ABSTRACT
The Bonin Archipelago is a United Nations Educational, Scientific and Cultural Organization's World Natural Heritage Site in Japan with a unique ecosystem; however, the invasive rodents preying on endemic species have been a significant concern. The anticoagulant rodenticide, diphacinone, sprayed by the Ministry of the Environment, has succeeded; however, its repeated use leads to rodenticide resistance. This study evaluated the sensitivity by in vivo pharmacokinetics/pharmacodynamics (PK/PD) analysis and physiologically-based pharmacokinetic modeling to diphacinone in black rats (Rattus rattus) captured on the Bonin Archipelago in February 2022. The Bonin rats exhibited prolonged coagulation time after diphacinone administration. They recovered earlier than susceptible black rats, indicating that Bonin rats were less susceptible, though there were no genetic mutations in Vkorc1, the target enzyme of diphacinone. After the administration of diphacinone, hepatic expression levels of Fsp1, identified as the vitamin K reductase, was decreased, however, the Bonin rats exhibited the most minor suppression. The PK analysis showed that the excretion capacity of the Bonin rats was lower than that of the resistant black rats. In the PBPK modeling, the resistant black rats showed higher clearance than the Bonin and susceptible black rats due to high hepatic metabolic capacity. The Bonin rats demonstrated slow absorption and relatively low clearance. This study highlighted the reduced rodenticide-sensitive tendency of wild black rats in the Bonin Archipelago at an in vivo phenotype level. At the same time, they do not have known rodenticide resistance mechanisms, such as hepatic metabolic enhancement or Vkorc1 mutations. It is crucial to monitor the biological levels to evaluate rodenticide sensitivity accurately.
Subject(s)
Phenindione/analogs & derivatives , Rodenticides , Rats , Animals , Rodenticides/pharmacology , Japan , EcosystemABSTRACT
IPOPI held its first Global Multi-Stakeholders' Summit on 23-24 June 2022 in Cascais, Portugal. This IPOPI initiative was designed to set the stage for a stimulating forward-thinking meeting and brainstorming discussion among stakeholders on the future priorities of the PID community. All participants were actively engaged in the entire Summit, bringing provocative questions to ensure a high level of discussion and engagement, and partnered in identifying the outlooks, unmet needs, hurdles and opportunities of PIDs for 2030. The topics that were covered include diagnosis (e.g., newborn screening [NBS], genomic sequencing- including ethical aspects on the application of genomics on NBS, the role of more accurate and timely diagnostics in impacting personalized management), treatment (e.g., the therapeutic evolution of immunoglobulins in a global environment, new therapies such as targeted therapies, new approaches in curative therapies), the interactions of Primary ID with Secondary ID, Autoinflammatory Diseases and other diseases as the field experiences an incessant evolution, and also the avenues for research in the field of humanities and human sciences such as Patient-Reported Outcome Measures (PROMs), Patient-Reported Experience Measures (PREMs), and Health-Related Quality Of Life (HRQoL). During this meeting, all participants contributed to the drafting of recommendations based on our common understanding of the future opportunities, challenges, and scenarios. As a collection of materials, perspectives and summaries, they are succinct and impactful and may help determine some of the next key steps for the PID community.
Subject(s)
Pelvic Inflammatory Disease , Phenindione , Infant, Newborn , Female , Humans , Quality of Life , Humanities , Chromosome Mapping , Genomics , Neonatal ScreeningABSTRACT
Anticoagulant rodenticides have been widely used to eliminate wild rodents, which as invasive species on remote islands can disturb ecosystems. Since rodenticides can cause wildlife poisoning, it is necessary to evaluate the sensitivity of local mammals and birds to the poisons to ensure the rodenticides are used effectively. The Bonin Islands are an archipelago located 1000 km southeast of the Japanese mainland and are famous for the unique ecosystems. Here the first-generation anticoagulant rodenticide diphacinone has been used against introduced black rats (Rattus rattus). The only land mammal native to the archipelago is the Bonin fruit bat (Pteropus pselaphon), but little is known regarding its sensitivity to rodenticides. In this study, the Egyptian fruit bats (Rousettus aegyptiacus) was used as a model animal for in vivo pharmacokinetics and pharmacodynamics analysis and in vitro enzyme kinetics using their hepatic microsomal fractions. The structure of vitamin K epoxide reductase (VKORC1), the target protein of the rodenticide in the Bonin fruit bat, was predicted from its genome and its binding affinity to rodenticides was evaluated. The Egyptian fruit bats excreted diphacinone slowly and showed similar sensitivity to rats. In contrast, they excreted warfarin, another first-generation rodenticide, faster than rats and recovered from the toxic effect faster. An in silico binding study also indicated that the VKORC1 of fruit bats is relatively tolerant to warfarin, but binds strongly to diphacinone. These results suggest that even chemicals with the same mode of action display different sensitivities in different species: fruit bat species are relatively resistant to warfarin, but vulnerable to diphacinone.
