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Superwarfarin (long-acting anticoagulant rodenticide) poisoning should be suspected in unexplained bleeding with prolonged prothrombin time, especially in the absence of another explanation. Diagnosis and treatment of this intoxication remain a challenge as the direct analysis of superwarfarin in serum is not always possible. Therefore, toxin bioavailability remains unknown and close monitoring and treatment for long periods are required to avoid serious bleeding complications. Here, we discuss a case of suspected superwarfarin poisoning to highlight the challenges in early diagnosis and the challenges we encountered in treatment management and ensuring compliance for long periods.

1-Butane sulfonic acid-3-methylimidazolium tosylate, [BSMIM]OTs, is a remarkable catalyst for the cascade synthesis of coumarin-functionalized indole derivatives via a tandem cyclization reaction of aniline and phenylglyoxal monohydrate.

Introduction and aim Portal vein thrombosis (PVT) is associated with a higher risk of liver-related complications. Recent guidelines recommend direct-acting anticoagulants (DOAC) in patients with cirrhosis and non-tumoral PVT. However, data on the efficacy and safety of DOAC in these patients remain limited. We aim to investigate the efficacy and safety of DOAC compared to vitamin K antagonists (VKA) to treat non-tumoral PVT in patients with cirrhosis. Methods We performed a systematic search of six electronic databases using MeSH term and free text. We selected all studies comparing the use of DOACs with vitamin K antagonist to treat PVT in cirrhosis. The primary outcome was PVT recanalization. Secondary outcomes were and PVT progression, major bleeding, variceal bleeding and death. Results From 944 citations, we included 552 subjects from a total of 11 studies (10 observational and 1 randomized trial) that fulfilled the inclusion criteria. We found that DOAC were associated with a higher pooled rate of PVT recanalization (RR = 1.67, 95%CI: 1.02, 2.74, I2 = 79%) and lower pooled risk of PVT progression (RR = 0.14, 95%CI: 0.03–0.57, I2 = 0%). The pooled risk of major bleeding (RR = 0.29, 95%CI: 0.08–1.01, I2 = 0%), variceal bleeding (RR = 1.29, 95%CI: 0.64–2.59, I2 = 0%) and death (RR = 0.31, 95%CI: 0.01–9.578, I2 = 80%) was similar between DOAC and VKA. Conclusion For the treatment of PVT in patients with cirrhosis, the bleeding risk was comparable between DOAC and VKA. However, DOAC were associated with a higher pooled rate of PVT recanalization. Dedicated randomized studies are needed to confirm these findings.

An asymmetric Michael/hemiketalization reaction between isatin-derived β,γ-unsaturated α-ketoesters and 4-hydroxycoumarins was developed in aqueous media. A series of chiral spirooxindole derivatives with an all-carbon quaternary stereogenic center were obtained in high yields (up to 93%) and excellent enantioselectivities (up to 98%).

Direct and selective C(sp2)-H/C(sp2)-H cross-dehydrogenative coupling has become a promising strategy to increase molecular complexity with a high atom economy. This study describes an efficient and straightforward protocol for the regioselective C3-H/C3-H cross-coupling of 4-hydroxycoumarin derivatives with quinoxalin-2(1H)-ones, including late-stage modification of natural drugs, promoted by visible light under aerobic conditions at room temperature. With this approach, a wide range of hybrid drug-like molecules were prepared, using air as the terminal oxidant. Remarkably, the C4 OH group at the coumarin ring is essential for the reaction and has been used as a handle for diverse functionalizations of the final products. Moreover, sunlight can promote the reaction under very mild and sustainable conditions, even on a gram scale. Qualitative and semi-quantitative tools were used to demonstrate the greenness advance of this methodology over previously reported ones. Several experiments were conducted to propose a plausible mechanism for this transformation. This work was financially supported by the Spanish Ministerio de Ciencia e Innovación (grant no. CTQ2017-88171-P), Generalitat Valenciana (SEJIGENT/2021/005, granted to I. B.), and the University of Alicante (GRE20-03-A granted to I. B.).

