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Rocha, Helena Clarisse Mota Fiuza da. "Novos anticoagulantes orais." Master's thesis, [s.n.], 2015. http://hdl.handle.net/10284/5306.
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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasDurante longos anos, os antagonistas da vitamina K e as heparinas foram os únicos anticoagulantes disponíveis. Apesar de eficazes na prevenção/tratamento das doenças tromboembólicas, apresentam numerosas limitações. No sentido de ultrapassar estas limitações, têm vindo a ser desenvolvidos novos fármacos, que ao contrário dos anteriores atuam num único fator da coagulação específico. Após vários estudos de eficácia e segurança, o dabigatrano etexilato (inibidor direto da trombina), o rivaroxabano e o apixabano (inibidores diretos do fator Xa) foram aprovados para prevenção de acidente vascular cerebral (AVC) e do tromboembolismo venoso em pacientes submetidos a artroplastia eletiva da anca ou joelho, para reduzir o risco de AVC e embolismo sistémico em pacientes com fibrilhação auricular não-valvular e também como tratamento em pacientes com trombembolismo venoso agudo. Estes novos anticoagulantes orais além de serem farmacologicamente previsíveis, não sofrem interações significativas com alimentos, nem com outros fármacos, não necessitam de monitorização laboratorial regular e são de administração oral. Os resultados dos estudos demonstraram que são pelo menos tão eficazes como a varfarina mas mais seguros, uma vez que apresentam um risco de hemorragias major inferior. No entanto, muito ainda está por explorar, sendo necessário prosseguir com as investigações nesta área, conhecendo melhor os efeitos a longo prazo e garantindo uma melhor eficácia e segurança para os pacientes.
For many years, vitamin K antagonists and heparins were the only available anticoagulants. Although effective in the prevention/treatment of thromboembolic diseases, they have numerous limitations. In order to overcome these drawbacks, new drugs that act on a single specific coagulation factor have been developed. After several studies on efficacy and safety, dabigatran etexilate (direct thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors) have been approved for prevention of stroke and venous thromboembolism in patients undergoing elective arthroplasty of hip or knee, to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and in the treatment of patients with acute venous thromboembolism. These new oral anticoagulants are pharmacologically predictable, do not suffer from interaction with other drugs or with food, do not require regular laboratory monitoring and are orally active. The results of the studies showed that are at least as effective as warfarin but safer, since the risk of major bleeding is shorter. However, much remains to be explored, it is necessary to proceed with the investigations in this area, ensuring better efficacy and safety for patients.
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Brüggemann, Stefan [Verfasser]. "Die Wirkung von Rivaroxaban auf die Frakturheilung der Ratte / Stefan Brüggemann." Kiel : Universitätsbibliothek Kiel, 2017. http://d-nb.info/1127044125/34.
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Coleman, Craig I., Jan Beyer-Westendorf, Thomas J. Bunz, Charles E. Mahan, and Alex C. Spyropoulos. "Postthrombotic Syndrome in Patients Treated With Rivaroxaban or Warfarin for Venous Thromboembolism." Sage, 2018. https://tud.qucosa.de/id/qucosa%3A35470.
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Postthrombotic syndrome (PTS) is a frequent complication of venous thromboembolism (VTE). Using MarketScan claims data from January 2012 to June 2015, we identified adults with a primary diagnosis code for VTE during a hospitalization/emergency department visit, ≥6 months of insurance coverage prior to the index event and newly started on rivaroxaban or warfarin within 30 days of the index VTE. Patients with <4-month follow-up postindex event or a claim for any anticoagulant during 6-month baseline period were excluded. Differences in baseline characteristics between rivaroxaban and warfarin users were adjusted for using inverse probability of treatment weights based on propensity scores. Patients were followed for the development of PTS starting 3 months after the index VTE. Cox regression was performed and reported as hazard ratios with 95% confidence intervals (CIs). In total, 10 463 rivaroxaban and 26 494 warfarin users were followed for a mean of 16 ± 9 (range, 4-39) months. Duration of anticoagulation was similar between cohorts (median = 6 months). Rivaroxaban was associated with a 23% (95% CI: 16-30) reduced hazard of PTS versus warfarin. Rivaroxaban was associated with a significant risk reduction in symptoms of PTS compared to warfarin in patients with VTE treated in routine practice.
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Leven, Cyril. "Pharmacologie des anticoagulants oraux directs à visée curative chez le patient obèse et après chirurgie bariatrique." Electronic Thesis or Diss., Brest, 2024. http://www.theses.fr/2024BRES0013.
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La sécurité d’emploi et l’efficacité des anti-Xa oraux directs (AOD) en cas d’obésité ont été démontrés dans la littérature. En revanche les données pharmacocinétiques spécifiques de cette population sont rares, et les données après chirurgie bariatrique sont encore plus rares. Une revue systématique des modèles pharmacocinétiques de population de ces AOD a montré que plusieurs modèles de l’apixaban étaient applicables à la population des patient atteints d’obésité traités pour maladie veineuse thromboembolique (MVTE). En revanche, au moment de l’étude aucun des modèles publiés du rivaroxaban n’était applicable à cette population. Les extrapolations à partir de ces modèles, ou les résultats des simulations ne sont pas valables pour la population des patients atteints d’obésité et traités pour MVTE par rivaroxaban. L’étude de phase 1 ABSORB (NCT04180436) a évalué la pharmacocinétique et la sécurité d’emploi du rivaroxaban a pleine dose chez des sujets atteints d’obésité et après chirurgie bariatrique (gastrectomie longitudinale ou bypass gastrique). Les résultats de cette étude suggéraient que la chirurgie bariatrique n’avait pas d’impact cliniquement significatif sur la pharmacocinétique et la sécurité d’emploi du rivaroxaban. Une exposition inférieure au rivaroxaban était observée dans les groupes chirurgicaux, toutefois les différences étaient faibles et inférieures à la variabilité interindividuelle rapportée dans la population générale. Enfin, un logiciel libre et gratuit qui permet la personnalisation de ces traitements par approche Bayésienne a été développé, et ses performances ont été validéesThe safety and efficacy of direct oral anti-Xa drugs (DOACs) in patients with obesity have been well established in the literature. However, pharmacokinetic data specific to this population are scarce, and data after bariatric surgery are even rarer. A systematic review of population pharmacokinetic models for these DOACs showed that several models for apixaban were applicable to the obese patient population treated for venous thromboembolic disease (VTE). None of the published models for rivaroxaban, however, were applicable to this population. Extrapolations from these models, the values of their pharmacokinetic parameters, or the results of simulations are not valid for the population of obese patients treated with rivaroxaban for VTE. The Phase 1 ABSORB study (NCT04180436) evaluated the pharmacokinetics and safety of full-dose rivaroxaban in patients with obesity and after bariatric surgery (gastric sleeve gastrectomy or gastric bypass). The results of this study indicated that bariatric surgery did not have a clinically significant effect on the pharmacokinetics and safety of rivaroxaban. Lower rivaroxaban exposure was observed in the surgical groups, but the differences were small and below the inter-individual variability reported in the general population. Finally, a free, open-source software package for personalizing these treatments using a Bayesian approach was developed and its performance was validated
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DIMATTEO, CLAUDIA. "Studio di associazione tra fattori genetici e livelli plasmatici in pazienti trattati con NAO: Dabigatran, Rivaroxaban e Apixaban." Doctoral thesis, Università di Foggia, 2016. http://hdl.handle.net/11369/338843.
