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Nature Communications Nov 2023Breakdown of reproductive isolation facilitates flow of useful trait genes into crop plants from their wild relatives. Hybrid sterility, a major form of reproductive...
Breakdown of reproductive isolation facilitates flow of useful trait genes into crop plants from their wild relatives. Hybrid sterility, a major form of reproductive isolation exists between cultivated rice (Oryza sativa) and wild rice (O. meridionalis, Mer). Here, we report the cloning of qHMS1, a quantitative trait locus controlling hybrid male sterility between these two species. Like qHMS7, another locus we cloned previously, qHMS1 encodes a toxin-antidote system, but differs in the encoded proteins, their evolutionary origin, and action time point during pollen development. In plants heterozygous at qHMS1, ~ 50% of pollens carrying qHMS1-D (an allele from cultivated rice) are selectively killed. In plants heterozygous at both qHMS1 and qHMS7, ~ 75% pollens without co-presence of qHMS1-Mer and qHMS7-D are selectively killed, indicating that the antidotes function in a toxin-dependent manner. Our results indicate that different toxin-antidote systems provide stacked reproductive isolation for maintaining species identity and shed light on breakdown of hybrid male sterility.
Topics: Male; Humans; Hybridization, Genetic; Crosses, Genetic; Oryza; Antidotes; Chromosome Mapping; Reproductive Isolation; Infertility, Male; Plant Infertility
PubMed: 37980335
DOI: 10.1038/s41467-023-43015-6 -
Blood May 2015Ticagrelor is a direct-acting reversibly binding P2Y12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute...
Ticagrelor is a direct-acting reversibly binding P2Y12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor. The Fab has a 20 pM affinity for ticagrelor, which is 100 times stronger than ticagrelor's affinity for its target, P2Y12. Despite ticagrelor's structural similarities to adenosine, the Fab is highly specific and does not bind to adenosine, adenosine triphosphate, adenosine 5'-diphosphate, or structurally related drugs. The antidote concentration-dependently neutralized the free fraction of ticagrelor and reversed its antiplatelet activity both in vitro in human platelet-rich plasma and in vivo in mice. Lastly, the antidote proved effective in normalizing ticagrelor-dependent bleeding in a mouse model of acute surgery. This specific antidote for ticagrelor may prove valuable as an agent for patients who require emergency procedures.
Topics: Adenosine; Animals; Antibodies; Antibodies, Neutralizing; Antibody Specificity; Antidotes; Broadly Neutralizing Antibodies; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Hemorrhage; Humans; Immunoglobulin Fab Fragments; Mice; Models, Molecular; Platelet Aggregation; Protein Engineering; Ticagrelor
PubMed: 25788700
DOI: 10.1182/blood-2015-01-622928 -
Bulletin of the World Health... Dec 2018Historically in Thailand, access to poison antidotes was limited and antivenom stock management was inefficient.
PROBLEM
Historically in Thailand, access to poison antidotes was limited and antivenom stock management was inefficient.
APPROACH
In 2010, the country established a national antidote programme, which created national and subnational antidote stocks, managed their distribution and trained health-care providers on clinical management and antidote use. In 2013, the programme incorporated antivenoms to improve stock management and avoid wastage due to stock expiry.
LOCAL SETTING
Before the programme, health-care providers consulted poison centres on clinical management of poisoning and some antidotes were not available. Individual hospitals stocked antivenoms, which often expired before use.
RELEVANT CHANGES
Today, the National Health Security Office finances and manages the centralized procurement of antidotes and antivenoms and all Thai patients have a right to antidotes regardless of health insurance. National and subnational stock levels are determined based on demand, treatment urgency and cost. A web-based system, which incorporates geographical information, was introduced for requesting antidotes and antivenoms. Poison centres provide training, 24-hour consultation services and outcome monitoring. Antidotes and antivenoms are now readily available and used correctly and clinical management has improved. Moreover, better stock and distribution control has helped avoid antivenom wastage and reduced antivenom costs, from US$ 2.23 million United States dollars (US$) to US$ 1.2 million.
LESSONS LEARNT
The programme's success depended on strong and sustained policy support, adequate funding, improved operational capacity, training for health-care professionals and the provision of 24-hour online consultation services. A web-based centralized procurement and distribution ensured these essential medicines were available, minimized costs, reduced waste and saved lives.
Topics: Antidotes; Antivenins; Government Programs; Health Services Accessibility; Thailand
PubMed: 30505033
DOI: 10.2471/BLT.18.217075 -
British Journal of Clinical Pharmacology Jun 2023Intravenous lipid emulsion (ILE) has been suggested as a potential universal antidote for cardiovascular and central nervous system toxicity resulting from a multitude...