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.).

Based on the pharmaceutical potentials of coumarins, which have antitumor activity, we synthesized new coumarin derivatives and evaluated their biological activities. The new coumarin derivatives were chemically synthesized from 4-hydroxycoumarin, and their structures were confirmed by nuclear magnetic resonance data. Ten of the synthesized compounds were investigated for antimetastatic activity against lung carcinoma cells. Several of the tested compounds showed good to mild inhibitory effects on lung cancer cell motility. There were no cytotoxic effects related to the use of these compounds. 4-Hydroxycoumarin derivatives, 4h and 4i, elicited the significant inhibitory effect on lung cancer cell motility by suppressing expression of the epithelial–mesenchymal transition markers N-cadherin, Snail, and Twist.

A series of novel 3-substituted-4-hydroxycoumarins 7 and 8 containing (5-aryl-1,3,4-oxadiazol-2-yl)thio or (4-amino-5-aryl-4H-1,2,4-triazol-3-yl)thio moieties have been synthesized and evaluated as anticancer agents. The in vitro MTT assay of compounds against hepatocellular carcinoma (HepG2), breast cancer (MCF7) cells, and a human colorectal adenocarcinoma cell line with epithelial morphology (HT29) indicated that the HepG2 cells had more susceptibility to the tested compounds. Indeed, all compounds (with the exception of 7b, 7c, 7g, and 8g) were more potent than the standard drug doxorubicin against HepG2 cells (IC

The present communication deals with a straightforward, efficient, and green synthesis of a series of racemic version of 3-[3-(2-hydroxyphenyl)-3-oxo-1-arylpropyl]-4-hydroxycoumarins as biologically interesting warfarin analogues upon decarboxylative hydrolysis of bis-coumarin derivatives in aqueous potassium hydroxide solution. The salient features of this practical method are operational simplicity, avoidance of any organic solvents and tedious column chromatographic purification, clean reaction profiles, excellent yields, and gram-scale synthetic applicability.

Summary Introduction Vitamin K antagonist (VKA) related adverse events are the first cause for iatrogenic events in France, particularly due to the narrow therapeutic margin. The risk of bleeding increases significantly when the INR level is ≥ 5. The main objective of this study was to assess the prevalence of VKA overdose in a hospital setting (at D2 of hospital entry) and to evaluate physicians’ adherence to clinical practice guidelines for the management of VKA overdose according to French National Authority for Health recommendations. Methods This single-center retrospective observational study consisted in querying the computerized database of a Parisian hospital on 21275 INR determinations (3995 patients, 6813 hospital stays) performed between 2013 and 2018. Results An INR level ≥ 5 was noted during 350 (6%) of the hospital stays, in 331 patients (of whom 57% were women). The mean age of the patient population with an INR ≥ 5 was 81.1 years. Infection, heart failure and renal failure were the most frequent acute medical conditions for hospital admission. Twenty-three patients (7%) had a bleeding complication, 11 of which were major bleeding complications. Older age was associated with the severity of bleeding complications. Fifteen in-hospital deaths (4%) were reported, not related to bleeding events. The management of VKA overdose did not comply with the recommendations in 43% of cases, in particular for the highest INRs (50% of noncompliance for an INR > 6.4). Non-compliance with recommendations for VKA overdose was related to: the delay until the INR was checked (44% of cases); the indication for prescribing vitamin K (34% of cases); the dose or route of administration of vitamin K therapy (19% of cases); and the interruption or not of VKA therapy (12% of cases). Conclusion The management of VKA overdose in a hospital setting remains non-compliant with the recommendations in almost half of the cases, mainly due to the delayed INR control and inappropriate management of vitamin K therapy. Computerized alert system would be helpful for personalized patient management and improved pharmacovigilance to prevent iatrogenic VKA events.

