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Expert Opinion on Drug Discovery Mar 2021Aptamers provide exciting opportunities for the development of specific and targeted therapeutic approaches. (Review)
Review
INTRODUCTION
Aptamers provide exciting opportunities for the development of specific and targeted therapeutic approaches.
AREAS COVERED
In this review, the authors discuss different therapeutic options available with nucleic acids, including aptamers, focussing on similarities and differences between them. The authors concentrate on case studies with specific aptamers, which exemplify their distinct advantages. The reasons for failure, wherever available, are deliberated upon. Attempts to accelerate the selection process have been discussed. Challenges with aptamers in terms of their specificity and targeted delivery and strategies to overcome these are described. Examples of precise regulation of systemic half-life of aptamers using antidotes are discussed.
EXPERT OPINION
Despite their nontoxic nature, a variety of reasons limit the therapeutic potential of aptamers in the clinic. The analysis of adverse effects observed with the pegnivacogin/anivamersen pair has highlighted the need to screen for preexisting PEG antibodies in any clinical trial involving pegylated molecules. Surprisingly, and promisingly, the ability of nucleic acid therapeutics to breach the blood brain barrier seems achievable. The recognition of specific motifs, e.g. G-quadruplex in thrombin-binding aptamers, or a 'nucleation' zone while designing aptamer-antidote pairs, is likely to accelerate the discovery of therapeutically efficacious molecules.
Topics: Animals; Antidotes; Aptamers, Nucleotide; Blood-Brain Barrier; Drug Delivery Systems; Drug Development; Half-Life; Humans
PubMed: 32990095
DOI: 10.1080/17460441.2021.1829587 -
Pharmaceutical Biology Aug 2016Spirulina (Arthrospira) exerts a wide spectrum of pharmacological activities which are mainly attributed to its antioxidant effect. However, Spirulina has also been... (Review)
Review
CONTEXT
Spirulina (Arthrospira) exerts a wide spectrum of pharmacological activities which are mainly attributed to its antioxidant effect. However, Spirulina has also been reported (both in preclinical and in clinical scenarios) to exhibit other bioactive effects, including an antitoxic potential.
OBJECTIVE
We performed a systematic review of the literature, conducted in TOXNET, PubMed/MEDLINE, and Science Direct-Scopus; all available years were included. Searching criteria included the effects of Spirulina on experimental poisonings from arsenic, cadmium, carbon tetrachloride, deltamethrin, fluoride, hexachlorocyclohexane, iron, lead, lindane, and mercury.
RESULTS
In all cases, it was established that the blue-green alga, and its isolated compounds, effectively counteracted these pollutants toxic effects on the exposed organisms. Some molecular mechanisms are proposed, although they have not been fully elucidated yet.
CONCLUSION
Spirulina could be a useful coadjuvant agent within clinical practice for treatment of these or other pollutants poisonings.
Topics: Animals; Antidotes; Antioxidants; Environmental Exposure; Environmental Pollutants; Humans; Occupational Exposure; Poisoning; Spirulina
PubMed: 26439611
DOI: 10.3109/13880209.2015.1077464 -
Internal and Emergency Medicine Oct 2022Colchicine is a tricyclic, lipid-soluble alkaloid which has long been used to treat gout and many immunological diseases. Due to its narrow therapeutic window and long... (Review)
Review
Colchicine is a tricyclic, lipid-soluble alkaloid which has long been used to treat gout and many immunological diseases. Due to its narrow therapeutic window and long half-life of elimination, colchicine overdose occurs occasionally. Unfortunately, some patients lost their lives because of colchicine overdose or suicide. Acute colchicine poisoning can lead to original gastrointestinal disorders, shock, progressive multiple organ failure, and myelosuppression. Although many researchers in the world performed lots of research, there are currently no specific antidotes for colchicine poisoning. Meanwhile, there are no management guidelines to treat patients with acute colchicine poisoning until now. Herein, we systematically elaborate on the clinical features and progress in the management of acute colchicine poisoning in adults according to the previous literature. This paper will provide some valuable and available information for clinicians.