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Introduzione: gli anticoagulanti orali svolgono un importante ruolo nel ridurre complicanze e mortalità associate ai disturbi tromboembolici. Il Warfarin, un antagonista della vitamina K (AVK), ha rappresentato per 50 anni l’unico farmaco disponibile ed efficace per la profilassi di eventi tromboembolici, i cui limiti sono dati da un monitoraggio dell’INR, da interazioni alimentari e farmacologiche. Tali limiti sono stati superati con i nuovi anticoagulanti orali (NAO), che si somministrano in dosi fisse, non necessitano di monitoraggio continuo, hanno una rapida insorgenza d’azione, un buon profilo di sicurezza, una farmacodinamica ed una farmacocinetica prevedibile, poche interazioni con cibo e farmaci, e sono utilizzati nella terapia anticoagulante orale di quei pazienti con patologie come fibrillazione atriale, cardiopatie dilatative, valvulopatie, malattie tromboemboliche e protesi valvolari cardiache. Si tratta del Dabigatran, inibitore diretto della trombina (fattore IIa), e del Rivaroxaban e Apixaban, inibitori del fattore Xa. È stata riportata una variabilità inter-individuale nelle concentrazioni di farmaco ritrovate nel sangue; in particolare i geni ABCB1 e CES1 esercitano un effetto importante nel metabolismo degli anticoagulanti e varianti alleliche in questi due loci giocano un ruolo determinante sulla suscettibilità del farmaco.
Obiettivi: analizzare i polimorfismi su geni coinvolti nel processo metabolico del Dabigatran, Rivaroxaban e Apixaban, in particolare sul gene ABCB1 che codifica per un trasportatore della glicoproteina P (pompa di efflusso ATP-dipendente) per tutti e tre i farmaci e sul gene CES1 che è un enzima metabolizzante carbossilesterasi 1, che interviene nella trasformazione del dabigatran etexilato in forma attiva. Inoltre, determinazione della concentrazione plasmatica dei 3 farmaci prima e dopo assunzione dello stesso.
Materiali e Metodi: In una coorte di 92 pazienti in terapia con i dabigatran, 51 con rivaroxaban e71 con apixaban, abbiamo esaminato, attraverso sequenziamento diretto, le varianti geniche del gene ABCB1(rs4148738) per tutti i farmaci e le varianti geniche del gene CES1 (rs8192935 e rs2244613) per i pazienti in dabigatran e determinato la concentrazione plasmatica di valle e di picco dei farmaci stessi, attraverso la tecnica combinata HPLC-spettrometria di massa.
Risultati e Conclusioni: Tra i 92 pazienti che assumono dabigatran (età media: 72.0 anni) analizzati, nessuna variabile clinico o genotipo è stata associata con una differenza significativa nelle concentrazioni di picco di dabigatran. Per quanto riguarda le concentrazioni di valle, oltre alla clearance della creatinina, e il sesso è stata rilevata una significativa associazione con i rs8192935 CES1 SNP (p = 0,023). I livelli plasmatici medi aggiustati erano più elevati tra i pazienti con il genotipo CC (86,3 ng / dl) rispetto a quelli che portano l’allele T (62,1 ng / dl). Nessun effetto significativo è stato rilevato per i rs4148738 ABCB1 SNP. Nel caso del Rivaroxaban per entrambe le dosi, non è stato trovato nessun effetto dello SNP ABCB1 sui livelli plasmatici. Per l’Apixaban, invece, è stata rilevata un’associazione con la dose di 10 mg, in particolare una significativa associazione con lo SPN di ABCB1 (p=0,048).
Abstract in English Background: the oral anticoagulants play an important role in reducing complications and mortality associated with thromboembolic disorders. Warfarin, a vitamin K antagonist (VKA), represented for 50 years the only drug available and effective for the prophylaxis of thromboembolic events, but it presents the limits, in particular it needs a monitoring of INR, interaction of food and drug. These limits have been exceeded with the new oral anticoagulants (NAO), which are administered in fixed doses, do not require continuous monitoring, they have a rapid onset of action, a good safety profile, pharmacodynamics and pharmacokinetics predictable, few interactions with food and drugs, and are used in the oral anticoagulation therapy for patients with diseases such as atrial fibrillation, dilated heart disease, valvular disease, thromboembolic disease and heart valve prostheses. They are the Dabigatran, direct inhibitor of thrombin (factor IIa), and the rivaroxaban and apixaban, factor Xa inhibitors. It was found an inter-individual variability in drug concentrations found in the blood; especially the ABCB1 and CES1 genes exert an important effect in the metabolism of anticoagulants and allelic variants in these two loci play a decisive role on the susceptibility of the drug.
Objectives: to analyze the polymorphisms of genes involved in the metabolic process of dabigatran, rivaroxaban and apixaban, in particular on the ABCB1 gene encoding a transporter P-glycoprotein (ATP-dependent efflux pump) for all three drugs and CES1 gene that is an enzyme carboxylesterase 1, which is involved in the transformation of dabigatran etexilate in active form. Furthermore, we have determined the plasma concentration of 3 drugs before and after intake of the same.
Patients/Methods: In a cohort of 92 patients treated with dabigatran, 51 with rivaroxaban and 71 with apixaban, we have examined by direct sequencing, gene variants of the ABCB1 (rs4148738 gene) for all drugs and genetic variants of CES1 gene (rs8192935 and rs2244613) for patients on dabigatran and we have determined the plasma concentration of trough and peak of the drugs, by the combined technique HPLC-mass spectrometry .
Results and Conclusion: Among the 92 patients treated with dabigatran (mean age: 72.0 years) analyzed, no clinical variable or genotype was associated with a significant difference in peak concentrations of dabigatran. As for trough concentrations, in addition to creatinine clearance and sex it is found a significant association with rs8192935 SNP CES1 (p=0.023) . The adjusted average plasma levels were higher among patients with the CC genotype (86.3 ng/dl) than those who carry the T allele (62.1 ng/dl). No significant effect was observed for the ABCB1 SNP rs4148738. In the case of rivaroxaban for both doses, it was not found any of the ABCB1 SNP effect on plasma levels. For the apixaban, instead, an association has been detected with the dose of 10 mg, in particular a significant association with the SPN of the ABCB1 (p = 0.048).
