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1.
Medicine (Baltimore) ; 100(32): e26883, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397907

RESUMO

BACKGROUND AND PURPOSE: This study aimed to evaluate the comparative efficacy and safety of 4 non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with non-valvular atrial fibrillation in real-world practice through a network meta-analysis of observational studies. METHODS: We searched multiple comprehensive databases (PubMed, Embase, and Cochrane library) for studies published until August 2020. Hazard ratios and 95% confidence intervals were used for the pooled estimates. Efficacy outcomes included ischemic stroke (IS), stroke/systemic embolism (SSE), myocardial infarction (MI), and all-cause mortality, and safety outcomes included major bleeding, gastrointestinal (GI) bleeding, and intracerebral hemorrhage (ICH). The P score was calculated for ranking probabilities. Subgroup analyses were separately performed in accordance with the dosage range of NOACs ("standard-" and "low-dose"). RESULTS: A total of 11, 6, and 8 studies were allocated to the total population, standard-dose group, and low-dose group, respectively. In the total study population, edoxaban ranked the best in terms of IS and ICH prevention and apixaban ranked the best for SSE, major bleeding, and GI bleeding. In the standard-dose regimen, apixaban ranked the best in terms of IS and SSE prevention. For major bleeding, GI bleeding, and ICH, edoxaban ranked the best. In the low-dose regimen, edoxaban ranked the best for IS, SSE, GI bleeding, and ICH prevention. For major bleeding prevention, apixaban ranked best. CONCLUSIONS: All 4 NOACs had different efficacy and safety outcomes according to their type and dosage. Apixaban and edoxaban might be relatively better and more well-balanced treatment for Asian patients with non-valvular atrial fibrillation.


Assuntos
Fibrilação Atrial , Inibidores do Fator Xa , Acidente Vascular Cerebral , Varfarina/farmacologia , Anticoagulantes/farmacologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Inibidores do Fator Xa/classificação , Inibidores do Fator Xa/farmacologia , Humanos , Avaliação de Resultados em Cuidados de Saúde , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico
2.
Methods Mol Biol ; 2342: 765-779, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272716

RESUMO

The potential for new chemical entities to inhibit the major cytochrome P450 (CYP) isoforms is routinely evaluated to minimize the risk of developing drugs with drug-drug interaction liabilities. CYP inhibition assays are routinely performed in a high-throughput format to efficiently screen large numbers of compounds. In evaluating a time-saving assay using diclofenac as the CYP2C9 probe substrate, a discrepancy was observed in which minimal inhibition was detected using diclofenac whereas using (S)-warfarin resulted in potent inhibition, supporting the presence of dual-binding sites in the relatively large CYP2C9 active site cavity.These observations provided further insights into explaining the reported ineffective inactivation of CYP2C9 for the pan-CYP inactivator 1-aminobenzotriazole (ABT). Mechanistic reversible and time-dependent inhibition experiments revealed that the ineffective CYP2C9 inactivation by ABT was also probe-dependent, with utilization of (S)-warfarin as the probe substrate resulting in more potent CYP2C9 inhibition by ABT compared to diclofenac. Addition of (S)-warfarin to the reversible and time-dependent inhibition experiments between ABT and diclofenac resulted in an attenuation of the inhibitory effects of ABT on CYP2C9-mediated diclofenac metabolism. Molecular docking studies further confirmed that (S)-warfarin and diclofenac preferentially bind in different regions of the CYP2C9 active site, with (S)-warfarin occupying a distal "warfarin-binding pocket" and diclofenac occupying a binding site close to the active heme moiety. ABT preferentially binds in the distal warfarin-binding pocket, supporting that diclofenac is minimally deterred from access to the CYP2C9 active site in the presence of ABT, thus resulting in minimal inactivation. Simultaneously docking of (S)-warfarin and ABT revealed that (S)-warfarin outcompetes ABT for the distal binding site and results in the binding of ABT to the CYP2C9 active site, supporting the observations of potent inactivation of CYP2C9 when (S)-warfarin is the probe substrate.These results highlight that probe selection is crucial when evaluating CYP inhibition potential, and it is recommended that multiple probes be utilized for CYP2C9, similar to the approach routinely employed for CYP3A4. Further, utilization of ABT as a pan-inhibitor of CYP activity for investigational compounds, both in vitro and in vivo, should be accompanied with the understanding that residual CYP-mediated oxidative metabolism could potentially be observed for CYP2C9 substrates and should not necessarily be attributed to non-P450-mediated metabolism.