Topics: Adult; Antidotes; Colchicine; Humans; Lipids; Multiple Organ Failure; Poisoning; Suicide
PubMed: 36028733
DOI: 10.1007/s11739-022-03079-6 -
Annual Review of Pharmacology and... Jan 2019Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the... (Review)
Review
Organophosphorus insecticide self-poisoning is a major global health problem, killing over 100,000 people annually. It is a complex multi-organ condition, involving the inhibition of cholinesterases, and perhaps other enzymes, and the effects of large doses of ingested solvents. Variability between organophosphorus insecticides-in lipophilicity, speed of activation, speed and potency of acetylcholinesterase inhibition, and in the chemical groups attached to the phosphorus-results in variable speed of poisoning onset, severity, clinical toxidrome, and case fatality. Current treatment is modestly effective, aiming only to reactivate acetylcholinesterase and counter the effects of excess acetylcholine at muscarinic receptors. Rapid titration of atropine during resuscitation is lifesaving and can be performed in the absence of oxygen. The role of oximes in therapy remains unclear. Novel antidotes have been tested in small trials, but the great variability in poisoning makes interpretation of such trials difficult. More effort is required to test treatments in adequately powered studies.
Topics: Animals; Antidotes; Humans; Insecticides; Organophosphate Poisoning; Organophosphorus Compounds
PubMed: 30230960
DOI: 10.1146/annurev-pharmtox-010818-021842 -
British Journal of Clinical Pharmacology Mar 2016Sometimes mistakenly characterized as a 'universal antidote,' activated charcoal (AC) is the most frequently employed method of gastrointestinal decontamination in the... (Review)
Review
Sometimes mistakenly characterized as a 'universal antidote,' activated charcoal (AC) is the most frequently employed method of gastrointestinal decontamination in the developed world. Typically administered as a single dose (SDAC), its tremendous surface area permits the binding of many drugs and toxins in the gastrointestinal lumen, reducing their systemic absorption. Like other decontamination procedures, the utility of SDAC attenuates with time, and, although generally safe, it is not free of risk. A large body of evidence demonstrates that SDAC can reduce the absorption of drugs and xenobiotics but most such studies involve volunteers and have little generalizability to clinical practice. Few rigorous clinical trials of SDAC have been conducted, and none validate or refute its utility in those patients who are intuitively most likely to benefit. Over the past decade, a growing body of observational data have demonstrated that SDAC can elicit substantial reductions in drug absorption in acutely poisoned patients. The challenge for clinicians rests in differentiating those patients most likely to benefit from SDAC from those in whom meaningful improvement is doubtful. This is often a difficult determination not well suited to an algorithmic approach. The present narrative review summarizes the data supporting the benefits and harms of SDAC, and offers pragmatic suggestions for clinical practice.
Topics: Animals; Antidotes; Charcoal; Drug Overdose; Humans; Time Factors
PubMed: 26409027
DOI: 10.1111/bcp.12793 -
Clinical and Applied... Mar 2015Anticoagulants have been used in clinical practice for more than 50 years. Their indications expand, as more people are diagnosed each year with atrial fibrillation and... (Review)
Review
Anticoagulants have been used in clinical practice for more than 50 years. Their indications expand, as more people are diagnosed each year with atrial fibrillation and venous thromboembolism. Vitamin K antagonists have been the most popular choice due to their effectiveness and their ability to reverse bleeding using a known antidote; oral and intravenous vitamin K have long been known to reverse the effects of warfarin. With new classes of anticoagulants making their way onto the market, such as factor Xa inhibitors (rivaroxaban, apixaban) and direct thrombin inhibitors (dabigatran), the need for new reversal agents is paramount. Patients tend to be more receptive to these medications because they do not require routine blood monitoring, can be used at fixed doses, and do not have major drug or food interactions. Antidotes for these medications have shown promise in animal models and are currently in clinical trials.