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Mrotzek, Silvia Jasmin [Verfasser]. "Effekte von Rivaroxaban und Enoxaparin auf die osteogene Differenzierung humaner mesenchymaler Stromazellen in vitro / Silvia Jasmin Mrotzek." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2017. http://d-nb.info/1137502193/34.
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Harrington, Amanda Rose. "Cost-Effectiveness of Apixaban, Dabigatran, Rivaroxaban, and Warfarin for the Prevention of Stroke Prophylaxis in Atrial Fibrillation." Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/268612.
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Objective: The primary objective of this study was to estimate the long-term cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the United States using new anticoagulant therapies - dabigatran 150 mg, apixaban 5 mg, and rivaroxaban 20 mg - as well as the standard treatment, warfarin. Methods: A Markov decision-analysis model was constructed using data from clinical trials that evaluated the new oral anticoagulants relative to warfarin (apixaban 5 mg & ARISTOTLE, dabigatran 150 mg & RE-LY, and rivaroxaban 20 mg & ROCKET-AF) to compare the lifetime cost and quality-adjusted life expectancy. The Markov model target population was a hypothetical cohort of 70-year old patients with nonvalvular atrial fibrillation, an increased risk for stroke (CHADS₂ ≥ 1, or equivalent), a renal creatinine clearance (CrCl) of 50 or above, and no contraindication to anticoagulant therapy. Using pair-wise comparisons of each therapy, analyses were conducted to evaluate incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs), lifetime costs, life-years, and quality-adjusted life-years (QALYs). Results: In the base case, warfarin had the lowest cost of $71,857 (95% confidence interval [CI]: $68,730, $77,452), followed by rivaroxaban 20 mg ($74,023; 95% CI: $70,943, $77,307), dabigatran 150 mg ($78,584; 95% CI: $75,277, $81,968), and apixaban 5 mg ($81,180; 95% CI: $78,642, $83,756). Apixaban 5 mg also yielded the highest QALY estimate, 8.63 (95% CI: 8.52, 8.72), followed by dabigatran 150 mg (8.55; 95% CI: 8.43, 8.67), rivaroxaban 20 mg (8.42; 95% CI: 8.31, 8.54), and warfarin (8.17; 95% CI: 8.1, 8.24). In a Monte Carlo probabilistic sensitivity analysis, apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg, and warfarin were cost effective in 45%, 37%, 19%, 0%, respectively, of the simulations using a willingness-to pay threshold of $50,000 per QALY gained. From the one-way sensitivity analyses, new anticoagulant (apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg) costs and probabilities associated with intracranial hemorrhage and stroke for patients receiving rivaroxaban 20 mg were identified as significant influential variables impacting model results. Conclusion: In patients with NVAF and an increased risk of stroke prophylaxis, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg may all be cost-effective alternatives to warfarin depending on pricing in the United States and neurologic events for rivaroxaban 20 mg.
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Wingert, Nathalie Ribeiro. "Desenvolvimento e validação de métodos analíticos e estudos de estabilidade da rivaroxabana." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/149500.
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A análise de fármacos é fundamental nas diversas fases do desenvolvimento farmacêutico, tais como estudos de formulação, estabilidade e controle de qualidade do produto. A rivaroxabana (RIV) é um anticoagulante de uso oral indicado para prevenção da formação de coágulos venosos. A literatura pesquisada apresenta poucos relatos de determinação quantitativa e de estudos de estabilidade do fármaco em comprimidos. E ainda nenhum método analítico em compêndios oficiais Diante do exposto, o objetivo deste trabalho foi desenvolver e validar métodos analíticos para determinação qualitativa e quantitativa da RIV por cromatografia líquida de alta eficiência com detecção por UV e de ultra eficiência com detecção por espectrometria de massas (CLAE-UV e CLUE-EM) e eletroforese capilar (EC). Os resultados encontrados foram adequados conforme o preconizado nos guias oficiais nacionais e internacionais. Foi avaliada também a viabilidade da técnica de eletroforese capilar em microchip para análise de RIV. Através de método desenvolvido por CLAE foi realizado estudo de cinética de degradação e posterior avaliação do potencial tóxico in vitro das amostras de degradação forçada da RIV. A identificação de três produtos de degradação majoritários da RIV, formados a partir de estresse ácido, alcalino e fotolítico, foi realizada por CLUE-EM/EM, possibilitando a proposição da estrutura molecular de cada produto de degradação. O potencial tóxico da RIV antes e depois da exposição à degradação forçada foi avaliado através dos métodos in vitro MTT, Vermelho Neutro, Ensaio Cometa e DNA de baixo peso molecular. Não foram encontrados sinais de dano ao DNA celular, contudo, amostras de RIV expostas ao meio alcalino apresentaram maior redução da viabilidade celular. O trabalho avaliou ainda o perfil de dissolução da RIV em comprimidos baseado nos dados de absorção in vitro conforme modelagem in silico dos dados, estabelecendo uma correlação linear entre a fração absorvida e fração dissolvida. As diferentes metodologias e técnicas desenvolvidas e aplicadas nesse trabalho contribuem para o desenvolvimento do controle de qualidade farmacêutico na direção de ensaios mais confiáveis que garantam a segurança e eficácia de medicamentos.Drug analysis is critical at various stages of pharmaceutical development, such as formulation studies, stability and quality control products. Rivaroxaban (RIV) is an oral anticoagulant indicated for prevention of thromboembolism. Literature contains few reports of quantitative determination and drug stability studies of RIV on pharmaceutical formulation. Analytical method for RIV quality control are not evaluable on official guides yet. This research work aimed to develop and validate analytical methods for qualitative and quantitative determination of RIV by high and ultra performance liquid chromatography with UV detection mass spectrometry detection (HPLC -UV and UPLC-MS) and capillary electrophoresis (CE). The results were adequate as recommended in national and international official guides. Reliability of RIV analysis by microchip capillary electrophoresis was also assessed. Through the method developed by HPLC degradation kinetic studies were performed, zero order kinetic has better description of RIV degradation behaviour. RIV toxic potential before and after exposure to forced degradation was assessed by in vitro methods of MTT, Neutral Red, Comet Assay, and Low Molecular Weight DNA. There were no signals of DNA damage however, RIV samples exposed to alkaline medium showed increased reduction in cell viability. Identification of RIV degradation products formed after exposure to acid and alkaline media and UVC radiation was performed by UPLC-MS / MS. It was possible to elucidate molecular structures of three major degradation products. This study also assessed the dissolution profile of RIV tablets based on in vitro absorption data, a linear point-to-point correlation was found for fraction absorbed and dissolved. Different methodologies and techniques developed and applied in this work can contribute to the development of pharmaceutical quality towards more reliable tests to ensure safety and efficacy of medicines.
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TOSCANO, Paulo Martins. "Perfil molecular em genes cyp3a4 e cyp2j2: um caminho para a farmacogenética do Rivaroxaban em uma população do Norte do Brasil." Universidade Federal do Pará, 2014. http://repositorio.ufpa.br/jspui/handle/2011/8911.