Assuntos
Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Diclofenaco/farmacologia , Triazóis/farmacologia , Varfarina/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Diclofenaco/química , Interações Medicamentosas , Inativação Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Conformação Proteica , Fatores de Tempo , Triazóis/química , Varfarina/química
3.
Clin Appl Thromb Hemost ; 27: 10760296211021495, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34142564

RESUMO

The treatment process of patients using warfarin is expected to be hindered during the COVID-19 pandemic. Therefore we investigated whether the time in therapeutic range (TTR) and bleeding complications were affected during the COVID-19 pandemic. 355 patients using warfarin were included between March 2019 to March 2021. Demographic parameters, INR (international normalized ratio), and bleeding rates were recorded retrospectively. The TTR value was calculated using Rosendaal's method. The mean age of the patients was 61 ± 12 years and 55% of them were female. The mean TTR value during the COVID-19 pandemic was lower than the pre-COVID-19 period (56 ± 21 vs 68 ± 21, P < 0.001). Among the patients, 41% had a lack of outpatient INR control. During the COVID-19 pandemic, 71 (20%) patients using VKA suffered bleeding. Among patients with bleeding, approximately 60% did not seek medical help and 6% of patients performed self-reduction of the VKA dose. During the COVID-19 pandemic, TTR values have decreased with the lack of monitoring. Furthermore, the majority of patients did not seek medical help even in case of bleeding.


Assuntos
Anticoagulantes/farmacologia , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , COVID-19/sangue , Hemorragia/induzido quimicamente , Coeficiente Internacional Normatizado , Pandemias , SARS-CoV-2 , Trombofilia/sangue , Varfarina/farmacologia , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , COVID-19/complicações , Relação Dose-Resposta a Droga , Feminino , Próteses Valvulares Cardíacas/efeitos adversos , Hemorragia/psicologia , Humanos , Hipertensão/complicações , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Embolia Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Automedicação , Trombofilia/tratamento farmacológico , Trombofilia/etiologia , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Varfarina/uso terapêutico
4.
Nefrología (Madrid) ; 41(2): 137-153, mar.-abr. 2021. tab
Artigo em Espanhol | IBECS | ID: ibc-201567

RESUMO

La enfermedad renal crónica (ERC) y la fibrilación auricular (FA) frecuentemente coexisten, amplificando el riesgo de eventos cardiovasculares y de mortalidad. En pacientes con ERC estadio 3 y FA no valvular los anticoagulantes orales de acción directa (ACOD) han demostrado, comparados con antagonistas de la vitamina K (AVK), igual o superior eficacia en la prevención de ictus y embolismo sistémico, y mayor seguridad. No existen ensayos aleatorizados de la eficacia y la seguridad de ACOD y AVK en la ERC avanzada. Por otra parte, estudios observacionales sugieren que los ACOD, comparados con warfarina, se asocian a menor riesgo de daño renal agudo y de generación/progresión de la ERC. En este trabajo se revisan los aspectos epidemiológicos y fisiopatológicos de la asociación ERC y FA, las evidencias de la eficacia y seguridad de la warfarina y de los ACOD en las diversas fases de la ERC con FA, así como la comparación entre warfarina y ACOD en la eficacia y seguridad anticoagulante, y en sus efectos renales


Chronic kidney disease (CKD) and atrial fibrillation (AF) frequently coexist, amplifying the risk of cardiovascular events and mortality. In patients with CKD stage 3 and non-valvular AF, direct oral anticoagulants (DOACs) have shown, compared to vitamin K antagonists (VKA), equal or greater efficacy in the prevention of stroke and systemic embolism, and greater safety. There are no randomized trials of the efficacy and safety of DOACs and VKA in advanced CKD. On the other hand, observational studies suggest that DOACs, compared to warfarin, are associated with a lower risk of acute kidney damage and generation/progression of CKD. This paper reviews the epidemiological and pathophysiological aspects of the CKD and AF association, the evidence of the efficacy and safety of warfarin and ACODs in various stages of CKD with AF as well as the comparison between warfarin and ACODs in efficacy and anticoagulant safety, and in its renal effects


Assuntos
Humanos , Insuficiência Renal Crônica/complicações , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Inibidores do Fator Xa/farmacologia , Varfarina/farmacologia , Fatores de Risco , Acidente Vascular Cerebral/prevenção & controle , Insuficiência Renal Crônica/terapia , Diálise Renal
5.
Biomolecules ; 11(3)2021 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805625

