Animal and epidemiologic studies suggest that the use of warfarin might reduce cancer incidence. The antitumor potential of warfarin is demonstrated in different experimental cancer models. Specifically, studies in murine cancer models have shown that warfarin blocks AXL receptor tyrosine kinase by inhibiting a vitamin K-dependent protein called GAS6, thereby may halt the spread of cancer cells. An off-target effect of the anticoagulant warfarin is inhibition of GAS6-AXL signaling, which enhances antitumor immunity and blocks tumorigenesis independently of anticoagulation. Hence, the observed association between warfarin use and lower cancer incidence is likely due to an enhanced antitumor immune surveillance of early cancer. The large observational study also showed a reduction in cancer incidence among regular warfarin users. The study data indicate that warfarin provides a possible cancer protection. Despite some limitations, the results of this study give further support for the hypothesis that warfarin use decreases cancer incidence, which warrants continued investigation. This finding may have important implications for choosing medications in patients who need anticoagulant therapy.

• Klíčová slova
• AXL receptor tyrosine kinase, antitumor immune surveillance, cancer incidence, warfarin,
• MeSH
• antikoagulancia farmakologie   terapeutické užití   MeSH
• incidence MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny metabolismus   MeSH
• myši MeSH
• nádory imunologie   prevence a kontrola   MeSH
• protoonkogenní proteiny antagonisté a inhibitory   metabolismus   MeSH
• tyrosinkinasové receptory antagonisté a inhibitory   metabolismus   MeSH
• tyrozinkinázový receptor AXL MeSH
• warfarin farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikoagulancia MeSH
• growth arrest-specific protein 6 MeSH Prohlížeč
• mezibuněčné signální peptidy a proteiny MeSH
• protoonkogenní proteiny MeSH
• tyrosinkinasové receptory MeSH
• tyrozinkinázový receptor AXL MeSH
• warfarin MeSH

Adverse effects of drugs are one of the objective criteria used for choosing the most appropriate anticoagulant. It is worrying that warfarin may be involved in the progression of systemic atherosclerosis, as more and more articles suggest. Warfarin has been widely used in the past and has greater efficacy compared to dabigatran in patients with mechanical heart valves; there is an antidote to it and it is cheap. Unfortunately, warfarin inhibits the synthesis and activity of Matrix-Gla-Protein, which is the major vitamin K-dependent inhibitor of arterial calcification - an active process associated with atherosclerosis, stimulated by inflammatory mechanisms. Vitamin K antagonizes the NF-κB signaling mechanism and contributes to the prevention of arterial calcifications. Warfarin given in experimental animal models of atherosclerosis contributed to the occurrence of an increased number of aortic calcifications. Warfarin treatment used in clinical trials was associated with the progressive increase of coronary atheroma calcification. Younger patients are more sensitive to warfarin-related arterial calcifications compared to older patients, due to warfarin-induced cellular senescence changes. Non-vitamin K antagonist direct oral anticoagulants do not interact with vitamin K. Edoxaban reduces the inflammatory process in the vascular walls and the proliferation of smooth vascular muscle cells, so it is involved in the prevention of vascular maladaptive remodeling process. Apixaban is able to stabilize the coronary atherosclerotic process. Randomized clinical trials are needed to evaluate the impact of warfarin on plaque stability and cardiovascular evolution of patients.

• Klíčová slova
• atherosclerosis, direct oral anticoagulants, thrombosis, vascular calcification, warfarin,
• MeSH
• antikoagulancia farmakologie   terapeutické užití   MeSH
• aplikace orální MeSH
• ateroskleróza * farmakoterapie   prevence a kontrola   MeSH
• cévní mozková příhoda * prevence a kontrola   MeSH
• fibrilace síní * farmakoterapie   MeSH
• lidé MeSH
• vitamin K terapeutické užití   MeSH
• warfarin škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antikoagulancia MeSH
• vitamin K MeSH
• warfarin MeSH