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Nos últimos anos, novos anticoagulantes têm sido desenvolvidos com o objetivo de minimizar as dificuldades encontradas no manejo clínico das drogas convencionais, porém não existem dados publicados sobre a sua farmacogenética. Diante da hipótese de que os polimorfismos relacionados à sua metabolização possam ser fonte de variabilidade genética, o presente estudo objetiva realizar inferências de epidemiologia molecular dos polimorfismos nos genes CyP3a4 (rs2246709) e CyP2j2 (rs890293), relacionados ao metabolismo do Rivaroxaban, um novo inibidor direto do fator Xa. São analisadas 136 amostras de indivíduos saudáveis de uma população do Norte do Brasil que apresenta um elevado grau de mistura interétnica. Para alcançar o objetivo farmacogenético foi realizada, em paralelo, análise de ancestralidade genômica nos indivíduos investigados. Os resultados demonstraram diferenças significativas entre os genótipos do CyP3a4 observados no estudo, quando comparados a todas as populações ancestrais para o polimorfismo 99365719 a>G (P<0,05). a população miscigenada do Norte do Brasil, portanto, apresentou diferença na distribuição das frequências genotípicas em relação aos grupos ancestrais, formadores de nossa população. O mesmo achado não é observado para polimorfismo do gene do CyP2j2. Destaca-se que o polimorfismo no gene do CyP3a4, na amostra investigada, sofre influência da contribuição étnica européia individual. Considerando, a elevada miscigenação que caracteriza a população local e o avanço da Farmacogenômica na medicina atual, os dados podem contribuir para a melhor compreensão da farmacogenética do novo anticoagulante.
In recent years, new anticoagulants have been developed with the purpose of minimizing the difficulties encountered in the clinical management of conventional dru- gs, but there are no published data on its pharmacogenetics. Considering the hypothe- sis that polymorphisms related to its metabolism may be the source of genetic variability, this study aims to make inferences on molecular epidemiology of polymorphisms in CyP3a4 (rs2246709) and CyP2j2 (rs890293) genes related to the metabolism of Rivaroxaban, a new direct factor Xa inhibitor. 136 samples from healthy individuals in a population of northern Brazil with a high degree of inter-ethnic mix, so as to guarantee that the pharmacogenetic goal was achieved, have been subjected to a parallel analysis of genomic ancestry for the individuals investigated. The results sho- wed significant differences among genotypes for CyP3a4 observed in the study com- pared to all ancestral populations for a polymorphism 99,365,719 a> G ( P < 0.05). The mixed population of northern Brazil, therefore, showed differences in the distribution of genotype frequencies in relation to ancestral groups, forming our population. The same finding was not observed for the CyP2j2 gene polymorphism. It is noteworthy that the polymorphism in the CyP3a4 gene in the investigated sample is influenced by indivi- dual ethnic European contribution. Considering the high miscegenation featuring local people, and the advancement of Pharmacogenomics in current medicine, such data can contribute to a better understanding of the pharmacogenetics of that new anticoagulant.
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Klee, Thorben [Verfasser]. "Die murine polymikrobielle Sepsis als Modell der disseminierten intravasalen Gerinnung und deren Beeinflussung durch die Medikamente Rivaroxaban und Clopidogrel / Thorben Klee." Greifswald : Universitätsbibliothek Greifswald, 2017. http://d-nb.info/1136294635/34.
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Ikesaka, Rick. "The Risk of Upper Extremity Deep Vein Thrombosis and Primary Thromboprophylaxis with Low Dose Rivaroxaban in Oncology Patients with Central Venous Catheters." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41954.
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Venous thromboembolism (VTE) is a common disorder which causes significant morbidity and mortality. Upper extremity deep vein thrombosis(UEDVT) is a relatively understudied subtype of VTE which is commonly associated with central venous catheters, cancer, and thrombophilia.
The goal of this project was to better characterize the risk of UEDVT and to design and execute a pilot study that will demonstrate the efficacy of a strategy preventing the occurrence of VTE in a high-risk population for UEDVT.
This M.Sc project, was conducted in three parts.
Chapter 1 of the thesis outlines a systematic review of the literature which assessed the risk of VTE in UEDVT patients by search for and including data from studies with patients with prospectively enrolled symptomatic UEDVT.
Chapter 2 describes the development and final protocol of the TRIM-Line pilot study, a randomized open-label study comparing 90 days of rivaroxaban 10mg po daily against the current standard of care (observation) in patients with active cancer and central venous catheters, two known risk factors for VTE.
Finally in Chapter 3 the TRIM-Line study was executed as a pilot trial involving The Ottawa Hospital and the Juravinski Cancer Centre located in Hamilton. The study was conducted from March 2019 until February 2020. 105 patients underwent randomization at the two Canadian centres. The study met its prespecified feasibility endpoint average enrolment rate of 7.5 per month (95% CI:4.56, 10.44) at the coordinating Ottawa Hospital site and 2.0 per month (95% CI:0.87, 3.13) for the Juravinski Cancer Centre site. The randomized controlled trial met its enrollment targets and demonstrated that a full scale randomized controlled trial on the topic of prevention of cancer associated venous thromboembolism is feasible.
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Zindel, Sonja [Verfasser]. "Eine multiperspektive Kosten-Effektivitäts-Analyse zum Vergleich von Rivaroxaban mit Enoxaparin sodium zur Thromboembolieprophylaxe nach Hüft- und Kniegelenkstotalendoprothesen im deutschen Gesundheitssystem / Sonja Zindel." Köln : Deutsche Zentralbibliothek für Medizin, 2014. http://d-nb.info/1064495923/34.
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Busse, Jessica [Verfasser], Ingvild [Gutachter] Birschmann, and Axel [Gutachter] Stachon. "Dabigatran, Rivaroxaban, Apixaban, Argatroban und Fondaparinux und ihre Effekte auf Point-of-Care- sowie Plättchenfunktionstests / Jessica Busse ; Gutachter: Ingvild Birschmann, Axel Stachon ; Medizinische Fakultät." Bochum : Ruhr-Universität Bochum, 2020. http://d-nb.info/1214443095/34.
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Jacqueroux, Elodie. "Rôles des transporteurs ABC dans la variabilité pharmacocinétique des anticoagulants oraux directs : approche in vitro." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSES057.