RESUMO

The pathological role of vitamin K2 in Alzheimer's disease (AD) involves a definite link between impaired cognitive functions and decreased serum vitamin K levels. Vitamin K2 supplementation may have a protective effect on AD. However, the mechanism underlying vitamin K2 protection has not been elucidated. With the amyloid-ß (Aß) cascade hypothesis, we constructed a clone containing the C-terminal fragment of amyloid precursor protein (ß-CTF/APP), transfected in astroglioma C6 cells and used this cell model (ß-CTF/C6) to study the protective effect of vitamin K2 against Aß cytotoxicity. Both cellular and biochemical assays, including cell viability and reactive oxygen species (ROS), assays assay, and Western blot and caspase activity analyses, were used to characterize and unveil the protective role and mechanism of vitamin K2 protecting against Aß-induced cytotoxicity. Vitamin K2 treatment dose-dependently decreased the death of neural cells. The protective effect of vitamin K2 could be abolished by adding warfarin, a vitamin K2 antagonist. The addition of vitamin K2 reduced the ROS formation and inhibited the caspase-3 mediated apoptosis induced by Aß peptides, indicating that the mechanism underlying the vitamin K2 protection is likely against Aß-mediated apoptosis. Inhibitor assay and Western blot analyses revealed that the possible mechanism of vitamin K2 protection against Aß-mediated apoptosis might be via regulating phosphatidylinositol 3-kinase (PI3K) associated-signaling pathway and inhibiting caspase-3-mediated apoptosis. Our study demonstrates that vitamin K2 can protect neural cells against Aß toxicity.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Citoproteção , Vitamina K 2/farmacologia , Animais , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Radicais Livres/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Modelos Biológicos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Varfarina/farmacologia , Proteína de Morte Celular Associada a bcl/metabolismo
6.
Bratisl Lek Listy ; 122(5): 320-324, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33848181

RESUMO

BACKGROUND: The aim of this study was to assess the effect of anticoagulation treatment on platelet aggregation. METHODS: The study group consisted of 24 patients on long-term warfarin therapy without any antiaggregation therapy. Platelet aggregation was measured using VerifyNow with arachidonic acid (AA) as an inducer in 23 patients and with light transmission aggregometry (LTA) in 19 patients using four different agonists. All patients had their international normalized ratio (INR) checked regularly. RESULTS: The mean INR value was 2.07 (SD 0.6). The average aggregation measured by VerifyNow was found to be 637.5 (SD 36.6) aspirin reaction units. The values of average aggregability in LTA were 73.3 % (SD 4.5 %), 73.2 % (SD 6 %) and 72.1 % (SD 4.8 %) in case of aggregation induced by AA, ADP, and collagen, respectively. Epinephrine­induced aggregability was 65.3 % (SD 14.7 %). Regression analysis between INR and values of collagen- or epinephrine­induced aggregability (r = 0.654 and 0.575) was found statistically significant (p = 0.004 and 0.016); every increase in INR by 0,1 brings about an increase in collagen- and epinephrine­induced aggregation values by 1.5 and 4, respectively. CONCLUSION: Administration of warfarin does not produce a significant reduction in platelet aggregation. On the contrary, prolonged INR evokes a mild increase in aggregation induced by collagen or epinephrine (Tab. 2, Fig. 3, Ref. 32). Text in PDF www.elis.sk Keywords: platelet aggregation, anticoagulation, warfarin, platelet function tests, chronic ischemic heart disease.


Assuntos
Agregação Plaquetária , Varfarina , Plaquetas , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Varfarina/farmacologia
7.
Int J Biol Macromol ; 181: 426-434, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33775768

RESUMO

Advanced glycation end products (AGEs) formation produces free radicals that play a role in diabetes mellitus; hence inhibition of glycation plays a part in minimizing diabetes-related complications. This study was intended to examine the AGEs formation of HSA upon prolonged incubation of 28 days at 37 °C and further investigate the antiglycation potential of folic acid (FA). FA shows a significant binding affinity to the HSA with a binding constant (K) of 104 M-1. The evaluation of enthalpy change (∆H0) and entropy change (∆So) implied that the HSA-FA complex is stabilized primarily by hydrophobic interaction and hydrogen bonding. Molecular docking analysis depicted that FA binds with HSA in subdomain IIA (Sudlow's site I) with a binding energy of -7.0 kcal mol-1. AGEs were characterized by free lysine and thiol groups, carbonyl content, and AGEs specific fluorescence. The presence of FA significantly decreased glycation from free lysine and carbonyl content estimation and AGEs specific fluorescence. Multispectroscopic observations and molecular docking and examination of various biomarkers demonstrate the antiglycation activity of FA and its capacity to prevent disease progression in diabetes.


