolism of cyanide takes place by a single major pathway that forms non-toxic thiocyanate that is subsequently excreted. Rhodanese is the primary enzyme... (Review)
Review
Physiological metabolism of cyanide takes place by a single major pathway that forms non-toxic thiocyanate that is subsequently excreted. Rhodanese is the primary enzyme to execute metabolism of cyanide with minor pathways from other sulfurtransferases in vivo. The rhodanese enzyme depends on sulfur donor availability to metabolize cyanide and poisoning occurs at elevated cyanide concentrations in vivo. Cyanide interacts with over 40 metalloenzymes, but its lethal action is non-competitive inhibition of cytochrome c oxidase, halting cellular respiration and causing hypoxic anoxia. Only a handful of antidotes for treatment of cyanide poisoning are known; they are primarily inorganic compounds and metal complexes which are intended to intercept cyanide before it inhibits cellular respiration. The inorganic compounds manipulate hemoglobin, forming methemoglobin, or supply sulfur for the rhodanese enzyme. The metal complexes intercept the cyanide and bind it before reaching its target. Cobalt complexes of corrins and vitamin B12 derivatives are the state-of-the-art agents, while the longest employed complex, Co2EDTA, is designed to deliver "free" cobalt for binding of cyanide. Compounds that are in development are discussed from the point of how they are designed to intercept cyanide. The challenge of reversing the cyanide inhibition of cytochrome c oxidase is based on the catalytic active site structure and reactivity. General information about history and occurrence of poisoning and clinical symptoms is discussed and the challenges related to analytical methods available to analyze blood cyanide levels and to confirm the presence of cyanide poisoning.
Topics: Antidotes; Cyanides; Electron Transport Complex IV; Humans; Metals
PubMed: 30855115
DOI: 10.1515/9783110527872-020 -
Anaesthesia May 1977
Topics: Antidotes; Humans; Intensive Care Units; Poisoning; Psychology; Suicide, Attempted; United Kingdom
PubMed: 869142
DOI: No ID Found -
Academic Emergency Medicine : Official... Sep 2009The objective was to asses the efficacy of lipid emulsion as antidotal therapy outside the accepted setting of local anesthetic toxicity. (Review)
Review
OBJECTIVES
The objective was to asses the efficacy of lipid emulsion as antidotal therapy outside the accepted setting of local anesthetic toxicity.
METHODS
Literature was accessed through PubMed, OVID (1966-February 2009), and EMBASE (1947-February 2009) using the search terms "intravenous" AND ["fat emulsion" OR "lipid emulsion" OR "Intralipid"] AND ["toxicity" OR "resuscitation" OR "rescue" OR "arrest" OR "antidote"]. Additional author and conference publication searches were undertaken. Publications describing the use of lipid emulsion as antidotal treatment in animals or humans were included.
RESULTS
Fourteen animal studies, one human study, and four case reports were identified. In animal models, intravenous lipid emulsion (ILE) has resulted in amelioration of toxicity associated with cyclic antidepressants, verapamil, propranolol, and thiopentone. Administration in human cases has resulted in successful resuscitation from combined bupropion/lamotrigine-induced cardiac arrest, reversal of sertraline/quetiapine-induced coma, and amelioration of verapamil- and beta blocker-induced shock.
CONCLUSIONS
Management of overdose with highly lipophilic cardiotoxic medications should proceed in accord with established antidotal guidelines and early poisons center consultation. Data from animal experiments and human cases are limited, but suggestive that ILE may be helpful in potentially lethal cardiotoxicity or developed cardiac arrest attributable to such agents. Use of lipid emulsion as antidote remains a nascent field warranting further preclinical study and systematic reporting of human cases of use.
Topics: Adrenergic beta-Antagonists; Animals; Antidepressive Agents; Antidotes; Cardiotoxins; Drug Overdose; Fat Emulsions, Intravenous; Heart Arrest; Humans
PubMed: 19845549
DOI: 10.1111/j.1553-2712.2009.00499.x -
Daru : Journal of Faculty of Pharmacy,... May 2015Saffron (Crocus sativus) is an extensively used food additive for its color and taste. Since ancient times this plant has been introduced as a marvelous medicine... (Review)
Review
Saffron (Crocus sativus) is an extensively used food additive for its color and taste. Since ancient times this plant has been introduced as a marvelous medicine throughout the world. The wide spectrum of saffron pharmacological activities is related to its major constituents including crocin, crocetin and safranal. Based on several studies, saffron and its active ingredients have been used as an antioxidant, antiinflammatory and antinociceptive, antidepressant, antitussive, anticonvulsant, memory enhancer, hypotensive and anticancer. According to the literatures, saffron has remarkable therapeutic effects. The protective effects of saffron and its main constituents in different tissues including brain, heart, liver, kidney and lung have been reported against some toxic materials either natural or chemical toxins in animal studies.In this review article, we have summarized different in vitro and animal studies in scientific databases which investigate the antidotal and protective effects of saffron and its major components against natural toxins and chemical-induced toxicities. Due to the lake of human studies, further investigations are required to ascertain the efficacy of saffron as an antidote or a protective agent in human intoxication.