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La prescription des AOD en remplacement des AVK est de plus en plus importante, du fait d'une utilisation moins contraignante pour le patient et d'une plus faible variabilité intra- et interindividuelle. Contrairement aux AVK, les AOD sont des substrats des pompes d'efflux. Ces transporteurs sont impliqués dans la pharmacocinétique des AOD, particulièrement dans leur absorption et dans leur élimination biliaire et rénale. L'objectif de ce travail de thèse a été d'évaluer in vitro le rôle des transporteurs P-gp et BCRP dans la variabilité pharmacocinétique du rivaroxaban, un inhibiteur direct du facteur Xa, La première étude a été axée sur l'étude d'une interaction entre le riociguat et deux AOD, l'apixaban et le rivaroxaban. L'estimation des IC50 a révélé la capacité des modèles cellulaires MDCK transfectés à détecter une inhibition de l'efflux lié à BCRP des deux AOD par le riociguat, bien que cette inhibition ne soit pas assez puissante pour être cliniquement pertinente. La seconde étude était centrée sur l'étude des facteurs pouvant faire varier les résultats des études de transport du rivaroxaban obtenus in vitro, en particulier la quantité des transporteurs ABC. Un analyse en spectrométrie de masse a révélé une expression plus élevée de P-gp et BCRP dans les cellules MDCK transfectées mais aussi une différence d'expression des transporteurs entre deux lignées Caco-2 issues d'une banque cellulaire différente. Les ratios d'efflux du rivaroxaban et les IC50 des inhibiteurs spécifiques étaient corrélés à la quantité de transporteurs mesurée dans les différents modèles. La troisième étude était basée sur la mise en place d'un modèle d'étude in vitro du transport hépatique, grâce à la lignée HepaRG. Ces cellules présentent des caractéristiques semblables aux hépatocytes in vivo, en particulier l'expression de transporteurs d'efflux fonctionnels au pôle canaliculaire, impliqués dans l'efflux biliaire du rivaroxaban. Des études d'accumulation ont démontré une prise en charge du rivaroxaban par les transporteurs d'efflux hépatiques, ainsi qu'une diminution de l'efflux dans les canalicules biliaires en présence d'inhibiteurs de P-gp et BCRP. Finalement, les modèles cellulaires in vitro démontrent que le rivaroxaban est pris en charge par deux transporteurs d'efflux, P-gp et BCRP, au niveau intestinal, rénal et hépatique, et que ce transport peut contribuer à la variabilité pharmacocinétique du rivaroxabanThe replacement of VKAs by DOACs is increasing, due to less constraining use for the patient and lower intra- and interindividual variability. Contrary to VKAs, DOACs are substrates of efflux pumps. These transporters are involved in the pharmacokinetics of DOACs, particularly in their absorption and both biliary and renal elimination. This work aimed to evaluate in vitro the role of P-gp and BCRP transporters in the pharmacokinetic variability of rivaroxaban, a direct specific activated factor X inhibitor. The first study focused on the interaction between riociguat and two DOACs, apixaban and rivaroxaban. The IC50 estimate highlighted the ability of the transfected MDCK cell models to detect the inhibition of BCRP-mediated efflux of both DOACs by riociguat, although this inhibition was not sufficiently strong to be clinically relevant. The second study focused on factors that could affect the results of in vitro rivaroxaban transport studies, in particular the expression levels of ABC transporters. Mass spectrometry analysis revealed a higher expression of P-gp and BCRP in transfected MDCK cells but also a different expression of transporters between two Caco-2 models coming from a different cell bank. Rivaroxaban efflux ratios and IC50s of specific inhibitors were correlated with the quantity of transporters detected in the different cell models. The third study was based on the development of an in vitro mode] of hepatic transport using the HepaRG cell line. HepaRG cells had characteristics similar to in vivo hepatocytes, particularly expression of functional canalicular efflux transporters which are involved in the biliary secretion of rivaroxaban. Accumulation studies showed that rivaroxaban was a substrate of hepatic efflux transporters and that canalicular secretion decreased in the presence of P-gp and BCRP inhibitors. Finally, in vitro cell models highlight the involvement of two efflux transporters, P-gp and BCRP, at the intestinal, renal and hepatic levels in the disposition of rivaroxaban, and that this transport can contribute to the pharmacokinetic variabilitv of rivaroxaban
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Dault, Roxanne. "Portrait de l’usage des anticoagulants et facteurs associés au choix de ceux-ci pour le traitement de la thromboembolie veineuse." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/7594.
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Depuis déjà quelques années au Canada, l’arrivée progressive de nouveaux anticoagulants oraux (NACO) propose des options dans le traitement de la thromboembolie veineuse (TEV). Le rivaroxaban, le premier NACO approuvé pour cette indication, possède des caractéristiques différentes des antagonistes de la vitamine K (AVK), les seuls agents anticoagulants oraux disponibles jusqu’à ce jour. Dans la littérature scientifique actuelle, peu de données sont disponibles sur le rivaroxaban et aucune étude n’a été identifiée concernant l’usage de ce médicament en contexte réel de soins de santé. Or, les objectifs de cette étude étaient de décrire le portrait de l’usage des anticoagulants pour le traitement initial et subséquent de la TEV au CHUS depuis l’introduction du rivaroxaban au formulaire thérapeutique de cet établissement et dans un deuxième temps, à identifier les facteurs associés au choix de l’anticoagulant oral prescrit pour le traitement subséquent de la TEV. Pour ce faire, une étude transversale a été réalisée. Les patients qui ont visité l’urgence ou qui ont été hospitalisés au CHUS entre le 18 février 2013 et le 18 septembre 2013 pour une thrombose veineuse profonde (TVP) et/ou une embolie pulmonaire (EP) ont été inclus. Les patients devaient toutefois nouvellement débuter un traitement anticoagulant durant le séjour, et ce dernier devait être poursuivi au congé de l’hôpital. Les anticoagulants prescrits pour le traitement initial et subséquent de la TEV ont été décrits. Les facteurs potentiels du choix ont d’abord été évalués à l’aide d’analyses bivariées et par la suite, une régression logistique multiple utilisant une méthode ascendante a été utilisée afin d’identifier les facteurs indépendamment associés au choix du rivaroxaban plutôt que de la warfarine (seul AVK disponible au CHUS). Ainsi, sur une période de 7 mois, 256 patients ont été inclus dans l’étude. Le traitement initial et le traitement subséquent les plus prescrits correspondaient respectivement, à l’héparine de bas poids moléculaire (HBPM; 61,7 %) et à la warfarine (54,7 %). Le rivaroxaban était peu utilisé en phase initiale de traitement (1,6 %) alors qu’il a été prescrit chez près de 20 % des individus au congé de l’hôpital pour le traitement subséquent de la TEV. Les facteurs indépendamment associés à la prescription de rivaroxaban plutôt que de warfarine étaient l’âge ˂ 65 ans (Rapport de cotes [RC] ajusté 2,86; Intervalle de confiance [IC] à 95 % 1,29–6,37), un diagnostic de TVP seule plutôt qu’une EP (RC ajusté 2,54; IC à 95 % 1,20–5,40) et une visite à l’urgence sans hospitalisation (RC ajusté 2,24; IC à 95 % 1,06–4,71). En conclusion, parmi les nouveaux utilisateurs d’anticoagulants pour le traitement de la TEV au CHUS, la thérapie conventionnelle (HBPM suivie d’un AVK) était la plus prescrite par les médecins malgré l’arrivée d’une nouvelle option pharmacologique de traitement. De plus, les jeunes patients, les individus qui avaient une TVP sans EP et ceux qui n’étaient pas hospitalisés étaient plus susceptibles de recevoir le rivaroxaban pour le traitement subséquent de la TEV.