Assuntos
Ácido Fólico/farmacologia , Simulação de Acoplamento Molecular , Albumina Sérica Humana/metabolismo , Análise Espectral , Sítios de Ligação , Dicroísmo Circular , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação/efeitos dos fármacos , Humanos , Ibuprofeno/farmacologia , Lisina/metabolismo , Concentração Osmolar , Carbonilação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Espectrometria de Fluorescência , Compostos de Sulfidrila/metabolismo , Termodinâmica , Varfarina/farmacologia
8.
Pestic Biochem Physiol ; 173: 104774, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33771253

RESUMO

Well-known 4-hydroxycoumarin derivatives, such as warfarin, act as inhibitors of the vitamin K epoxide reductase (VKOR) and are used as anticoagulants. Mutations of the VKOR enzyme can lead to resistance to those compounds. This has been a problem in using them as medicine or rodenticide. Most of these mutations lie in the vicinity of potential warfarin-binding sites within the ER-luminal loop structure (Lys30, Phe55) and the transmembrane helix (Tyr138). However, a VKOR mutation found in Tokyo in warfarin-resistant rats does not follow that pattern (Leu76Pro), and its effect on VKOR function and structure remains unclear. We conducted both in vitro kinetic analyses and in silico docking studies to characterize the VKOR mutant. On the one hand, resistant rats (R-rats) showed a 37.5-fold increased IC50 value to warfarin when compared to susceptible rats (S-rats); on the other hand, R-rats showed a 16.5-fold lower basal VKOR activity (Vmax/Km). Docking calculations exhibited that the mutated VKOR of R-rats has a decreased affinity for warfarin. Molecular dynamics simulations further revealed that VKOR-associated warfarin was more exposed to solvents in R-rats and key interactions between Lys30, Phe55, and warfarin were less favored. This study concludes that a single mutation of VKOR at position 76 leads to a significant resistance to warfarin by modifying the types and numbers of intermolecular interactions between the two.


Assuntos
Rodenticidas , Varfarina , Animais , Resistência a Medicamentos/genética , Mutação , Ratos , Rodenticidas/toxicidade , Vitamina K Epóxido Redutases/genética , Varfarina/farmacologia
9.
Eur J Clin Pharmacol ; 77(3): 341-348, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33409685

RESUMO

PURPOSE: To provide practical guidance by providing weekly descriptions of warfarin requirements for the onset and offset of the rifampin-warfarin interaction. METHODS: A retrospective chart review within an outpatient Anticoagulation Clinic (AC). Patients were eligible for the onset phase provided they had known ambulatory-based warfarin steady-state requirements prior to rifampin initiation. For the offset phase, warfarin must be managed by the AC following rifampin discontinuation. Each phase was described separately with warfarin proportionate dose changes (median, IQR) for weeks 1, 2, and 4 as well as the change required to reach warfarin steady state. RESULTS: Ten patients with 11 courses of warfarin-rifampin were included. For onset, clinicians should anticipate proportionate warfarin dose increases of 30-80% from week 1 to week 2 and a further 20-100% from week 2 to 4, with an overall warfarin dose increase of 165% (IQR 99, 227) to reach steady state at 30 days. For offset, clinicians should anticipate proportionate warfarin dose decreases of 15-25% for both week 1 and 2, and a further 20% for both week 3 and 4, resulting in an overall warfarin decrease of 67% (IQR - 70, - 58) to reach steady state at 4 weeks for most patients. CONCLUSION: Close monitoring with at least twice weekly INRs for weeks 1 to 2 of both phases is needed to respond to substantially changing warfarin dose requirements. While inter- and intra-patient variability for proportionate warfarin dose changes for both the onset and offset of this drug interaction exists, our data provides general guidance.


Assuntos
Antibióticos Antituberculose/administração & dosagem , Anticoagulantes/administração & dosagem , Rifampina/administração & dosagem , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial , Antibióticos Antituberculose/farmacologia , Anticoagulantes/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rifampina/farmacologia , Fatores de Tempo , Varfarina/farmacologia
10.
Drug Metab Pharmacokinet ; 36: 100364, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341662

RESUMO

The inhibition of CYP2C9-mediated warfarin metabolism by acid or lactone forms of statin converted in the body and effects of CYP2C9 genetic variants on their inhibition are not fully understood. Here, the effects of acid and lactone forms of statins on S-warfarin 7-hydroxylation were investigated in vitro. S-Warfarin 7-hydroxylase activities of human liver microsomes (HLMs), recombinant CYP2C9.1 (rCYP2C9.1), and rCYP2C9.3 (Ile359Leu variant) in the presence of statins were determined by high-performance liquid chromatography. Lactone forms of atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin inhibited the activity of HLMs more potently than the corresponding acid forms, whereas fluvastatin acid showed stronger inhibition than fluvastatin lactone. When the effects of statins on rCYP2C9 variants were examined, inhibition profiles of acid versus lactone forms of statins except for fluvastatin were similar between rCYP2C9.1 and rCYP2C9.3. However, the degrees of inhibition by atorvastatin lactone, fluvastatin acid, fluvastatin lactone, lovastatin lactone, and pitavastatin lactone (Ki values) were significantly different between these variants. These results indicated that lactone forms of statins other than fluvastatin showed more potent inhibition of CYP2C9-catalyzed S-warfarin 7-hydroxylation than the corresponding acid forms. Furthermore, our results indicated that Ile359Leu substitution in CYP2C9 affected the inhibitory potencies of statins.


