Warfarin: from rat poison to clinical use

Lim, Gregory B.

doi:10.1038/nrcardio.2017.172

Cited by 52 publications

(44 citation statements)

References 6 publications

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“…The blood coagulation system of the rat has long been investigated. Because this system is extremely rapid in the rat, this special property was used for the application of a specific rodenticide, influencing and acting on the coagulation system by disrupting vitamin K metabolism [29, 30]. Since 1948, the compound ‘warfarin’ has been successfully marketed as a rodenticide.…”

Section: Coagulation Systemmentioning

confidence: 99%

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Modeling trauma in rats: similarities to humans and potential pitfalls to consider

et al. 2019

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Trauma is the leading cause of mortality in humans below the age of 40. Patients injured by accidents frequently suffer severe multiple trauma, which is life-threatening and leads to death in many cases. In multiply injured patients, thoracic trauma constitutes the third most common cause of mortality after abdominal injury and head trauma. Furthermore, 40–50% of all trauma-related deaths within the first 48 h after hospital admission result from uncontrolled hemorrhage. Physical trauma and hemorrhage are frequently associated with complex pathophysiological and immunological responses. To develop a greater understanding of the mechanisms of single and/or multiple trauma, reliable and reproducible animal models, fulfilling the ethical 3 R’s criteria (Replacement, Reduction and Refinement), established by Russell and Burch in ‘The Principles of Human Experimental Technique’ (published 1959), are required. These should reflect both the complex pathophysiological and the immunological alterations induced by trauma, with the objective to translate the findings to the human situation, providing new clinical treatment approaches for patients affected by severe trauma. Small animal models are the most frequently used in trauma research. Rattus norvegicus was the first mammalian species domesticated for scientific research, dating back to 1830. To date, there exist numerous well-established procedures to mimic different forms of injury patterns in rats, animals that are uncomplicated in handling and housing. Nevertheless, there are some physiological and genetic differences between humans and rats, which should be carefully considered when rats are chosen as a model organism. The aim of this review is to illustrate the advantages as well as the disadvantages of rat models, which should be considered in trauma research when selecting an appropriate in vivo model. Being the most common and important models in trauma research, this review focuses on hemorrhagic shock, blunt chest trauma, bone fracture, skin and soft-tissue trauma, burns, traumatic brain injury and polytrauma.

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Section: Coagulation Systemmentioning

confidence: 99%

“…Later, this substance was used as a therapeutic anticoagulant in the clinic and was preferred to other anticoagulants because of its special and beneficial properties. Therefore, the substance was approved as a therapeutic substance for humans in 1954 [29].…”

Section: Coagulation Systemmentioning

confidence: 99%

Modeling trauma in rats: similarities to humans and potential pitfalls to consider

et al. 2019

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“…Today, many people are familiar with the anticoagulant warfarin as an orally administered human medicine which acts as a blood thinner to prevent thrombosis. Warfarin (CAS number 81-81-2) was named for the Wisconsin Alumni Research Foundation (WARF), the organization that identified its anticoagulant properties and went on to develop it as both a rodenticide and therapeutic anticoagulant around 1950 [15]. Warfarin is one of a family of anticoagulant compounds based on a ‘coumarin’ chemical structure (Figure 1).…”

Section: Anticoagulant Rodenticidesmentioning

confidence: 99%

Anticoagulant Rodenticides, Islands, and Animal Welfare Accountancy

Fisher

Campbell

Howald³

et al. 2019

Animals

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Simple SummaryAnticoagulant rodenticides are a mainstay of rodent management in many domestic, municipal, agricultural, and conservation settings. Anticoagulant poisoning has poor welfare outcomes for mammals and birds and, worldwide, this means potentially very large numbers of animals are poisoned annually consequent (intended or not) to rodenticide use. Critical differences in use patterns of anticoagulants applied for ongoing rodent control, versus application for rodent eradication especially on islands, have clear implications for animal welfare costs measured as cumulative number of animals affected over time. Here we outline these differences and discuss how animal welfare considerations can be weighed in decisions to use anticoagulant rodenticides for island eradication attempts.AbstractAnticoagulant rodenticides are used to manage rodents in domestic, municipal, agricultural, and conservation settings. In mammals and birds, anticoagulant poisoning causes extensive hemorrhagic disruption, with the primary cause of death being severe internal bleeding occurring over days. The combined severity and duration of these effects represent poor welfare outcomes for poisoned animals. Noting a lack of formal estimates of numbers of rodents and nontarget animals killed by anticoagulant poisoning, the ready availability and worldwide use of anticoagulants suggest that very large numbers of animals are affected globally. Scrutiny of this rodent control method from scientific, public, and regulatory perspectives is being driven largely by mounting evidence of environmental transfer of residual anticoagulants resulting in harmful exposure in wild or domestic animals, but there is also nascent concern for the welfare of targeted rodents. Rodent control incurs a cumulative ledger of animal welfare costs over time as target populations reduced by poisoning eventually recover to an extent requiring another reduction. This ‘rolling toll’ presents a critical contrast to the animal welfare accountancy ledger for eradication scenarios, where rodent populations can be completely removed by methods including anticoagulant use and then kept from coming back (e.g., on islands). Successful eradications remove any future need to control rodents and to incur the associated animal welfare costs.

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“…Coumarins have proved to be effective in the treatment of thromboembolic disease and despite the introduction of direct oral anticoagulants, they remain one of the most widely prescribed family of drugs worldwide …”

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confidence: 99%

Effect of CYP4F2,VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single‐Patient Data Meta‐Analysis in More Than 15,000 Individuals

Danese

Raimondi

Montagnana

et al. 2019

Clin Pharma and Therapeutics

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The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

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Warfarin: from rat poison to clinical use

Cited by 52 publications

References 6 publications

Modeling trauma in rats: similarities to humans and potential pitfalls to consider

Modeling trauma in rats: similarities to humans and potential pitfalls to consider

Anticoagulant Rodenticides, Islands, and Animal Welfare Accountancy

Effect of CYP4F2,VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single‐Patient Data Meta‐Analysis in More Than 15,000 Individuals

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