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Brendel, Lukas Constantin [Verfasser], Ilka V. [Akademischer Betreuer] Ott, Heribert [Gutachter] Schunkert, and Ilka V. [Gutachter] Ott. "Gerinnungsaktivierung während Radiofrequenzablation von Vorhofflimmern unter Therapie mit Heparin in Kombination mit Apixaban oder Rivaroxaban / Lukas Constantin Brendel ; Gutachter: Heribert Schunkert, Ilka V. Ott ; Betreuer: Ilka V. Ott." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1167402219/34.
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Busch, Sonia [Verfasser], Isabel V. [Akademischer Betreuer] Deisenhofer, and Adnan [Akademischer Betreuer] Kastrati. "Safety of Continuous Periprocedural Rivaroxaban versus Phenprocoumon for Patients Undergoing Left Atrial Catheter Ablation Procedures / Sonia Busch geb. Ammar. Gutachter: Isabel V. Deisenhofer ; Adnan Kastrati. Betreuer: Isabel V. Deisenhofer." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1069128074/34.
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Sjögren, Vilhelm. "Oral anticoagulation and stroke risk." Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-141597.
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Background: The risk of ischaemic stroke in patients with atrial fibrillation (AF) and mechanical heart valve (MHV) prostheses can be reduced by oral anticoagulation (OAC), which increases the risk of serious bleeding. The aims of this thesis were [1] to find out how effective and safe warfarin is where treatment quality is high, i.e. Sweden, with proportion of time that patients spend within the therapeutic range (TTR) >70%, [2] whether there is evidence for administering low-molecular-weight heparin (LMWH) during temporary interruptions of OAC (bridging therapy), and whether non-vitamin K-dependent oral anticoagulants (NOACs) as a group, [3] or individually, [4] are more effective and safer than warfarin when used for stroke prevention in patients with AF. Materials and methods: All four studies were retrospective, based on the Swedish anticoagulation register Auricula, and done with merging of data from some or all of the National Patient Register, the Prescribed Drug Register, the Swedish Stroke Register (Riksstroke), and the Cause of Death Register. In studies 2–4, propensity score matching was performed to obtain treatment groups with similar risk profiles. Outcomes were defined as haemorrhages or thromboses requiring specialist care, or death. Haemorrhages were intracranial, gastrointestinal, or other. Thromboses were ischaemic stroke, systemic embolism, myocardial infarction, or venous thromboembolism (VTE). Study 1 described all patients on warfarin during 2006–2011, which was before the introduction of NOACs. Study 2 was a cohort study of all patients who had a planned interruption of warfarin during the same period. Study 3 included all 49,011 patients starting OAC for stroke prevention due to AF between 1 July 2011 and 31 December 2014, and study 4 all 64,382 patients with the same indication between 1 January 2013 and 31 December 2015. Results: Study 1 showed that for the 77,423 patients on warfarin with 217,804 treatment years, TTR was 77.4% for patients with AF, 74.5% with MHV, and 75.9% with VTE. Annual rates of intracranial bleeding were 0.38%, 0.51%, and 0.30%. In study 2, with 14,556 warfarin interruptions, the 30-day risk of a bleeding requiring specialist care was 0.64% for LMWH treated and 0.46% for controls. For patients with VTE as indication for OAC, bleeding rate with LMWH was significantly higher at 0.85% vs. 0.16% (hazard ratio 5.24, 95% confidence interval 1.39–19.77), but with no difference for patients with MHV or AF. The incidence of ischaemic complications was higher in the LMWH bridging group overall and for patients with MHV and AF, but not for patients with VTE. In study 3, for the 12,694 patients starting NOAC (10,392 treatment years) or matched warfarin patients (9,835 treatment years, TTR 70%) due to AF, annual incidence of ischaemic stroke and systemic embolism did not differ between the groups (1.35% vs. 1.58%), but risks of major bleedings and intracranial bleedings were significantly lower: 2.76% vs. 3.61% and 0.40% vs. 0.69%. In study 4, patients on individual NOACs (6,574 dabigatran, 8,323 rivaroxaban, 12,311 apixaban) were compared to 37,174 patients starting warfarin (in total 81,176 treatment years). No NOAC showed any difference in risk of ischaemic stroke or systemic embolism, but there were fewer intracranial bleedings, serious bleedings overall, and deaths for dabigatran and apixaban compared to warfarin. For patients starting rivaroxaban the risk of gastrointestinal bleeding was higher than for matched warfarin counterparts, with no significant differences in other bleeding risks, or mortality. Conclusions: Swedish warfarin treatment shows TTR levels that are high by international standards, correlating to low incidences of ischaemic and haemorrhagic events. LMWH bridging has not been proven beneficial, even for patients with MHV, meaning that bridging in general cannot be recommended. NOACs as a group were safer than high-quality warfarin treatment. Efficacy did not differ, even when comparing individual NOACs to warfarin, but there were fewer bleedings on dabigatran and apixaban. Although not more efficient than warfarin with a high TTR, NOACs should be the recommended first choice for OAC in AF, on the merit of lower bleeding risks.Finansiär: Forskning och Utveckling, Region Västernorrland
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Tahir, Faryal, Haris Riaz, Talha Riaz, Maaz Badshah, Irbaz Riaz, Ameer Hamza, and Hafsa Mohiuddin. "The new oral anti-coagulants and the phase 3 clinical trials - a systematic review of the literature." BioMed Central, 2013. http://hdl.handle.net/10150/610256.
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BACKGROUND:Anticoagulation with vitamin K antagonists such as warfarin has historically been used for the long term management of patients with thromboembolic disease. However, these agents have a slow onset of action which requires bridging therapy with heparin and its analogues, which are available only in parenteral route. To overcome these limitations, new oral anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors have been developed. The aim of this article is to systematically review the phase 3 clinical trials of new oral anticoagulants in common medical conditions.METHODS:We searched PubMed (Medline) from January 2007 to February 2013 using "Oral anticoagulants", "New oral anticoagulants", "Randomized controlled trial", "Novel anticoagulants", "Apixaban", "Rivaroxaban", "Edoxaban", "Dabigatran etexilate", "Dabigatran" and a combination of the above terms. The available evidence from the phase 3 RCTs was summarized on the basis of individual drug and the medical conditions categorized into "atrial fibrillation", "acute coronary syndrome", "orthopedic surgery", "venous thromboembolism" and "medically ill patients".RESULTS:Apixaban, rivaroxaban and dabigatran have been found to be either non-inferior or superior to enoxaparin in prophylaxis of venous thromboembolism in knee and hip replacement with similar bleeding risk, superior to warfarin for stroke prevention in atrial fibrillation with significant reduction in the risk of major bleeding, non-inferior to aspirin for reducing cardiovascular death and stroke in acute coronary syndrome with significant increase in the risk of major bleed. Rivaroxaban and dabigatran are also superior to the conventional agents in the management of symptomatic venous thromboembolism. However, compared to enoxaparin, apixaban and rivaroxaban use lead to significantly increased bleeding risk in medically ill patients. Additional studies evaluating the specific reversal agents of these new drugs for the management of life-threatening bleeding or other adverse effects are necessary.CONCLUSION:Considering their pharmacological properties, their efficacy and bleeding complications, the new oral agents offer a net favourable clinical profile in orthopedic surgery, atrial fibrillation, acute coronary syndrome and increase the risk of bleeding in critically ill patients. Further studies are necessary to determine the long term safety and to identify the specific reversal agents of these new drugs.