Assuntos
Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Microssomos Hepáticos/metabolismo , Variantes Farmacogenômicos/fisiologia , Varfarina/metabolismo , Ácidos/metabolismo , Catálise , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Feminino , Humanos , Hidroxilação/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lactonas/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Varfarina/farmacologia
11.
PLoS One ; 15(12): e0243866, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33315930

RESUMO

BACKGROUND: Little is known about the effects of anticoagulation in patients with atrial fibrillation (AF) and left atrial enlargement (LAE). METHODS: Data of patients with AF were retrieved from Chang Gung Research Database during 2007-2016. We excluded patients who were not using oral anticoagulants, used anticoagulants for <30 days, used ≥2 agents concomitantly or switched anticoagulants, had left atrial diameter missing from their data, were aged <65, had received valve surgeries, had mitral stenosis, or had a history of cancer. The primary outcomes were ischemic stroke (IS)/systemic embolism (SE), major bleeding, and death from any cause. RESULTS: We identified 40,777 patients who received a diagnosis of AF. After the exclusion criteria were applied, 6,445 patients remained, 4,922 with LAE, and they were followed up for 2.4 ±1.9 years. The mean age of the patients was 77.32 ± 0.18 in the NOAC group and 76.58 ± 6.91 in the warfarin group (p < 0.0001); 48.24% of patients in the NOAC group and 46.98% of patients in the warfarin group were men (p > 0.05). The mean CHA2DS2-VASc score was 3.26 ± 1.05 in the NOAC group and 3.07 ± 1.12 in the warfarin group (p < 0.0001). The mean HAS-BLED score was 3.87 ± 3.81 in the NOAC group and 3.86 ± 3.80 in the warfarin group (p > 0.05). Furthermore, the mean LA diameter was 4.75 ± 0.63 cm in the warfarin group and 4.79 ± 0.69 cm in the warfarin group (p > 0.05). Among patients with LAE, NOAC was associated with significantly reduced IS/SE events (CRR = 0.63, 95% CI = 0.52-0.77), no difference in major bleeding (CRR = 0.91, 95% CI = 0.78-1.05), and significantly reduced death from any cause (aHR = 0.65, 95% CI = 0.52-0.80) compared with warfarin. CONCLUSIONS: In elderly patients with AF and LAE, NOAC was associated with reduced IS/SE and death from any cause compared with warfarin, whereas no difference in major bleeding was observed between these treatments.


Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Cardiomegalia/complicações , Cardiomegalia/tratamento farmacológico , Átrios do Coração/patologia , Varfarina/uso terapêutico , Administração Oral , Idoso , Feminino , Seguimentos , Átrios do Coração/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Resultado do Tratamento , Varfarina/farmacologia
12.
Oxid Med Cell Longev ; 2020: 2043762, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33149806

RESUMO

Warfarin, a vitamin K antagonist (VKA), is known to promote arterial calcification (AC). In the present study, we conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis (MESA); 6655 participants were included. From MESA data, we found that AC was related to both age and vitamin K; furthermore, the score of AC increased with SASP marker including interlukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) rising. Next, a total of 79 warfarin users in our center developed significantly more calcified coronary plaques as compared to non-VKA users. We investigated the role of warfarin in phosphate-induced AC in different ages by in vitro experimental study. Furthermore, dose-time-response of warfarin was positively correlated with AC score distribution and plasma levels of the SASP maker IL-6 among patients < 65 years, but not among patients ≥ 65 years. In addition, in vitro research suggested that warfarin treatment tended to deteriorate calcification in young VSMC at the early stage of calcification. Our results suggested that aging and warfarin-treatment were independently related to increased AC. Younger patients were more sensitive to warfarin-related AC than older patients, which was possibly due to accumulated warfarin-induced cellular senescence.