A simple and practical method for the synthesis of 2-methylenebenzothiazoles via the coupling of a benzothiazole salts and 4-hydroxycoumarins have been described herein. The reaction showed a good substrate range and functional compatibility under mechanochemical conditions, and proceeded without catalysts or solvents. The 2-methylenebenzothiazoles products were achieved via the formation of a C=C double bond and exhibited strong luminescence and typical aggregation-induced emission (AIE) properties, indicating their potential for use as fluorescent materials.

Control of rodent populations is a big challenge because of the rapid evolution of resistance to commonly used rodenticides and the collateral negative impacts that these products may have on biodiversity. Second-generation anticoagulants are very efficient but different single nucleotide polymorphisms (SNPs) in the Vkorc1 gene may confer resistance in rodents. We sequenced exons 1, 2 and 3 of the Vkorc1 gene from 111 mice (Mus musculus domesticus) captured across the city of Barcelona and found SNPs associated with resistance to first- and second-generation anticoagulants in all of them. Although most of the SNPs were associated with resistance to bromadiolone, we also found SNPs associated with resistance to brodifacoum. Out of all the individuals analyzed, 94.59 % carried mutations associated to introgression events with Mus spretus, a sympatric rodent species. Currently most of the chemical products for rodent control commercialized in the area are based on bromadiolone, although recent public control campaigns have already shifted to other products. Thus, the widespread occurrence of resistant mice to bromadiolone represents a challenge for rodent control in Barcelona and may increase the risk of secondary poisoning of animals preying on this species. Public health managers, pest control companies and citizens should be aware that the use of bromadiolone based products is ineffective and represents a risk for the environment, including human and animal health.

Bromadiolone, a widely-used rodent control drug, could act as a long-acting anticoagulant. Patients of bromadiolone poisoning often present with multiorgan hemorrhage. However, neurological symptoms of bromadiolone poisoning are seldom reported. We report a rare case with convulsive status epilepticus as the initial presentation of bromadiolone poisoning. A previously healthy 18-year-old man presented with persistent unconsciousness and repeated convulsive seizures. Magnetic resonance imaging revealed lesions in the corpus callosum. Laboratory test revealed the microscopic hematuria, prolonged prothrombin time, prolonged activated partial thromboplastin time and the presence of bromadiolone. The patient was diagnosed as the bromadiolone poisoning and treated with hemofiltration, vitamin K and prothrombin complex. Consciousness of the patient was regained and all neurological symptoms diminished after 7 days. Coagulopathy was totally corrected after 3 weeks, and a 2-month regimen of vitamin K supplementation was prescribed after discharge. Our case suggests that bromadiolone poisoning may involve the central nervous system. The atypical and initial symptoms of neurological disorders might lead to misdiagnosis of bromadiolone poisoning. Poisoning should be considered when acute neurological symptoms are combined with bleeding tendency. The vitamin K treatment is effective for both coagulopathy and central nervous system disorders in bromadiolone poisoning.

The lack of quality control for patient point-of-care (POC) INR devices is an issue that has led the French health authorities to make recommendations: a laboratory INR (lab INR) has to be performed at the same time as the POC INR every 6 months. However, the differences observed between the two INRs, POC and lab INRs, are not necessarily due to a failure of the POC INR device. We present here a review of the different causes of discrepancies between INR results, which are the basis of the proposals of the Groupe français d'études sur l'hémostase et la thrombose (GFHT) on the management of lab and POC INR discrepancies. Pre-analytical conditions may account for discrepancies (sampling, transport and storage conditions), as well as analytical factors (mainly the nature of the thromboplastin used) and the clinical context (inflammatory or autoimmune diseases, polycythaemia...). The interpretation of INR discrepancies is not always easy and these proposals aim at standardizing the procedure to be followed in order to make the most appropriate decision for the patient.

Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).