Topics: Animals; Antidotes; Crocus; Humans; In Vitro Techniques; Plant Extracts; Protective Agents
PubMed: 25928729
DOI: 10.1186/s40199-015-0112-y -
BMC Biology Mar 2020CRISPR gene drive systems allow the rapid spread of a genetic construct throughout a population. Such systems promise novel strategies for the management of vector-borne...
BACKGROUND
CRISPR gene drive systems allow the rapid spread of a genetic construct throughout a population. Such systems promise novel strategies for the management of vector-borne diseases and invasive species by suppressing a target population or modifying it with a desired trait. However, current homing-type drives have two potential shortcomings. First, they can be thwarted by the rapid evolution of resistance. Second, they lack any mechanism for confinement to a specific target population. In this study, we conduct a comprehensive performance assessment of several new types of CRISPR-based gene drive systems employing toxin-antidote (TA) principles, which should be less prone to resistance and allow for the confinement of drives to a target population due to invasion frequency thresholds.
RESULTS
The underlying principle of the proposed CRISPR toxin-antidote gene drives is to disrupt an essential target gene while also providing rescue by a recoded version of the target as part of the drive allele. Thus, drive alleles tend to remain viable, while wild-type targets are disrupted and often rendered nonviable, thereby increasing the relative frequency of the drive allele. Using individual-based simulations, we show that Toxin-Antidote Recessive Embryo (TARE) drives targeting an haplosufficient but essential gene (lethal when both copies are disrupted) can enable the design of robust, regionally confined population modification strategies with high flexibility in choosing promoters and targets. Toxin-Antidote Dominant Embryo (TADE) drives require a haplolethal target gene and a germline-restricted promoter, but they could permit faster regional population modification and even regionally confined population suppression. Toxin-Antidote Dominant Sperm (TADS) drives can be used for population modification or suppression. These drives are expected to spread rapidly and could employ a variety of promoters, but unlike TARE and TADE, they would not be regionally confined and also require highly specific target genes.
CONCLUSIONS
Overall, our results suggest that CRISPR-based TA gene drives provide promising candidates for flexible ecological engineering strategies in a variety of organisms.
Topics: Antidotes; Antitoxins; CRISPR-Cas Systems; Gene Drive Technology; Genes, Essential; Haploinsufficiency; Models, Genetic
PubMed: 32164660
DOI: 10.1186/s12915-020-0761-2 -
Human Vaccines & Immunotherapeutics Feb 2013If new scientific knowledge is to be more efficiently generated and applied toward the advancement of health, human safety must be more effectively addressed in the... (Review)
Review
If new scientific knowledge is to be more efficiently generated and applied toward the advancement of health, human safety must be more effectively addressed in the conduct of research. Given the present difficulties of accurately predicting biological outcomes of novel interventions in vivo, the imperative of human safety suggests the development of novel pharmaceutical products in tandem with their prospective antidotes in anticipation of possible adverse events, to render the risks of initial clinical trials more acceptable from a regulatory standpoint. Antibody-mediated immunity provides a generally applicable mechanistic basis for developing antidotes to both biologicals and small-molecule drugs (such that antibodies may serve as antidotes to pharmaceutical agents as a class including other antibodies) and also for the control and prevention of both infectious and noninfectious diseases via passive or active immunization. Accordingly, the development of prophylactic or therapeutic passive-immunization strategies using antipeptide antibodies is a plausible prelude to the development of corresponding active-immunization strategies using peptide-based vaccines. In line with this scheme, global proliferation of antibody- and vaccine-production technologies, especially those that obviate dependence on the cold chain for storage and transport of finished products, could provide geographically distributed breakout capability against emerging and future health challenges.
Topics: Antibodies; Antidotes; Biological Products; Clinical Trials as Topic; Drug Discovery; Humans; Immunization, Passive
PubMed: 23291934
DOI: 10.4161/hv.22858 -
Journal of Medical Toxicology :... Mar 2016Sodium bicarbonate is a well-known antidote for tricyclic antidepressant (TCA) poisoning. It has been used for over half a century to treat toxin-induced sodium channel... (Review)
Review
Sodium bicarbonate is a well-known antidote for tricyclic antidepressant (TCA) poisoning. It has been used for over half a century to treat toxin-induced sodium channel blockade as evidenced by QRS widening on the electrocardiogram (ECG). The purpose of this review is to describe the literature regarding electrophysiological mechanisms and clinical use of this antidote after poisoning by tricyclic antidepressants and other agents. This article will also address the literature supporting an increased serum sodium concentration, alkalemia, or the combination of both as the responsible mechanism(s) for sodium bicarbonate's antidotal properties. While sodium bicarbonate has been used as a treatment for cardiac sodium channel blockade for multiple other agents including citalopram, cocaine, flecainide, diphenhydramine, propoxyphene, and lamotrigine, it has uncertain efficacy with bupropion, propranolol, and taxine-containing plants.
Topics: Action Potentials; Anti-Arrhythmia Agents; Antidepressive Agents, Tricyclic; Antidotes; Antimalarials; Arrhythmias, Cardiac; Drug Overdose; Heart Conduction System; Heart Rate; Humans; Risk Factors; Sodium Bicarbonate; Sodium Channel Blockers
PubMed: 26159649
DOI: 10.1007/s13181-015-0483-y