Assuntos
Valva Aórtica/patologia , Biomarcadores/metabolismo , Senescência Celular/efeitos dos fármacos , Calcificação Vascular/patologia , Varfarina/farmacologia , Abdome/patologia , Idoso , Animais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/efeitos dos fármacos , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/patologia , Relação Dose-Resposta a Droga , Eletrocardiografia , Análise Fatorial , Feminino , Humanos , Interleucina-6/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fosfatos , Ratos Sprague-Dawley , Fatores de Risco , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos , Calcificação Vascular/diagnóstico por imagem , Vitamina K/farmacologia
13.
CMAJ Open ; 8(4): E706-E714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33158928

RESUMO

BACKGROUND: Antithrombotic drugs decrease stroke risk in patients with atrial fibrillation, but they increase bleeding risk, particularly in older adults at high risk for falls. We aimed to determine the most cost-effective antithrombotic therapy in older adults with atrial fibrillation who are at high risk for falls. METHODS: We conducted a mathematical modelling study from July 2019 to March 2020 based on the Ontario, Canada, health care system. We derived the base-case age, sex and fall risk distribution from a published cohort of older adults at risk for falls, and the bleeding and stroke risk parameters from an atrial fibrillation trial population. Using a probabilistic microsimulation Markov decision model, we calculated quality-adjusted life years (QALYs), total cost and incremental cost-effectiveness ratios (ICERs) for each of acetylsalicylic acid (ASA), warfarin, apixaban, dabigatran, rivaroxaban and edoxaban. Cost data were adjusted for inflation to 2018 values. The analysis used the Ontario public payer perspective with a lifetime horizon. RESULTS: In our model, the most cost-effective antithrombotic therapy for atrial fibrillation in older patients at risk for falls was apixaban, with an ICER of $8517 per QALY gained (5.86 QALYs at $92 056) over ASA. It was a dominant strategy over warfarin and the other antithrombotic agents. There was moderate uncertainty in cost-effectiveness ranking, with apixaban as the preferred choice in 66% of model iterations (given willingness to pay of $50 000 per QALY gained); edoxaban, 30 mg, was preferred in 31% of iterations. Sensitivity analysis across ranges of age, bleeding risk and fall risk still favoured apixaban over the other medications. INTERPRETATION: From a public payer perspective, apixaban is the most cost-effective antithrombotic agent in older adults at high risk for falls. Health care funders should implement strategies to encourage use of the most cost-effective medication in this population.


Assuntos
Acidentes por Quedas/prevenção & controle , Fibrilação Atrial/complicações , Análise Custo-Benefício , Fibrinolíticos/economia , Acidente Vascular Cerebral/prevenção & controle , Acidentes por Quedas/economia , Idoso , Idoso de 80 Anos ou mais , Aspirina/economia , Aspirina/farmacologia , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/economia , Dabigatrana/farmacologia , Feminino , Fibrinolíticos/farmacologia , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Masculino , Modelos Teóricos , Ontário , Pirazóis/economia , Pirazóis/farmacologia , Piridinas/economia , Piridinas/farmacologia , Piridonas/economia , Piridonas/farmacologia , Anos de Vida Ajustados por Qualidade de Vida , Rivaroxabana/economia , Rivaroxabana/farmacologia , Acidente Vascular Cerebral/economia , Acidente Vascular Cerebral/etiologia , Tiazóis/economia , Tiazóis/farmacologia , Varfarina/efeitos adversos , Varfarina/economia , Varfarina/farmacologia
14.
S Afr Med J ; 110(10): 999-1002, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33205728

RESUMO

The venom of the boomslang (Dispholidus typus) has potent effects on the coagulation system. It is known to produce a venom-induced consumptive coagulopathy (VICC) through the proposed activation of clotting factor II (prothrombin), factor X, and possibly factor IX. Warfarin, an anticoagulant medication, decreases the circulating vitamin K-dependent clotting factors II, VII, IX and X. We report a unique case of a boomslang bite in a patient on warfarin therapy. During the patient's hospital stay he developed abnormal clotting profiles indicating an underlying VICC, but without major bleeding. He received monovalent antivenom and recovered with no complications. We discuss two possible outcomes of a boomslang bite in a patient on warfarin therapy, exploring the underlying pathophysiology that could lead to the presentation of a reduced risk of overall bleeding or, alternatively, that the bleeding could be compounded and exacerbated. It is possible that in our case the anticoagulant effect of warfarin was wholly obscured by the VICC of the boomslang venom. The composition of the snake venom may have been a contributory factor in the reduced clinical bleeding observed.