Subject(s)
Chiroptera , Rodenticides , Animals , Anticoagulants/toxicity , Chiroptera/metabolism , Ecosystem , Mammals/metabolism , Phenindione/analogs & derivatives , Rats , Rodenticides/toxicity , Toxicokinetics , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Warfarin/toxicityABSTRACT
Malgré leur prescription en seconde intention après les anticoagulants oraux directs, les antivitamines K (AVK) sont encore largement utilisés en soins premiers. En France, la fluindione représentait 82 % des AVK prescrits en 2016 contre 13 % pour la warfarine. Pourtant, la warfarine est l'AVK de référence ailleurs dans le monde et sa demi-vie plus longue devrait la rendre plus adaptée avec des International Normalized Ratio (INR) plus stables. Les objectifs de notre travail étaient de comparer ces deux molécules en termes de stabilité de leur effet anticoagulant au long cours et sur la fréquence des INR réalisés. Nous avons mené une étude rétrospective de type exposé/non-exposé sur données issues d'un laboratoire de biologie médicale ornais concernant des patients majeurs traités par fluindione ou warfarine du 1er janvier 2014 au 31 décembre 2016 inclus, quelle que soit l'indication. La stabilité du traitement était évaluée par le temps passé dans l'intervalle thérapeutique (TTR), calculé selon la méthode de Rosendaal, à partir des INR dosés en pratique courante. Les comparaisons entre les deux groupes ont été faites par régression linéaire multi-niveaux avec analyse univariée puis multivariée avec ajustement sur l'âge, le genre et la fonction rénale. Deux-cent-quatre patients ont été inclus (77,0 ± 10,0 ans, 49,5 % de femmes), 170 sous fluindione et 34 sous warfarine. Le TTR moyen sous fluindione était de 68,0 % contre 72,0 % sous warfarine (p = 0,085). Le délai moyen entre deux INR était de 22,8 jours sous fluindione contre 31,1 jours sous warfarine (p = 0,049). Par rapport à la fluindione, la warfarine semble présenter un bénéfice en termes de qualité de vie pour les patients. Malgré nos résultats, nous invitons à privilégier la warfarine à la fluindione en soins premiers.
Subject(s)
Primary Health Care , Warfarin , Humans , International Normalized Ratio , Phenindione/analogs & derivatives , Retrospective StudiesABSTRACT
Poisoning of nontarget species is a major concern with the use of anticoagulant rodenticides (ARs). At postmortem examination, differentiating toxicosis from incidental exposure is sometimes difficult. Clotting profiles cannot be performed on postmortem samples, and clinically significant serum, blood, and liver AR concentrations are not well-established in most species. We chose diphacinone for our study because, at the time, it was the publicly available AR most commonly detected in samples analyzed at the University of Kentucky Veterinary Diagnostic Laboratory. We determined an approximate minimum toxic dosage (MTD) of oral diphacinone in 3 horses and measured corresponding serum, blood, and liver diphacinone concentrations. Diphacinone was administered orally to healthy horses. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and serum and blood diphacinone concentrations were measured daily. At the study endpoint, the horses were euthanized, and diphacinone concentration was measured in each liver lobe. The horse that received 0.2 mg/kg diphacinone developed prolonged (>1.5× baseline) PT and aPTT; the horse that received 0.1 mg/kg did not. This suggests an approximate oral MTD in horses of 0.2 mg/kg diphacinone. Median liver diphacinone concentration at this dosage was 1,780 (range: 1,590-2,000) ppb wet weight. Marginal (model-adjusted) mean diphacinone concentrations of liver lobes were not significantly different from one another (p = NS). Diphacinone was present in similar concentrations in both serum and blood at each time after administration, indicating that both matrices are suitable for detection of diphacinone exposure in horses.