Warfarin is a widely used anticoagulant and, unfortunately, is a drug that is commonly implicated in serious adverse events including fatalities. Although several factors, including the metabolism of warfarin via CYP450, have been reported to affect the safety and efficacy of warfarin therapy, the wide variance in the warfarin dosage in patients has not been completely clarified. In addition to the oxidative metabolism of warfarin mediated by CYP450, reductive metabolism is involved in warfarin biotransformation. However, the reductive metabolism of warfarin has been largely unexplored and deserves further investigation. We studied warfarin reduction by human liver fractions and found a 9-fold higher velocity of warfarin reduction in the cytosol than in microsomes (Vmax=77.2 vs. 8.7pmol/mgprotein/min, respectively). Furthermore, of nine recombinant cytosolic carbonyl reducing enzymes tested for their ability to reduce warfarin, AKR1C3 and CBR1 were identified as warfarin reductases and their kinetic parameters were determined. The internal clearance of warfarin was 3 orders of magnitude higher with AKR1C3 than with CBR1 (CLint=65.922 vs. 0.070μl/mgprotein/min, respectively). This is the first time that warfarin reducing enzymes in human liver subcellular fraction have been identified. Moreover, we have described the chiral aspects of warfarin reduction using an HPLC method that enabled the detection of individual warfarin alcohol stereoisomers. Cytosol and AKR1C3 exhibit the stereoselective metabolism of (R)-warfarin to preferentially form (SR)-warfarin alcohol as the primary in vivo metabolite of warfarin. On the other hand, microsomes and CBR1 preferentially reduce (S)-warfarin to form (RS)-warfarin alcohol and (SS)-warfarin alcohol, respectively.

• Klíčová slova
• (RS)-warfarin alcohol (PubChem CID: 54736486), (SS)-warfarin alcohol (PubChem CID: 56842683), Aldo–keto reductase (AKR), Carbonyl reducing enzymes, Carbonyl reductase (CBR), Drug metabolism, Short-chain dehydrogenase/reductase, Warfarin, Warfarin (PubChem CID: 54678486), Warfarin alcohol (PubChem CID: 54712717),
• MeSH
• 3-hydroxysteroid dehydrogenasy metabolismus   MeSH
• aldehydreduktasa metabolismus   MeSH
• alkoholoxidoreduktasy metabolismus   MeSH
• antikoagulancia metabolismus   MeSH
• biotransformace MeSH
• Escherichia coli genetika   metabolismus   MeSH
• exprese genu MeSH
• hydroxyprostaglandindehydrogenasy metabolismus   MeSH
• izoenzymy metabolismus   MeSH
• jaterní mikrozomy enzymologie   MeSH
• játra enzymologie   MeSH
• kinetika MeSH
• kultivační média chemie   MeSH
• lidé MeSH
• oxidace-redukce MeSH
• protein AKR1C3 MeSH
• rekombinantní proteiny metabolismus   MeSH
• stereoizomerie MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• warfarin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3-hydroxysteroid dehydrogenasy MeSH
• AKR1A1 protein, human MeSH Prohlížeč
• AKR1B1 protein, human MeSH Prohlížeč
• AKR1C3 protein, human MeSH Prohlížeč
• aldehydreduktasa MeSH
• alkoholoxidoreduktasy MeSH
• antikoagulancia MeSH
• CBR1 protein, human MeSH Prohlížeč
• hydroxyprostaglandindehydrogenasy MeSH
• izoenzymy MeSH
• kultivační média MeSH
• protein AKR1C3 MeSH
• rekombinantní proteiny MeSH
• warfarin MeSH

In this article, the author reviews and updates the basis of interactions with warfarin, illustrated with appropriate examples. The interactions with drugs, medicinal herbs and foods are summarised.

• MeSH
• antikoagulancia škodlivé účinky   MeSH
• fytoterapie MeSH
• interakce bylin a léků MeSH
• interakce mezi potravou a léky MeSH
• léčivé rostliny MeSH
• lékové interakce MeSH
• lidé MeSH
• warfarin škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antikoagulancia MeSH
• warfarin MeSH

Warfarin is widely used anticoagulant drug for a variety of diseases (thromboembolic disease, atrial fibrillation, etc.). It has three most important parallel metabolic pathways, CYP1A2, CYP3A4 and CYP2C9. Terbinafine is a potent CYP2D6 inhibitor. A possible drug interaction could lead to an increased pharmacological effect of the above drugs. Enzyme induction with CYP3A4, CYP2C9, CYP1A2 inducers may have occurred. Case report: We present a case report of an 88-year-old male patient who has been successfully anticoagulated with warfarin due to atrial fibrillation. He was orally administered terbinafine to treat onychomycosis. Two weeks after initiation of this drug the patient experienced dizziness and feelings of instability, for which he was admitted to the neurology department. A low-efficient INR level was found at the baseline, presumably due to warfarin interaction with terbinafine. The induction of liver enzymes lasts 10-14 days, which matches the introduction of the antifungal agent. Conclusion: Combined therapy with warfarin and oral terbinafine is actually rarely prescribed but, if used, their interaction can have serious consequences in many clinical situations for which anticoagulation therapy with warfarin is indicated.