Assuntos
Anticoagulantes/farmacologia , Antivenenos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/fisiopatologia , Venenos de Serpentes/farmacologia , Varfarina/farmacologia , Anticoagulantes/uso terapêutico , Antivenenos/uso terapêutico , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/fisiopatologia , Interações Medicamentosas , Humanos , Masculino , Pessoa de Meia-Idade , Venenos de Serpentes/efeitos adversos , Varfarina/uso terapêutico
15.
Medicine (Baltimore) ; 99(46): e22987, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181661

RESUMO

To investigate the frequency and degree of azole antifungal agents that influence the anticoagulant activity of warfarin to reduce the potential bleeding risk and provide a reference for rational administration of warfarin in clinics.Patients with an abnormal international normalized ratio (INR; INR ≥ 4.5) and treated with warfarin plus azole antifungal agents were screened from February 2011 to July 2016, and their data were extracted.Thirty-two patients treated with warfarin plus azole antifungal agents were included. The INR of all the included patients increased by more than 20% of the INR of warfarin alone, and the warfarin sensitivity index showed an upward trend. The INRs of 21 patients treated with fluconazole (FLCZ) and warfarin was closely monitored for 1 week after the combination treatment, and the interaction between warfarin and the azole antifungal agents peaked on the seventh day. The INRs when warfarin was coadministered with azoles (Y) correlated significantly with those in the absence of azoles (X): FLCZ: Y = 1.2515X + 2.1538, R = 0.8128; and voriconazole Y = 2.4144 X + 2.6216, R2 = 0.7828.The combination of FLCZ and voriconazole will enhance the anticoagulant effect of warfarin. Therefore, it is recommended to detect the genotype of CYP2C9 in patients and evaluate the interaction between the 2 drugs to adjust the warfarin dose. It is also recommended to closely monitor INR within 1 week of the addition of azole antifungal agents.


Assuntos
Anticoagulantes/farmacologia , Antifúngicos/farmacologia , Azóis/farmacologia , Varfarina/farmacologia , Adulto , Idoso , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Citocromo P-450 CYP2C9/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Erros Inatos do Metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
16.
Elife ; 92020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32870157

RESUMO

Vitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR's pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an evolutionary coupling analysis, supports a four transmembrane domain topology, with variants in transmembrane domains exhibiting strongly deleterious effects on abundance and activity. Functionally constrained regions of the protein define the active site, and we find that, of four conserved cysteines putatively critical for function, only three are absolutely required. Finally, 25% of human VKOR missense variants show reduced abundance or activity, possibly conferring warfarin sensitivity or causing disease.


Assuntos
Domínio Catalítico , Variação Genética , Mutação de Sentido Incorreto , Vitamina K Epóxido Redutases/química , Vitamina K Epóxido Redutases/genética , Cisteína/química , Resistência a Medicamentos , Células HEK293 , Humanos , Erros Inatos do Metabolismo , Modelos Moleculares , Análise de Sequência de DNA , Varfarina/farmacologia
17.
Clin Appl Thromb Hemost ; 26: 1076029620945039, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32875827

RESUMO

Low SAMe-TT2R2 score of <2 was validated as a predictor of optimum anticoagulation control, reflected by mean time in therapeutic range (TTR) above 65% to 70%, among warfarin-treated atrial fibrillation patients. This study aimed to validate the ability of SAMe-TT2R2 score and its individual components in predicting anticoagulation control (mean TTR and clinical events) among a cohort of venous thromboembolism (VTE) patients in Qatar. A total of 295 patients were retrospectively evaluated. There was a trend toward statistical significance in mean TTR between low (<2) and high (≥ 2) SAMe-TT2R2 score groups (P = .05), a difference that was not sustained when a cutoff of 3 was used (ie, a score of 3 or more). Patients with poor INR control (TTR <70%) were numerically less likely to have SAMe-TT2R2 score of <2 compared with those with good INR control, though the difference was not statistically significant (16.7% vs 83.3%, respectively, P = .4). No thromboembolic events were reported, and no association was found between the score and risk of bleeding. Non-Caucasian origin was the only significant predictor of good anticoagulation in the studied cohort. In conclusion, SAMe-TT2R2 score could not predict quality of anticoagulation control in a cohort of VTE patients treated with warfarin in Qatar. Contribution of other clinical factors and whether a different scoring may yield better prediction of anticoagulation control remains to be tested.