Subject(s)
Phenindione , Rodenticides , Animals , Anticoagulants , Horses , Liver , Phenindione/analogs & derivatives , Phenindione/toxicity , Pilot Projects , Rodenticides/toxicity , SerumABSTRACT
INTRODUCTION: The aim of our study was to compare the time spent within the target INR or Time in Therapeutic Range (TTR) of patients treated with fluindione to that of patients treated with warfarin for non-valvular atrial fibrillation (NVAF) and followed in general practice, with the hypothesis of a better TTR with warfarin, which is the VKA most commonly prescribed in France. METHOD: Liberal nurses and general practitioners working in the Auvergne region recruited patients treated with fluindione or warfarin for NVAF. Patients' INRs (International Normalized Ratios) were recorded by medical analysis laboratories for 6 months. The primary endpoint was TTR, the secondary endpoint the number of hemorrhagic and/or thromboembolic events. RESULTS: Of the 342 participants with a mean age of 75.3 ± 9.8 years, 239 (70%) were treated with fluindione and 103 (30%) with warfarin. The mean number of INRs achieved per patient was 9.2 ± 4.0 in the fluindione group and 9.3 ± 4.0 in the warfarin group (p=0.73). The median TTR of fluindione was 81.9% [63.5; 94.1] and that of warfarin was 81.3% [65.6; 92.6] (p=0.98). Twenty-eight of 263 patients reported hemorrhage (10.6%) and 4 reported thromboembolic events (0.8%), with no significant difference between the groups. CONCLUSION: The TTRs of patients treated for NVAF with fluindione versus warfarin do not differ significantly over an observation period of 6 consecutive months in a patient population comparable to that of the publications in this field. However, these TTRs are significantly higher than those reported in the literature, with no difference between the two treatments. The TTRs of patients treated for VANF with fluindione versus warfarin do not differ significantly over a 6-month observation period in a patient population comparable to that of the publications in this indication.
Subject(s)
Atrial Fibrillation , Stroke , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , Atrial Fibrillation/complications , Flowers , Hemorrhage/chemically induced , Humans , International Normalized Ratio , Phenindione/analogs & derivatives , Primary Health Care , Retrospective Studies , Stroke/complications , Warfarin/therapeutic useABSTRACT
BACKGROUND: The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS: We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS: A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS: In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).
Subject(s)
4-Hydroxycoumarins/therapeutic use , Atrial Fibrillation/drug therapy , Factor Xa Inhibitors/therapeutic use , Pyridines/therapeutic use , Thiazoles/therapeutic use , Transcatheter Aortic Valve Replacement , Vitamin K/antagonists & inhibitors , 4-Hydroxycoumarins/adverse effects , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Factor Xa Inhibitors/adverse effects , Female , Gastrointestinal Hemorrhage/chemically induced , Humans , Intention to Treat Analysis , Kaplan-Meier Estimate , Male , Mortality , Phenindione/analogs & derivatives , Phenindione/therapeutic use , Postoperative Complications/prevention & control , Pyridines/adverse effects , Thiazoles/adverse effects , Thromboembolism/prevention & control , Transcatheter Aortic Valve Replacement/adverse effectsABSTRACT
Anticoagulant rodenticides are a common tool used to manage rodents in agricultural systems, but they have received increased scrutiny given concerns about secondary exposure in non-target wildlife. Rodenticide application strategy is one factor that influences exposure risk. To understand the impact of application strategy, we tested residues of a first-generation anticoagulant (diphacinone) in liver tissue of radiotransmittered California ground squirrels (Otospermophilus beecheyi) following spot treatments, broadcast applications, and bait station applications in rangelands in central California during summer and autumn 2018-2019. We also documented the amount of bait applied, the mean time from bait application until death, and the proportion of ground squirrels that died belowground. We documented the greatest amount of bait applied via bait stations and the least by broadcast applications. We did not document a difference in diphacinone residues across any application strategy, although survivors had an order of magnitude lower concentration of diphacinone than mortalities, potentially lowering secondary exposure risk. We did not observe any difference among bait delivery methods in time from bait application to death, nor did we identify any impact of seasonality on any of the factors we tested. The vast majority of mortalities occurred belowground (82-91%), likely reducing secondary exposure. Secondary exposure could be further reduced by daily carcass searches. Results from this study better define risk associated with first-generation anticoagulant rodenticide applications, ultimately assisting in development of management programs that minimize non-target exposure.