Intravenous lipid emulsion (ILE) has been suggested as a potential universal antidote for cardiovascular and central nervous system toxicity resulting from a multitude of pharmaceutical and nonpharmaceutical poisonings. While there is some evidence to suggest that ILE may have a positive effect in cardiovascular system toxicity after accidental intravenous lipophilic local anaesthetic overdose, this cannot be extrapolated to cases of severe poisoning resulting from oral drug overdose. Treatment recommendations are based upon variable outcome animal studies and low-level clinical evidence with a significant degree of positive reporting bias. Currently, there is a paucity of controlled clinical data to support ILE use to treat severe drug poisoning after oral overdose. ILE use should be limited to well-designed, ethically approved, controlled clinical trials aimed at determining the true effectiveness of this therapy. This should replace the current scattergun clinical use in a multiplicity of poisoning scenarios and subsequent anecdotal reporting approach.
Topics: Animals; Fat Emulsions, Intravenous; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Cardiovascular System; Antidotes; Poisoning
PubMed: 37016734
DOI: 10.1111/bcp.15717 -
Current Pharmaceutical Biotechnology Aug 2012More than 90% of all fatal mushroom poisonings worldwide are due to amatoxin containing species that grow abundantly in Europe, South Asia, and the Indian subcontinent.... (Review)
Review
More than 90% of all fatal mushroom poisonings worldwide are due to amatoxin containing species that grow abundantly in Europe, South Asia, and the Indian subcontinent. Many cases have also been reported in North America. Initial symptoms of abdominal cramps, vomiting, and a severe cholera-like diarrhea generally do not manifest until at least six to eight hours following ingestion and can be followed by renal and hepatic failure. Outcomes range from complete recovery to fulminant organ failure and death which can sometimes be averted by liver transplant. There are no controlled clinical studies available due to ethical reasons, but uncontrolled trials and case reports describe successful treatment with intravenous silibinin (Legalon® SIL). In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin. Silibinin, a proven antioxidative and anti-inflammatory acting flavonolignan isolated from milk thistle extracts, has been shown to interact with specific hepatic transport proteins blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin. The addition of intravenous silibinin to aggressive intravenous fluid management serves to arrest and allow reversal of the manifestation of fulminant hepatic failure, even in severely poisoned patients. These findings together with the available clinical experience justify the use of silibinin as Legalon® SIL in Amanita poisoning cases.
Topics: Amanitins; Animals; Antidotes; Chemical and Drug Induced Liver Injury; Humans; Molecular Structure; Mushroom Poisoning; Silymarin; Tissue Distribution; Treatment Outcome
PubMed: 22352731
DOI: 10.2174/138920112802273353 -
Systematic Reviews Dec 2018Toxic alcohols have been implicated in accidental ingestions and intentional exposures. Recognition of toxic alcohol poisoning is challenging. The main treatment...
BACKGROUND
Toxic alcohols have been implicated in accidental ingestions and intentional exposures. Recognition of toxic alcohol poisoning is challenging. The main treatment modalities include antidotes with alcohol dehydrogenase inhibitors and dialysis. Current guidelines exist for both methanol and ethylene glycol intoxication. However, treatment consensus related to other toxic alcohols is limited. Furthermore, uncertainties regarding thresholds for when to initiate antidotes and dialysis persist. As a consequence, variations exist in the interventions utilized for management of all toxic alcohol poisonings. To our knowledge, no prior systematic review of clinical outcomes of toxic alcohols exists. The objective of this study is to summarize existing evidence on short- and long-term outcomes of patients following toxic alcohol poisonings, including methanol, ethylene glycol, isopropanol, propylene glycol, and diethylene glycol.
METHODS
A literature search in PubMed, MEDLINE, and EMBASE will be performed based on pre-determined criteria. There will be no restrictions on publication dates or languages. The search will be supplemented by manual scan of bibliographies of eligible studies and gray literature assessment. Observational studies and clinical trials will be included in this review. Once eligible studies have been selected based on pre-specified criteria, two investigators will extract relevant data independently and perform quality assessment per validated tools. A pooled analysis of mortality and short- and long-term secondary outcomes will be performed. Pre-specified subgroup analyses will be performed according to the type of toxic alcohol intoxication, mode of renal replacement therapy, and medical interventions received. A meta-analysis will be performed if three or more studies with similar populations, type of toxic alcohol poisoning, and outcome measures, as well as adequate quality, are identified. This review will be reported according to the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) Statement.
DISCUSSION
This systematic review aims to synthesize current evidence in the short- and long-term outcomes of post-toxic alcohol poisoning. The results will enhance the understanding of patient morbidity and mortality after toxic alcohol poisoning, help inform uniform concrete management guideline development, identify gaps in the current state of knowledge, and provide evidence to help implement post-treatment follow-up.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42018101955.
Topics: Humans; Antidotes; Clinical Protocols; Ethylene Glycol; Methanol; Renal Dialysis; Treatment Outcome; Systematic Reviews as Topic
PubMed: 30593287
DOI: 10.1186/s13643-018-0926-z -
British Journal of Anaesthesia May 1993
Review
Topics: Acute Disease; Adolescent; Adult; Antidotes; Charcoal; Child, Preschool; Female; Gastric Lavage; Hemoperfusion; Humans; Male; Poisoning; Renal Dialysis; Resuscitation
PubMed: 8318332
DOI: 10.1093/bja/70.5.562 -
Emergencias : Revista de La Sociedad... Jun 2022To identify the most common problems related to use of N-acetylcysteine to reverse the toxic effects of paracetamol poisoning. (Observational Study)
Observational Study
OBJECTIVES
To identify the most common problems related to use of N-acetylcysteine to reverse the toxic effects of paracetamol poisoning.