• Klíčová slova
• anticoagulation, atrial fibrillation, liver inductor, terbinafine, warfarin,
• MeSH
• antifungální látky aplikace a dávkování   škodlivé účinky   MeSH
• antikoagulancia aplikace a dávkování   škodlivé účinky   MeSH
• aplikace orální MeSH
• fibrilace síní farmakoterapie   MeSH
• lékové interakce * MeSH
• lidé MeSH
• onychomykóza farmakoterapie   MeSH
• senioři nad 80 let MeSH
• terbinafin aplikace a dávkování   škodlivé účinky   MeSH
• warfarin aplikace a dávkování   škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antifungální látky MeSH
• antikoagulancia MeSH
• terbinafin MeSH
• warfarin MeSH

The review paper deals with some aspects of warfarin history and its use, at the beginning as a rodenticide and later as an anticoagulant. It describes its principal physical-chemical properties and it analyzes schematically the possibilities of its preparation by both selective and non-selective synthesis from coumarin derivatives. A survey of syntheses and its results are tabulated, including the literary references, and the paper is concluded with an evaluation of the prospects of this agent in comparison with alternative anticoagulants and its advantages, disadvantages and prospects.

• MeSH
• antikoagulancia * chemická syntéza   dějiny   farmakologie   terapeutické užití   MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• kumariny chemie   MeSH
• lidé MeSH
• rodenticidy * chemická syntéza   dějiny   farmakologie   terapeutické užití   MeSH
• warfarin * chemická syntéza   dějiny   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• přehledy MeSH
• Názvy látek
• antikoagulancia * MeSH
• kumariny MeSH
• rodenticidy * MeSH
• warfarin * MeSH

OBJECTIVE: This study aimed to comprehensively evaluate the risk of gastrointestinal bleeding (GIB) with statin monotherapy or with concomitant warfarin use. DATA SOURCES: PubMed, Web of Science, and EMBASE (via Scopus) were searched for observational studies that reported the risk of GIB in adults on statin therapy or with concomitant warfarin use until August 28, 2021. STUDY SELECTION AND DATA EXTRACTION: Observational studies evaluating the risk of GIB in adults (age >18 years) on statin medication or concomitant use with warfarin were included. DATA SYNTHESIS: In all, 14 studies with a total of 5 235 123 participants, reporting 48 677 GIB events (43 734 from statin users and 4943 from users of statin combined with warfarin), were included in the analyses. The pooled analysis revealed no difference in the risk of GIB with statin monotherapy (relative risk [RR]: 0.65; 95% CI: 0.42-1.02) or concomitant statin + warfarin use (RR: 0.97; 95% CI: 0.91-1.02). Prior use of statin was not associated with GIB risk (RR: 0.88; 95% CI: 0.63-1.22), whereas a shorter duration of statin use (<5 years) was associated with a lower risk of GIB (RR: 0.42; 95% CI: 0.18-0.97). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This analysis provides strong evidence on the association between statin use (with/without warfarin) and risk of GIB. CONCLUSION: Statin alone or combined with warfarin was not significantly associated with either an increased or decreased risk of GIB. The GIB risk was significantly lower when statins were used for a short duration (<5 years). The putative relationship between statins and GIB in warfarin users warrant further investigation.

• Klíčová slova
• anticoagulant, bleeding, gastrointestinal hemorrhage, hydroxymethylglutaryl-CoA reductase inhibitors, review, warfarin,
• MeSH
• antikoagulancia škodlivé účinky   MeSH
• dospělí MeSH
• gastrointestinální krvácení chemicky indukované   farmakoterapie   epidemiologie   MeSH
• lidé MeSH
• mladiství MeSH
• statiny * škodlivé účinky   MeSH
• warfarin * škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• antikoagulancia MeSH
• statiny * MeSH
• warfarin * MeSH

This experimental study describes the method of direct compression of powder mixtures composed of warfarinum sodium salt. Warfarinum is a drug with a narrow therapeutics index. The aim of this study is to find a suitable composition and a process of preparing tablets with the best uniformity. The content uniformity is very important for the safety of the therapy. This study links up with the already published article including the results of content uniformity of mixtures and tablets prepared by direct compression. These mixtures contain fillers with different density and distribution size of the particles (excipients with digger particles were used in this experiment). The study is focused on the influence of magnesium stearate, which was added at the beginning of the homogenization or after the mixing of the other components. In addition to content uniformity and physical characteristics of the tablets, the study also evaluated the uniformity and physical characteristics of the mixtures. In this experimental study it has been found out that content uniformity is influenced by the total time of homogenization and the addition of magnesium stearate and much less by the distribution size of the particles of excipients in the mixtures. The appropriate selection of process parameters is important for obtaining tablets respecting the strict criterion of Bergum distribution. This distribution is a part of the GMP by the evaluation of the content uniformity in the U.S.