Subject(s)
Phenindione , Rodenticides , Animals , Anticoagulants , Phenindione/analogs & derivatives , SciuridaeABSTRACT
BACKGROUND: Anticoagulant rodenticides are used worldwide to control pest rodent species. However, the risks posed to non-target reptiles have not been well characterized. In this study, 46 giant ameivas (Ameiva ameiva), 39 boa constrictors (Boa constrictor), 33 wood turtles (Rhinoclemmys pulcherrima), and 47 green iguanas (Iguana iguana) were orally dosed with one of two levels of either diphacinone or brodifacoum anticoagulant in propylene glycol solutions. Dosages were derived using daily food intake (DFI) equations, converting DFI to an equivalent anticoagulant bait amount and gavaging the solution volume needed to deliver the quantity of anticoagulant in that amount of bait. Animals were dosed on days 0 and 7 and monitored for a further 7 days for signs of anticoagulant intoxication and differences in behaviors and postures. At necropsy on day 14, animals were examined for thoracic and abdominal bleeding, and both tissue and organ samples were taken for histology. Liver and whole-body anticoagulant residues were assessed. RESULTS: No turtles or boas died due to anticoagulant exposure. However, anticoagulant intoxication was suspected in one iguana dosed with brodifacoum. A few treated ameivas died but exhibited no hemorrhaging. Liver residue levels were higher than whole-body remainder residue levels for all species. Unlike the other species, turtles had higher diphacinone residue levels than brodifacoum. CONCLUSION: Turtles and boas exhibited a relative insensitivity to diphacinone and brodifacoum, while the lizards appeared to be somewhat more sensitive to these compounds. This study provides data for future assessments of the risks to these species associated with anticoagulant use. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.
Subject(s)
Reptiles , 4-Hydroxycoumarins , Animals , Anticoagulants , Phenindione/analogs & derivatives , RodenticidesABSTRACT
Diphacinone (DPN) is an extensively used anticoagulant rodenticide that is also considered a hazardous chemical, which poses a threat to nontarget species. DPN poisoning cases in humans or other species frequently occur, while rapid and sensitive detection methods are rarely reported. Thus, it is meaningful to develop an immunoassay for DPN detection with high sensitivity and specificity. In this study, a hapten was synthesized and then conjugated with carrier proteins to prepare the immunogens with different conjugation ratios for the preparation of antibody. After evaluation of the antisera using an indirect competitive enzyme-linked immunosorbent assay (icELISA) and statistical analysis, we found that the immunogen prepared using the N,N-dicyclohexylcarbodiimide (DCC) method with a conjugation ratio of 28.5 could elicit mice to generate antibodies with high performance. Using hybridoma technology, we obtained the specific monoclonal antibody (mAb) 4G5 with a half maximal inhibitory concentration (IC50) of 0.82 ng/mL in buffer solution. We initially explored the recognition mechanism of DPN/CLDPN and mAb from both conformational and electronic aspects. Then, mAb 4G5 was applied to develop icELISA for biological samples. The limits of detection (LODs) of icELISA were 0.28 µg/L, 0.32 µg/L, and 0.55 µg/kg for swine plasma, urine, and liver samples, respectively, and the recoveries ranged from 72.3 to 103.3% with a coefficient of variation (CV) of less than 12.3% in spiked samples. In summary, we developed a sensitive, specific, and accurate icELISA for the detection of DPN in biological samples, which showed potential in food safety analysis and clinical diagnosis. Graphical abstract.