Topics: Administration, Oral; Antidotes; Factor Xa Inhibitors; Hemorrhage; Humans
PubMed: 25115762
DOI: 10.1177/1076029614545211 -
Clinical Toxicology (Philadelphia, Pa.) Dec 2017Intraosseous (IO) access is an established route of administration in resuscitation situations. Patients with serious poisoning presenting to the emergency department... (Review)
Review
CONTEXT
Intraosseous (IO) access is an established route of administration in resuscitation situations. Patients with serious poisoning presenting to the emergency department may require urgent antidote therapy. However, intravenous (IV) access is not always readily available.
OBJECTIVE
This study reviews the current evidence for IO administration of antidotes that could be used in poisoning. The primary outcome was mortality as a surrogate of efficacy. Secondary outcomes included hemodynamic variables, electrocardiographic variables, neurological status, pharmacokinetics outcomes, and adverse effects as defined by each article.
METHODS
A medical librarian created a systematic search strategy for Medline, subsequently translated to Embase, BIOSIS, PubMed, Web of Science, Cochrane, Database of Abstracts of Reviews of Effects (DARE), and the CENTRAL clinical trial register, all of which we searched from inception to 30 June 2016. Interventions included IO administration of selected antidotes. Articles included volunteer studies, poisoning, or other resuscitation contexts such as cardiac arrest, burns, dehydration, seizure, hemorrhagic shock, or undifferentiated shock. We considered all human studies and animal experiments to the exception of in vitro studies. Two reviewers independently selected studies, and a third adjudicated in case of disagreement. Three reviewers extracted all relevant data. Three reviewers evaluated the risk of bias and quality of the articles using specific scales according to each type of study design.
RESULTS
A total of 47 publications (46 articles and one abstract) met our inclusion criteria and described IO administration of 13 different antidotes. These included one case series and 21 case reports describing 26 patients, and 25 animal experiments. Of those, seven human case reports and four animal experiments specifically reported the use of antidotes in poisoning. Human case reports suggested favorable outcomes with IO use of atropine, diazepam, hydroxocobalamin, insulin, lipid emulsion, methylene blue, phentolamine, prothrombin complex concentrate, and sodium bicarbonate. Clinical outcomes varied according to the antidote used. The only reported adverse event was ventricular tachycardia following IO naloxone. Regarding the animal experiments, IO administration of lipid emulsion and of hydroxocobalamin showed improved survival in bupivacaine-poisoned rats and in cyanide-intoxicated swine, respectively. Animal data also suggested an equivalent bio-availability between IO and IV administration for atropine, calcium chloride, dextrose 50%, diazepam, methylene blue, pralidoxime, and sodium bicarbonate. Adverse effect reporting of fat emboli after IO administration of sodium bicarbonate, for example, was conflicting due to the significant heterogeneity in the timing of lung examination across studies.
CONCLUSION
The evidence supporting the use of IO route for the administration of antidotes in a context of poisoning is scarce. The majority of the evidence consists of case reports and animal experiments. Common antidotes such as acetylcysteine, fomepizole, and digoxin-specific antibody fragments have not been studied or reported with the use of the IO route. Despite the low-quality evidence available, IO access is a potential option for antidotal treatments in toxicological resuscitation when IV access is unavailable.
Topics: Animals; Antidotes; Humans; Infusions, Intraosseous; Poisoning; Resuscitation
PubMed: 28644688
DOI: 10.1080/15563650.2017.1337122 -
Bioorganic Chemistry Jul 2024Thrombosis leads to elevated mortality rates and substantial medical expenses worldwide. Human factor IXa (HFIXa) protease is pivotal in tissue factor (TF)-mediated...