A novel AgNO3/K2S2O8 catalyzed radical cascade cyclization reaction of 2-(allyloxy)arylaldehydes with 4-hydroxycoumarins and 4-hydroxy-6-methyl-2-pyrone produces two new series of chroman-2-ones.

Background Clinically, bromadiolone poisoning is characterized by severe bleeding complications in various organs and tissues. Bromadiolone-induced toxic encephalopathy is extremely rare. Here, we report a special case of bromadiolone-induced reversible toxic encephalopathy in a patient who had symmetrical lesions in the deep white matter. Case presentation A 23-year-old woman mainly presented with dizziness, fatigue, alalia and unsteady gait after the ingestion of bromadiolone. The laboratory examinations showed normal coagulation levels. Brain magnetic resonance imaging (MRI) showed apparent diffusion restriction in the bilateral deep white matter. The clinical manifestations and MRI alterations were reversible within one month of treatment with vitamin K. The neuropsychological assessment showed no neurodegenerative changes at the 2-year follow-up. Conclusion With the increased use of bromadiolone as a rodenticide, more cases of ingestion have been reported annually over the past several years. Bromadiolone-induced toxic encephalopathy has no special clinical manifestations and is potentially reversible with timely treatment. Because of the reversible restricted diffusion on diffusion-weighted images (DWI) and low apparent diffusion coefficient (ADC) values, transient intramyelinic cytotoxic oedema is thought to be the cause rather than persistent ischaemia. The underlying pathophysiological mechanism is still unknown and may be coagulant-independent. This clinical case extends the current knowledge about neurotoxicity in cases of bromadiolone poisoning and indicates that MRI is useful for the early detection of bromadiolone-induced toxic encephalopathy.

The house mouse (Mus musculus) is a globally distributed rodent pest species against which anticoagulant rodenticides are widely used for the protection of human and animal health and the conservation of threatened wildlife. Anticoagulant-resistant house mice have been known for more than half a century. A house mouse strain was developed in the laboratory that was homozygous resistant for the single nucleotide polymorphism (SNP) Tyrosine139Cysteine (Y139C) and, subsequently, heterozygous resistant animals were produced from this strain by crossing with the homozygous susceptible strain.Using blood clotting response tests, resistance factors at the EDY139C SNP homozygous resistant mice are more resistant to anticoagulants than heterozygous resistant animals. All first-generation anticoagulants are highly resisted and, among the second-generation compounds, Y139C mice are resistant to bromadiolone and sometimes to difenacoum. © 2022 The Authors. Pest Management Science published by John WileySons Ltd on behalf of Society of Chemical Industry.

Bifunctional chiral tridentate bis(pyrroloimidazolone)pyridine (PyBPI) ligands have been designed, synthesized, and applied in an asymmetric Michael addition. With a 0.05 mol % PyBPI-Co(II) complex, β,γ-unsaturated α-keto esters reacted with 4-hydroxycoumarin to give the adducts in 93-99% yields and 90-97% ee. Experiments and DFT calculations supported the dual activation manner, in which the tridentate ligand coordinated with Co(II) to activate the keto ester, and the hydroxyl and carbonyl groups in PyBPI interacted with 4-hydroxycoumarin via two different H bonds.

Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.

Inhibitors of muscle myosin ATPases are needed to treat conditions that could be improved by promoting muscle relaxation. The lead compound for this study ((3-(N-butylethanimidoyl)ethyl)-4-hydroxy-2H-chromen-2-one; BHC) was previously discovered to inhibit skeletal myosin II. BHC and 34 analogues were synthesized to explore structure–activity relationships. The properties of analogues, including solubility, stability, and toxicity, suggest that the BHC scaffold may be useful for developing therapeutics. Inhibition of actin-activated ATPase activity of fast skeletal and cardiac muscle myosin II, inhibition of skeletal muscle contractility ex vivo, and slowing of in vitro actin-sliding velocity were measured. Several analogues with aromatic side arms showed improved potency (half-maximal inhibitory concentration (IC(50))