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Castro, Júnior José Resende de. "Custo-utilidade da rivaroxabana comparada a varfarina na prevenção do acidente vascular cerebral na fibrilação atrial não valvar no Sistema Único de Saúde." Universidade Federal de Juiz de Fora (UFJF), 2016. https://repositorio.ufjf.br/jspui/handle/ufjf/6337.
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PROQUALI (UFJF)
A fibrilação atrial é a arritmia cardíaca sustentada mais comum, acometendo principalmente idosos e aumenta o risco de acidente vascular cerebral. É atualmente um problema de saúde pública pela sua elevada morbimortalidade e custos crescentes. A varfarina é o anticoagulante que se mostrou efetivo na prevenção deste evento, contudo apresenta limitações que contribuem para a sua baixa aderência e subutilização. O surgimento de novos anticoagulantes, como a rivaroxabana, evidenciou que esta medicação pode ser tão efetiva quanto à varfarina, mas, com menores taxas de complicações hemorrágicas graves, principalmente cerebrais, não havendo necessidade de exames de monitorização, porém com um custo maior. O objetivo deste estudo foi avaliar a custo-utilidade da rivaroxabana comparada à varfarina nesta arritmia, ou seja, comparar o custo da intervenção com sua efetividade medida como ganho em anos de vida ajustada pela qualidade. Inicialmente foi realizada uma revisão sistemática de estudos econômicos sugerindo que a rivaroxabana pode ser uma opção custo-efetiva, principalmente em países desenvolvidos. Houve apenas um estudo realizado em país em desenvolvimento que mostrou resultado divergente. Posteriormente, foi desenvolvido um modelo econômico de Markov, na perspectiva do Sistema Único de Saúde, que permitiu simular a evolução de uma coorte de idosos com fibrilação atrial, em ciclos trimestrais durante toda a vida. Os resultados evidenciaram que os custos incrementais da rivaroxabana foram superiores à varfarina (R$ 7.135,48), com um discreto aumento de utilidade, resultando numa razão de custo-utilidade incremental de R$ 206.816,45/anos de vida ajustada pela qualidade. Este valor encontra-se acima do limiar proposto pela Organização Mundial da Saúde, podendo não ser uma opção custo-efetiva. Apesar das limitações, este trabalho conseguiu reunir as evidências disponíveis e mostrou a necessidade de se ajustar os protocolos clínicos e diretrizes para uma prática clínica que possa conciliar os princípios de integralidade do cuidado à sustentabilidade do sistema de saúde.
Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting mainly the elderly and increases the risk of stroke. It is currently a public health problem because of its high morbidity and mortality and increasing costs. Warfarin is an anticoagulant that was effective in preventing this type of stroke, but has limitations that contribute to its low adhesion and underutilization. The emergence of new anticoagulants such as rivaroxaban, suggest that this drug may be as effective as warfarin, but with lower rates of major bleeding complications, mainly brain. Also, with this drug, there is no need for monitoring tests, but is more expensive. The aim of this study was to evaluate the cost-utility of rivaroxabana compared to warfarin in this arrhythmia, or compare the cost of a health intervention with effectiveness measured as a gain in years of life adjusted for quality. Initially, a systematic review of economic studies was performed that suggest that rivaroxaban can be a cost-effective option compared to warfarin, especially in developed countries. There was only one study in a developing country which showed divergent results. Later, it was developed an economic model of Markov was developed with the Unified Health System perspective, which allowed simulation of the evolution of a cohort of elderly patients with Atrial fibrillation in quarterly cycles throughout life. The results showed that the incremental costs of rivaroxaban was superior to warfarin (R$ 7.135,48), with a slight increase of utility, resulting in incremental cost-utility ratio of R$ 206.816,45/years of life adjusted for quality. This value is above the threshold proposed by the Wolrd Health Organization, may not be a cost-effective option. Despite the limitations, this study brought together the available evidence and showed the need to adjust the clinical protocols and guidelines for clinical practice that can reconcile the principles of comprehensive care to the sustainability of the health system.
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Guillou, Sophie. "Évaluation de molécules à activité anti-Xa dans la cardioprotection." Thesis, Poitiers, 2018. http://www.theses.fr/2018POIT1404.
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L’infarctus du myocarde est une des premières causes de décès dans le monde. Sa prise en charge repose sur une reperfusion précoce. De façon paradoxale, la reperfusion induit des lésions délétères qui participent à la nécrose de l’organe. Parmi les stratégies de cardioprotection qui visent à limiter la formation de ces lésions, il a été décrit que l’utilisation d’anticoagulants au moment de la reperfusion avait un effet bénéfique sur la taille finale d’infarctus chez l’animal. La cardioprotection induite par ces molécules serait liée à la modulation des phénomènes thrombo-inflammatoires impliqués dans la formation des lésions de reperfusion. Nous nous sommes intéressés à deux anticoagulants inhibant le facteur X activé, le fondaparinux et le rivaroxaban, à l’aide d’un modèle d’ischémie-reperfusion (IR) myocardique chez le rat et de modèles cellulaires d’hypoxie-réoxygénation. Nos résultats montrent que ces deux molécules ont un effet cardioprotecteur à la phase aigue de la reperfusion via des mécanismes différents. La cardioprotection induite par le fondaparinux n’est pas liée à un effet anti-inflammatoire. En revanche, cet anticoagulant induit une modulation du phénotype endothélial au cours de l’IR avec l’augmentation de l’expression de deux molécules cytoprotectrices, la thrombomoduline et le récepteur endothélial de la protéine C. Concernant le rivaroxaban, son effet bénéfique serait lié à un effet cytoprotecteur au niveau des cardiomyocytes. Cette étude confirme l’intérêt des anticoagulants dans la cardioprotection et précise les cibles cellulaires impliquées, ouvrant des perspectives intéressantes concernant l’inhibition de la coagulation au cours de l’IRMyocardial infarction is a leading cause of death worldwide. Prompt reperfusion therapy is essential to limit the infarct size. Paradoxically, reperfusion itself can induce deleterious lesions contributing to necrosis, called reperfusion injuries. Among cardioprotective strategies aiming to reduce the formation of these lesions, the use of anticoagulants during reperfusion has been proven to be effective in animals. Anticoagulants-induced cardioprotection would be related to the modulation of thrombo-inflammatory phenomenoms involved in the formation of reperfusion injuries. We studied two anticoagulants inhibiting activated factor X, fondaparinux and rivaroxaban, in a myocardial ischemia-reperfusion (IR) model in rat and in cellular models of hypoxia-reoxygenation. Our results showed that these two anticoagulants were cardioprotective at early-stage reperfusion via distinct mechanisms. Fondaparinux protective effet was not associated with anti-inflammatory properties. However, this anticoagulant increased the expression of two cytoprotective endothelial molecules, thrombomodulin and endothelial protein C receptor. Rivaroxaban beneficial effect was related to cytoprotective effect on cardiomyocytes. This study confirms the of use anticoagulants as a relevant cardioprotective strategy and specifies the cellular targets involved, opening new perspectives regarding the inhibition of coagulation in the setting of IR
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Chien-LungTu and 杜建龍. "Mosapride as a hepatic CYP3A probe in rats: application to rivaroxaban pharmacokinetics." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/v86m9j.