• MeSH
• chemie farmaceutická MeSH
• kyseliny stearové chemie   MeSH
• pomocné látky chemie   MeSH
• prášky, zásypy, pudry MeSH
• příprava léků MeSH
• tablety MeSH
• warfarin chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyseliny stearové MeSH
• pomocné látky MeSH
• prášky, zásypy, pudry MeSH
• stearic acid MeSH Prohlížeč
• tablety MeSH
• warfarin MeSH

Human serum albumin (HSA) is the most abundant plasma protein in circulation. The three most important drug-binding sites on HSA are Sudlow's Site I (subdomain IIA), Sudlow's Site II (subdomain IIIA), and Heme site (subdomain IB). Heme site and Site I are allosterically coupled; therefore, their ligands may be able to allosterically modulate the binding affinity of each other. In this study, the effects of four Heme site ligands (bilirubin, biliverdin, hemin, and methyl orange) on the interaction of the Site I ligand warfarin with HSA were tested, employing fluorescence spectroscopic, ultrafiltration, and ultracentrifugation studies. Our major results/conclusions are the following. (1) Quenching studies indicated no relevant interaction, while the other fluorescent model used suggested that each Heme site ligand strongly decreases the albumin binding of warfarin. (2) Ultrafiltration and ultracentrifugation studies demonstrated the complex modulation of warfarin-HSA interaction by the different Heme site markers; for example, bilirubin strongly decreased while methyl orange considerably increased the bound fraction of warfarin. (3) Fluorescence spectroscopic studies showed misleading results in these diligand-albumin interactions. (4) Different Heme site ligands can increase or decrease the albumin binding of warfarin and the outcome can even be concentration dependent (e.g., biliverdin and hemin).

• Klíčová slova
• Sudlow’s site I, allosteric modulation, heme site, human serum albumin, warfarin,
• MeSH
• bilirubin MeSH
• biliverdin * MeSH
• hem metabolismus   MeSH
• hemin MeSH
• lidé MeSH
• ligandy MeSH
• sérový albumin metabolismus   MeSH
• warfarin * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bilirubin MeSH
• biliverdin * MeSH
• hem MeSH
• hemin MeSH
• ligandy MeSH
• methyl orange MeSH Prohlížeč
• sérový albumin MeSH
• warfarin * MeSH

Warfarin is intensively discussed in terms of generic substitution due to particular cases of bleeding, which are attributable to fluctuations in API content or the substitution of crystalline (WSC) for amorphous (WSA) warfarin. The aim of this study was to assess to what extent the in vitro release was affected by the form of API depending on the composition and technology. Bioequivalent tablets containing 5 mg of WSA or WSC prepared by wet granulation or direct compression were used. Furthermore, tablets of the same composition with WSC or WSA prepared by direct compression were evaluated. Raman spectroscopy was used to confirm the presence of WSA or WSC. The dissolution was more influenced by the technology than by the form of API but even tablets with dissimilar profiles were bioequivalent. This is probably due to the precipitation of WSA and WSC in the stomach on a poorly soluble acidic form, which subsequently dissolves in the neutral environment of the small intestine. Recrystallization was demonstrated in the in vitro assay at a pH of 1.2 and 4.5 using Raman spectroscopy and X-ray diffraction. In summary, the content uniformity appears to be the main factor affecting the safety of the treatment.

• Klíčová slova
• Dissolution, Generic substitution, Polymorphism, Raman spectroscopy, Warfarin sodium, X-ray,
• MeSH
• antikoagulancia chemie   farmakokinetika   MeSH
• krystalizace MeSH
• tablety MeSH
• terapeutická ekvivalence MeSH
• uvolňování léčiv MeSH
• warfarin chemie   farmakokinetika   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikoagulancia MeSH
• tablety MeSH
• warfarin MeSH