To compare the efficacy of a self-monitoring programme vs. the conventional method used before the intervention in maintaining the international normalised ratio (INR) in the therapeutic range in patients receiving oral anticoagulants, as well as complications, quality of life and the time invested in the tests.Pre-pospilot and feasibility study. The study included 15 patients over the age of 18 years who had been attending the monitoring programme for more than 6months. In the pre phase, patients performed the tests and follow-up in the outpatient clinic. After conducting an individual training session with each patient to teach them how to perform venipuncture, use the coagulometer, manage dosing tables and subsequent follow-up from the virtual clinic, we compared the percentage of in-range INR tests, complications, quality of life, and the time invested in performing the tests pre- (conventional) and post-intervention (intervention for self-monitoring).The percentage of INR tests in the therapeutic range was significantly higher in the post-phase than in the pre-phase (65.6% vs. 37.8%, p.001). Likewise, the incidence of both minor and serious complications decreased in the post-phase (20% vs. 0%, and 6.7% vs. 0%, respectively). Finally, all 5dimensions of the quality of life questionnaire improved significantly, while the time invested decreased.In our experience, OAT self-monitoring is associated with a significant improvement in patient management, a reduction in the rate of complications, improved quality of life and timesaving.

In this study, we applied a direct condensation between 3-acetyl-4-hydroxy-2H-chromen-2-one and different amines (anilines and benzyl amines) in order to synthesize some coumarin-based imines/enamines (3a-o) as cytotoxic agents. All the compounds were characterized by means of FT-IR, NMR, mass spectroscopy and elemental analyses. Since the title compounds can exist as different forms including (s-cis)-imine and (s-trans)-imine or (E and Z)-enamines, their conformational and geometrical aspects were investigated computationally by DFT method. The optimized geometry parameters, ΔE, ΔG, ΔH, Mulliken atomic charge, HOMO and LUMO energy, and NBO analysis suggested that these compounds can exist predominantly in (E)-enamine form. All the synthesized compounds (3a-o) were evaluated in vitro for their cytotoxic activities against cancer cell lines (MCF-7 and A549) and normal cell line (BEAS-2B) using the MTT assay. The 4-hydroxybenzyl derivative 3k was found to be the most potent cytotoxic agent with no selectivity, similar to doxorubicin. However, the 4-chlorobenzyl analog 3o could be considered as an equipotent compound respect to doxorubicin with higher selectivity.

Background Superwarfarins, second-generation long-acting anticoagulant rodenticides, are 4-hydroxycoumarin analogues of warfarin that contain a large hydrophobic side chain. These compounds contain two chiral centers and are synthesized for commercial use as two pairs of diastereomer. Objective To support studies of superwarfarin pharmacokinetics and other efforts to improve clinical care for poisoning victims, a quantitative assay was developed for the measurement of diastereomer of bromadiolone, difenacoum, flocoumafen, brodifacoum, and difethialone in human plasma. Method Based on ultrahigh-pressure liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS), this method was validated according to U.S. Food and Drug Administration (FDA) guidelines. Sample preparation involved simple protein precipitation followed by reversed phase UHPLC, which resolved all five pairs of cis/trans diastereomer in less than 10 min. Superwarfarins were measured using negative ion electrospray followed by selected-reaction monitoring on a triple quadrupole mass spectrometer. Results Calibration curves covered 3–4 orders of magnitude with linear regression coefficients of >0.999. The lower limits of quantitation were from 0.013 to 2.41 ng/mL, and intra-day and inter-day accuracy and precision coefficients of variation were Conclusions A 10-min UHPLC-MS/MS assay was developed and validated for the separation and quantitative analysis of the pairs of diastereomer of five superwarfarins in human plasma. Highlights This method was used to identify and measure superwarfarins and their cis/trans diastereomers in plasma obtained from patients treated for coagulopathy following consumption of contaminated synthetic cannabinoid products.