MATERIAL AND METHODS
Retrospective descriptive observational study of clinical records for patients treated for paracetamol poisoning in 4 emergency departments during 3 years (2017-2019). We analyzed epidemiologic, clinical, and care variables, especially those related to the suitability and safety of using N-acetylcysteine as an antidote.
RESULTS
We included 332 cases of poisoning of 260 patients (78%) were over the age of 16 years, and 242 (73%) were female. Two hundred sixty-eight poisonings (81%) were the result of voluntary intake. The elimination half-life was determined in 20 cases (6%). Gastrointestinal decontamination was incorrectly prescribed on 39 occasions (28%). Treatment with the antidote was begun in 195 cases (58.7%). No serious clinical signs or symptoms were present in 282 cases (85%). The correlation of paracetamol levels in urine was stronger with the amount of drug ingested voluntarily (R2 = 0.23) than with accidental intake (R2 = 0.007). Predefined severity criteria were significantly related to reported dose ingested per body weight (P = .001) and the interval between intake and first medical assistance (P = .008).
CONCLUSION
Even though clear protocols are available to guide the use of antidote treatment in cases of paracetamol poisoning, variability in fundamental aspects of management is excessive.
Topics: Acetaminophen; Acetylcysteine; Adolescent; Antidotes; Emergency Service, Hospital; Female; Humans; Male; Retrospective Studies
PubMed: 35736523
DOI: No ID Found -
European Journal of Hospital Pharmacy :... Nov 2022Antidotes are an important part of the emergency preparedness in hospitals. In the case of a major chemical accident or a fire, large quantities of antidotes may be...
OBJECTIVES
Antidotes are an important part of the emergency preparedness in hospitals. In the case of a major chemical accident or a fire, large quantities of antidotes may be needed within a short period of time. For time-critical antidotes it is therefore necessary that they be immediately available. We wanted to evaluate the antidote preparedness in Norwegian hospitals as regards the national recommendations and compare this with other international guidelines.
METHODS
A digital survey was sent to the 50 hospitals in Norway that treat acute poisonings. Of these, four hospitals are categorised as regional hospitals, 15 as large hospitals and 31 as small hospitals. Each hospital was asked which antidotes they stockpiled from a list of 35 antidotes. The financial costs (low, moderate, high) were added to an established efficacy scale to illustrate the cost-effectiveness of the different antidotes.
RESULTS
The response rate was 100%. Eleven of fifty (22%) hospitals stockpiled all antidotes recommended for their hospital size. All four regional hospitals had all the recommended antidotes. Large hospitals which were not regional hospitals had the least availability of antidotes, and only one large hospital stockpiled all antidotes recommended for this hospital size.
CONCLUSIONS
We found varying compliance with the national recommendations for antidote storage in hospitals. To strengthen antidote preparedness, we recommend standardised European guidelines to support national guidelines.
Topics: Antidotes; Pharmacy Service, Hospital; Emergency Service, Hospital; Hospitals; Surveys and Questionnaires
PubMed: 33483361
DOI: 10.1136/ejhpharm-2020-002544 -
Biological & Pharmaceutical Bulletin 2022Cardiac electropharmacological effects of an antidiarrheal drug loperamide and its antidote naloxone were assessed in isoflurane-anesthetized guinea pigs. Intravenous...
Cardiac electropharmacological effects of an antidiarrheal drug loperamide and its antidote naloxone were assessed in isoflurane-anesthetized guinea pigs. Intravenous administration of loperamide at 0.01-0.1 mg/kg did not affect parameters of electrocardiogram (ECG) or monophasic action potential (MAP) of the right ventricle. Additional administration of loperamide at 1 mg/kg prolonged the QT interval and MAP duration of the ventricle accompanied with increments of the PQ interval and QRS width. The potency of loperamide for QT-interval prolongation was about 100-times lower than that of dofetilide, in spite that similar inhibitory effects on the human Ether-a-go-go Related Gene (hERG) K channels have been reported between loperamide and dofetilide, implying lower accessibility of loperamide to the K channels. Intravenous administration of naloxone at 0.003-0.3 mg/kg, which effectively inhibits µ-opioid receptors, did not affect ECG parameters including QT interval or MAP duration. Furthermore, the loperamide-induced cardiac electrophysiological changes were not modified in the presence of naloxone at 0.3 mg/kg. These results suggest that loperamide has a potential to delay cardiac conduction and repolarization in the in vivo condition. Since naloxone did not modify ECG parameters and loperamide-induced ECG changes, naloxone is confirmed to possess acceptable cardiac safety when used as an antidote.
Topics: Animals; Antidiarrheals; Antidotes; Guinea Pigs; Heart; Loperamide; Naloxone
PubMed: 35370282
DOI: 10.1248/bpb.b22-00024