Subject(s)
Anticoagulants/analysis , Enzyme-Linked Immunosorbent Assay/methods , Phenindione/analogs & derivatives , Rodenticides/analysis , Animals , Antibodies, Monoclonal/immunology , Antibody Formation , Anticoagulants/blood , Anticoagulants/immunology , Anticoagulants/urine , Female , Limit of Detection , Liver/chemistry , Mice, Inbred BALB C , Models, Molecular , Phenindione/analysis , Phenindione/blood , Phenindione/immunology , Phenindione/urine , Rodenticides/blood , Rodenticides/immunology , Rodenticides/urine , SwineSubject(s)
Digoxin/pharmacology , Drug Overdose/etiology , Hematemesis/chemically induced , Phenindione/analogs & derivatives , Phenylthiohydantoin/analogs & derivatives , Aged , Atrial Fibrillation/blood , Atrial Fibrillation/drug therapy , Benzamides , Digoxin/therapeutic use , Drug Interactions , Drug Overdose/therapy , Drug Substitution , Hematemesis/therapy , Humans , International Normalized Ratio , Male , Nitriles , Phenindione/pharmacology , Phenindione/therapeutic use , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic use , Polypharmacy , Prostatic Neoplasms/drug therapy , Tinzaparin/therapeutic useSubject(s)
Blood Coagulation Tests/methods , Factor X/metabolism , Prothrombin/metabolism , Vitamin K/antagonists & inhibitors , Acenocoumarol/therapeutic use , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , Female , Humans , Male , Middle Aged , Phenindione/analogs & derivatives , Phenindione/therapeutic use , Reference Values , Warfarin/therapeutic useSubject(s)
4-Hydroxycoumarins/adverse effects , Anticoagulants/adverse effects , Drug Overdose/complications , Indenes/adverse effects , Macular Degeneration/drug therapy , Retinal Detachment/chemically induced , Retinal Hemorrhage/chemically induced , Vitamin K/antagonists & inhibitors , 4-Hydroxycoumarins/administration & dosage , Aged, 80 and over , Allopurinol/therapeutic use , Anticoagulants/administration & dosage , Drug Interactions , Drug Overdose/diagnosis , Humans , Iatrogenic Disease , Indenes/administration & dosage , Macular Degeneration/diagnosis , Male , Phenindione/analogs & derivatives , Retinal Detachment/diagnosis , Retinal Hemorrhage/diagnosis , Vitamin K/administration & dosage , Vitamin K/adverse effectsABSTRACT
Warfarin, acenocoumarol, phenprocoumon, and fluindione are commonly prescribed oral anticoagulants for the prevention and treatment of thromboembolic disorders. These anticoagulants function by impairing the biosynthesis of active vitamin K-dependent coagulation factors through the inhibition of vitamin K epoxide reductase (VKOR). Genetic variations in VKOR have been closely associated with the resistant phenotype of oral anticoagulation therapy. However, the relative efficacy of these anticoagulants, their mechanisms of action, and their resistance variations among naturally occurring VKOR mutations remain elusive. Here, we explored these questions using our recently established cell-based VKOR activity assay with the endogenous VKOR function ablated. Our results show that the efficacy of these anticoagulants on VKOR inactivation, from most to least, is: acenocoumarol > phenprocoumon > warfarin > fluindione. This is consistent with their effective clinical dosages for stable anticoagulation control. Cell-based functional studies of how each of the 27 naturally occurring VKOR mutations responds to these 4 oral anticoagulants indicate that phenprocoumon has the largest resistance variation (up to 199-fold), whereas the resistance of acenocoumarol varies the least (<14-fold). Cell-based kinetics studies show that fluindione appears to be a competitive inhibitor of VKOR, whereas warfarin is likely to be a mixed-type inhibitor of VKOR. The anticoagulation effect of these oral anticoagulants can be reversed by the administration of a high dose of vitamin K, apparently due to the existence of a different enzyme that can directly reduce vitamin K. These findings provide new insights into the selection of oral anticoagulants, their effective dosage management, and their mechanisms of anticoagulation.