Thrombosis leads to elevated mortality rates and substantial medical expenses worldwide. Human factor IXa (HFIXa) protease is pivotal in tissue factor (TF)-mediated thrombin generation, and represents a promising target for anticoagulant therapy. We herein isolated novel DNA aptamers that specifically bind to HFIXa through systematic evolution of ligands by exponential enrichment (SELEX) method. We identified two distinct aptamers, seq 5 and seq 11, which demonstrated high binding affinity to HFIXa (K = 74.07 ± 2.53 nM, and 4.93 ± 0.15 nM, respectively). Computer software was used for conformational simulation and kinetic analysis of DNA aptamers and HFIXa binding. These aptamers dose-dependently prolonged activated partial thromboplastin time (aPTT) in plasma. We further rationally optimized the aptamers by truncation and site-directed mutation, and generated the truncated forms (Seq 5-1t, Seq 11-1t) and truncated-mutated forms (Seq 5-2tm, Seq 11-2tm). They also showed good anticoagulant effects. The rationally and structurally designed antidotes (seq 5-2b and seq 11-2b) were competitively bound to the DNA aptamers and effectively reversed the anticoagulant effect. This strategy provides DNA aptamer drug-antidote pair with effective anticoagulation and rapid reversal, developing advanced therapies by safe, regulatable aptamer drug-antidote pair.
Topics: Aptamers, Nucleotide; Humans; Factor IXa; Antidotes; Dose-Response Relationship, Drug; Anticoagulants; Structure-Activity Relationship; Molecular Structure; SELEX Aptamer Technique
PubMed: 38776649
DOI: 10.1016/j.bioorg.2024.107463 -
American Journal of Health-system... Feb 2023Inadequate hospital antidote inventory is a widely documented international issue due to high medication costs, lack of emphasis on antidote importance, variable...
PURPOSE
Inadequate hospital antidote inventory is a widely documented international issue due to high medication costs, lack of emphasis on antidote importance, variable international standards, hospital size, and drug availability. A large health system underwent process and policy implementation for antidote stocking, availability tracking, and administration strategies to ensure appropriate inventory and improve patient safety.
SUMMARY
Process and policy implementation occurred over a 12-month period across the health system's 11 acute care hospitals with emergency department services. Opportunities for optimization were identified following data capture surrounding institution-specific antidote inventory and usage across the health system. Specifically, minimum par levels at each institution were determined from 2018 expert recommendations for both the central pharmacy and automated dispensing machines within the emergency department. These quantities ensured the availability of an antidote within a specific timeframe contingent on the acquisition acuity for at least one 100-kg patient. Entries for order sets, order statements, and smart pump drug libraries were modified or formulated to facilitate standardized practices and minimize safety errors before a system-wide electronic health record transition.
CONCLUSION
It is prudent for all institutions, independent or within a health system, to identify areas of improvement for antidote inventory and management. Implementation of a similar process for antidote stocking, sharing, and delivery at other institutions is feasible and necessary to mitigate issues with drug acquisition and timely administration.
Topics: Humans; Antidotes; Pharmacy Service, Hospital; Emergency Medical Services; Emergency Service, Hospital; Drug Costs
PubMed: 35861156
DOI: 10.1093/ajhp/zxac191 -
Basic & Clinical Pharmacology &... Jun 2023Antidote stocking has been described in several studies from many countries to be problematic and constantly insufficient. During our institution's previous experience... (Review)
Review
Antidote stocking has been described in several studies from many countries to be problematic and constantly insufficient. During our institution's previous experience with a medication event that resulted from lack of antidote stocking, we initiated a review of all our antidotes and realized the lack of data on utilization in the literature that would help us in planning for our stocks. Therefore, we conducted this retrospective review of antidotes utilized at a large tertiary care hospital over a period of 6 years. The paper describes the types of antidotes and toxins involved, together with important patient characteristics and antidote utilization data that can be useful to other healthcare institutions in planning for their antidote stocks.
Topics: Humans; Antidotes; Retrospective Studies; Saudi Arabia; Tertiary Care Centers; Pharmacy Service, Hospital; Poisoning
PubMed: 36894519
DOI: 10.1111/bcpt.13856