Assuntos
Anticoagulantes/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Anticoagulantes/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Varfarina/farmacologia
18.
J Cell Mol Med ; 24(19): 11546-11557, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32845082

RESUMO

We aimed to investigate the role of the miR-29b and its effect on TGF-ß3 pathway in vascular and valvular calcification in a rat model of calcific aortic valve diseases (CAVD). A rat model of CAVD was established by administration of warfarin plus vitamin K. The expression levels of miR-29b, osteogenic markers and other genes were determined by qRT-PCR, Western blot and/or immunofluorescence and immunohistochemistry. The calcium content and alkaline phosphatase (ALP) activity were measured. The calcium content, ALP activity and osteogenic markers levels in calcified aorta and aortic valve were augmented compared to controls. The expression of miR-29b, p-Smad3, and Wnt3 and ß-catenin was significantly up-regulated, whereas TGF-ß3 was markedly down-regulated. However, compared with the CAVD model group, the calcium content and ALP activity in rats treated with antagomiR-29b were significantly decreased, and antagomiR-29b administration reversed the effects of CAVD model on the expression of miR-29b and osteogenic markers. Inhibition of miR-29b in CAVD rats prevented from vascular and valvular calcification and induced TGF-ß3 expression, suggesting that the miR-29b/TGF-ß3 axis may play a regulatory role in the pathogenesis of vascular and valvular calcification and could play a significant role in the treatment of CAVD and other cardiovascular diseases.


Assuntos
Antagomirs/uso terapêutico , Estenose da Valva Aórtica/tratamento farmacológico , Estenose da Valva Aórtica/fisiopatologia , Valva Aórtica/patologia , Calcinose/tratamento farmacológico , Calcinose/fisiopatologia , Coração/fisiopatologia , MicroRNAs/antagonistas & inibidores , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/fisiopatologia , Animais , Antagomirs/farmacologia , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/genética , Calcificação Fisiológica/efeitos dos fármacos , Calcificação Fisiológica/genética , Calcinose/genética , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteopontina/metabolismo , Ratos Sprague-Dawley , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta3/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Varfarina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
19.
Yakugaku Zasshi ; 140(10): 1269-1274, 2020 Oct 01.
Artigo em Japonês | MEDLINE | ID: mdl-32684555

RESUMO

We previously reported that tolvaptan may influence warfarin pharmacodynamics in vivo; however, the mechanism responsible for this influence was not clear. In this study, we investigated the drug-drug interactions between warfarin and tolvaptan by measuring warfarin blood concentrations in 18 patients who received warfarin therapy and in 24 who received warfarin+tolvaptan therapy. The free warfarin concentrations significantly increased in patients who were also receiving oral tolvaptan (p=0.04). In vitro albumin-binding experiments showed that the free warfarin concentrations significantly increased with the addition of tolvaptan, in a dose-dependent manner, through albumin-binding substitution (approximately 2.5 times). Both clinical and in vitro data showed that tolvaptan increased the unbound warfarin serum concentration. The prothrombin time-international normalized ratio (PT-INR) tended to increase within 2 weeks when tolvaptan was added at clinically used doses (p=0.14). Special attention is warranted in cases with a serum tolvaptan concentration of ≥125 ng/mL (≥7.5 mg/d) for at least 2 weeks following oral tolvaptan administration.


Assuntos
Anticoagulantes/sangue , Interações Medicamentosas , Coeficiente Internacional Normatizado , Tempo de Protrombina , Tolvaptan/farmacologia , Varfarina/sangue , Varfarina/farmacologia , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , Anticoagulantes/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Fatores de Tempo , Tolvaptan/administração & dosagem , Varfarina/administração & dosagem , Varfarina/metabolismo
20.
Sci Rep ; 10(1): 11613, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669629

RESUMO

Warfarin is a frequently prescribed oral anticoagulant with a narrow therapeutic index, requiring careful dosing and monitoring. However, patients respond with significant inter-individual variability in terms of the dose and responsiveness of warfarin, attributed to genetic polymorphisms within the genes responsible for the pharmacokinetics and pharmacodynamics of warfarin. Extensive warfarin pharmacogenetic studies have been conducted, including studies resulting in genotype-guided dosing guidelines, but few large scale studies have been conducted with the Saudi population. In this study, we report the study design and baseline characteristics of the Saudi WArfarin Pharmacogenomics (SWAP) cohort, as well as the association of the VKORC1 promoter variants with the warfarin dose and the time to a stable INR. In the 936 Saudi patients recruited in the SWAP study, the minor allele C of rs9923231 was significantly associated with a 8.45 mg higher weekly warfarin dose (p value = 4.0 × 10-46), as well as with a significant delay in achieving a stable INR level. The addition of the rs9923231 status to the model, containing all the significant clinical variables, doubled the warfarin dose explained variance to 31%. The SWAP cohort represents a valuable resource for future research with the objective of identifying rare and prevalent genetic variants, which can be incorporated in personalized anticoagulation therapy for the Saudi population.


Assuntos
Variação Genética , Vitamina K Epóxido Redutases/genética , Varfarina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Anticoagulantes/farmacologia , Estudos de Coortes , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Estudos Prospectivos , Arábia Saudita/epidemiologia
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