Subject(s)
Anticoagulants/pharmacology , Enzyme Inhibitors/pharmacology , Vitamin K Epoxide Reductases/antagonists & inhibitors , Administration, Oral , Anticoagulants/administration & dosage , Cell Line , Drug Resistance , Enzyme Inhibitors/administration & dosage , Humans , Phenindione/administration & dosage , Phenindione/analogs & derivatives , Phenindione/pharmacology , Point Mutation , Vitamin K/metabolism , Vitamin K Epoxide Reductases/genetics , Vitamin K Epoxide Reductases/metabolism , Warfarin/administration & dosage , Warfarin/pharmacologyABSTRACT
Isolated arthralgia, without hemorrhagic side effect, exists and is considered as a very rare adverse drug reaction according to vitamin K antagonists' (VKAs) summary of product characteristics. Up to now, there are no literature reports of isolated, nonhemorrhagic joint complications in patients receiving VKAs. Hence, the objective of this study was to describe cases of VKA-related nonhemorrhagic joint disorders (fluindione, warfarin, and acenocoumarol) reported in the French Pharmacovigilance Database (FPVD). Sixty-one reports (male : female ratio, 1.18; median [interquartile range (IQR)] age: 60 [49-72]) were found. Fluindione, warfarin, and acenocoumarol were respectively suspected in 42, 12, and 7 cases. Arthralgia was reported in 47 cases (77%), arthritis in nine cases (15%), capsulitis in three cases (5%), and bursitis in two cases (3%). Although the joint symptoms mainly concerned the lower limbs, all types of joints were affected. Arthralgia was associated with myalgia in 14 cases and with tendinitis in three cases. The median (IQR) time interval between VKA introduction and arthralgia onset was 26 (10-98) days (range: 1-6935). VKA was withdrawn in 44 cases, and a decrease in the intensity of joint symptoms was observed in 30 cases. In three cases, reintroduction of the same VKA led to the recurrence of symptoms. In view of the large prescription of this drug class worldwide, patients and clinicians (and especially primary care physicians and geriatricians) should be aware of this possible adverse drug reaction when confronted with joint disorders in patients of all ages taking VKAs.
Subject(s)
Anticoagulants/adverse effects , Drug-Related Side Effects and Adverse Reactions/etiology , Joint Diseases/chemically induced , Vitamin K/antagonists & inhibitors , Acenocoumarol/adverse effects , Aged , Female , Humans , Male , Middle Aged , Pharmacovigilance , Phenindione/adverse effects , Phenindione/analogs & derivatives , Warfarin/adverse effectsABSTRACT
INTRODUCTION: Despite the increasing utilization of direct oral anticoagulant (DOAC) prescriptions, vitamin K antagonists (VKAs) remain the treatment of choice for treating and preventing thromboembolic events. The morbidity and mortality of VKAs are partly due to the difficulty of keeping the patient within the therapeutic range. For patients treated by VKA, time in therapeutic range (TTR) is a quality parameter of treatment, widely used in clinical trials but rarely by prescribers. It is well established that its use correlates with the risk of hemorrhage, thrombosis or mortality. We studied this parameter in a cohort of patients to evaluate the quality of their therapeutic follow-up and tried to identify risk factors for low TTR. METHODS: The study was made in collaboration with LaboSud Oc Biologie for a duration of 4 months. It included 3387 patients representing 2,4029 INR. We calculated the patients' TTR. The laboratory transmitted to us the sex and age of each patient and the VKA molecule used, the therapeutic range and the specialty of the prescriber. We then analyzed the odds ratio associated with these different factors. RESULTS: The mean TTR was 68%, close to the TTR recommended by scientific societies. Patient's sex was the only statistically correlated factor, with a worse equilibrium in females taking VKAs (OR=1.22, 95% CI: 1.06-1.39, P=0.00552). Many factors usually correlated with poor equilibrium under VKA have not been studied due to lack of information. CONCLUSION: Given the context of economic restriction and the TTR of our cohort close to the recommended 70%, there would be no benefit in terms of safety to prefer DOAC for the patients involved in this study. Regular monitoring of the individual patient's as well as the cohort's TTR should optimize the management of patients receiving VKAs.
Subject(s)
Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Thromboembolism/drug therapy , Vitamin K/antagonists & inhibitors , Acenocoumarol/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Anticoagulants/administration & dosage , Atrial Fibrillation/complications , Cohort Studies , Female , Humans , International Normalized Ratio , Male , Middle Aged , Phenindione/analogs & derivatives , Phenindione/therapeutic use , Risk Factors , Sex Factors , Thromboembolism/prevention & control , Treatment Outcome , Vitamin K/blood , Warfarin/therapeutic useABSTRACT
RATIONALE: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. PATIENT CONCERNS: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. DIAGNOSES: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. INTERVETIONS: The anticoagulant was withdrawn, and corticosteroids (1âmg/kg/day) and acenocoumarol were started. OUTCOMES: Clinical improvement ensued. At follow-up the patient is well. LESSONS: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.
Subject(s)
Drug Hypersensitivity Syndrome , Glucocorticoids/administration & dosage , Lymphatic Abnormalities , Noonan Syndrome , Phenindione/analogs & derivatives , Thrombotic Microangiopathies , Adult , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Diagnosis, Differential , Drug Hypersensitivity Syndrome/blood , Drug Hypersensitivity Syndrome/diagnosis , Drug Hypersensitivity Syndrome/etiology , Drug Hypersensitivity Syndrome/physiopathology , Humans , Lymphatic Abnormalities/diagnosis , Lymphatic Abnormalities/etiology , Male , Mediastinum/diagnostic imaging , Mediastinum/pathology , Mutation , Noonan Syndrome/genetics , Noonan Syndrome/physiopathology , Phenindione/administration & dosage , Phenindione/adverse effects , Retroperitoneal Space/diagnostic imaging , Retroperitoneal Space/pathology , Son of Sevenless Proteins/genetics , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/etiology , Withholding TreatmentSubject(s)
Anticoagulants/adverse effects , Antimalarials/adverse effects , Atovaquone/adverse effects , Malaria, Falciparum/complications , Phenindione/analogs & derivatives , Proguanil/adverse effects , Anticoagulants/therapeutic use , Antimalarials/therapeutic use , Atovaquone/therapeutic use , Drug Combinations , Drug Interactions , Female , Heart Valve Prosthesis Implantation , Humans , Malaria, Falciparum/drug therapy , Middle Aged , Phenindione/adverse effects , Phenindione/therapeutic use , Proguanil/therapeutic use , Thrombosis/prevention & control , TravelABSTRACT
The anticoagulant rodenticides brodifacoum, chlorophacinone, and diphacinone have been proposed for broadcast application in some forested areas in Hawai'i to protect rare and endangered native bird species from introduced mice and rats. Groundwater resources in Hawai'i are prone to contamination due to the intrinsic aquifer vulnerability to leaching from the land surface. Because of the hydrogeologic complexity, Hawai'i uses a Tier-I leaching assessment tool, CLERS, to make registration decisions for new or existing chemicals. The CLERS tool uses soil and pesticide properties as well as water recharge through the soil profile in a GIS framework to estimate mass attenuation of the chemicals at a given depth and compares against this attenuation factor against those of a known leacher and a non-leacher. Disturbed soil samples were collected across the state of Hawai'i, including the islands of Hawai'i, Kaho'olawe, Kaua'i, Lana'i, Maui, Moloka'i, and O'ahu, with two sampling locations per island, except for Kaua'i which had three. As only limited information on chemical properties of these anticoagulants in soils is available, laboratory experiments were performed to determine the sorption capacity (Kd) and the degradation rate (T1/2) of brodifacoum, chlorophacinone, and diphacinone to construct a proper chemical database. Depending on the soil type, T1/2 values ranged between 37 and 248days for diphacinone, between 39 and 1000days for chlorophacinone, and between 72 and 462days for brodifacoum. These data were used in the CLERS tool to estimate leaching risks for these chemicals primarily in forested areas of the state where the chemicals are likely to be applied. The results from the CLERS tool indicate low risks of leaching of these three compounds into aquifers in five out of six major Hawaiian Islands. Diphacinone showed medium risk of leaching in a few remote areas in Maui.