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碩士國立成功大學
藥理學研究所
101
Introduction Rivaroxaban, an oral, direct, specific inhibitor of factor Xa, is indicated for the prophylaxis of deep vein thrombosis. About two-thirds of the administered dose of rivaroxaban undergoes metabolic degradation. CYP3A isozymes, one of the most important and abundant CYP450 subfamilies in the liver, are the major enzymes that responsible for the metabolism of rivaroxaban, thus drugs that induce or inhibit the CYP3A would change the clearance of rivaroxaban. The use of selected drugs as in vivio CYP3A probes in drug therapy is of great importance. Mosapride, a new prokinetic agent, is metabolism mainly by CYP3A enzymes. Previous studies have demonstrated that mosapride correlated well with hepatic and intestinal CYP3A contents and reflected the in vivo CYP3A activity. Therefore mosapride could be a potential in vivo CYP3A probe. Purpose The objectives of this study were to use the in vivo CYP3A probe - mospride for measuring hepatic CYP3A activity and evaluating the rivaroxaban clearance in rats to support the application of mosapride. A new HPLC method for determination of rivaroxaban in rat plasma was also developed and applied to explore its kinetics. Methods Rats received different dose of rivaroxaban intravenously in the dose-linearity experiment. To investigate the applicability of mosapride as a CYP3A probe, each rat was first introduced mosapride intravenously followed by the administration of rivaroxaban in the control groups. CYP3A activities of rats were modulated by the pretreatment with dexamethasone (induction), ketoconazole (inhibition) or through hormone regulation. The plasma concentrations of mosapride and rivaroxaban were followed for 480 min, and the kinetics parameters were estimated by two-compartmental analysis. Results A sensitive HPLC assay was developed and applied to quantify rivaroxaban in small volume of rat plasma. Rivaroxaban displayed linear kinetics in the dose range studied. Induction with dexamethasone significantly altered the clearance of rivaroxaban, whereas that of mosapride remained unchanged in male rats. In the presence of ketoconazole, clearance of rivaroxaban and mosapride decreased significantly. The plasma concentration of rivaroxaban and mosapride in male rats increased dramatically after surgical castration. The supplemental testosterone significantly decreased the systemic exposure of mosapride in female rats. Clearance of mosapride and rivaroxaban can be well predicted by using a single point (90 min) of plasma concentration of mosapride. Conclusion The pharmacokinetics of rivaroxaban in rats following intravenous administration was linear. Clearance of rivaroxaban could be well evaluated by single time point of plasma concentration of mosapride. These results provide more evidences on the applicability of mosapride as an in vivo hepatic CYP3A probe, and it provided a useful, simple and time-saved method to assess the CYP3A activity and CYP3A related drug interactions in drug development and in clinical application.
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Rosa, Tânia Margarida Teixeira. "Novos Anticoagulantes Orais: Que Desafios?" Master's thesis, 2018. http://hdl.handle.net/10316/84516.
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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de FarmáciaOs novos anticoagulantes orais vieram revolucionar a terapêutica anticoagulante oral, que até então era baseada nos antagonistas da vitamina K. As limitações apresentadas por este último grupo de fármacos foi o fator que desencadeou o desenvolvimento dos inibidores diretos dos fatores da coagulação. Contrariamente aos antagonistas da vitamina K, estas novas moléculas têm como alvo terapêutico um fator específico da cascata da coagulação. Em Portugal, estão já aprovados e comercializados quatro fármacos: o apixabano, o edoxabano, o rivaroxabano e o dabigatrano etexilato. Estes novos anticoagulantes, para além de apresentarem uma margem terapêutica mais alargada e, consequentemente um perfil de segurança mais favorável, apresentam um perfil farmacocinético e farmacodinâmico mais previsível. Por conseguinte, estes fármacos carecem de monitorização regular, contrariamente ao que sucede com os antagonistas da vitamina K. No entanto, é de ressalvar que em determinadas situações clínicas é fundamental a monitorização da atividade anticoagulante destes fármacos, como é o caso de hemorragias potencialmente fatais e de intervenções cirúrgicas de urgência. Apesar de os testes da coagulação mais comummente usados estarem prolongados com a administração destes fármacos, não traduzem os seus efeitos farmacodinâmicos. Estão a ser levados a cabo estudos com o intuito de definir testes de coagulação que permitam uma monitorização adequada. Também nas situações referidas poderá haver necessidade de administrar um agente de reversão. Atualmente, já se encontra comercializado o primeiro agente de reversão específico para o dabigatrano, o idarucizumab. O andexanet alfa aguarda aprovação e o ciparantag encontra-se em ensaios clínicos.O Relatório de Estágio Curricular diz respeito ao estágio realizado em Farmácia Comunitária, tomando a forma de uma análise SWOT.
The new oral anticoagulants came to revolutionize oral anticoagulant therapy, which until now was based on vitamin K antagonists. The limitations presented by this last group of drugs was the factor that triggered the development of direct inhibitors of coagulation factors. Unlike vitamin K antagonists, these novel molecules target a specific coagulation cascade factor.In Portugal, four drugs have already been approved and marketed: apixaban, edoxaban, rivaroxaban and dabigatran etexilate. These new anticoagulants, in addition to having a wide therapeutic window and consequently a more favorable safety profile, present a more predictable pharmacokinetic and pharmacodynamic profile. Therefore, these drugs lack regular monitoring, contrary to what happens with the vitamin K antagonists. However, it is important to note that in certain clinical situations, monitoring of the anticoagulant activity of these drugs is essential, as is the case of potentially fatal bleeding and emergency surgery. Although the most commonly used coagulation tests are prolonged with the administration of these drugs, they do not translate their pharmacodynamic effects. Studies are being carried out to establish coagulation tests that allow adequate monitoring. Also in such situations it may be necessary to administer a reversal agent. Currently, the first specific reversal agent for dabigatran, idarucizumab, has been approved. Andexanet alfa is awaiting approval and ciparantag is in clinical trials.The Internship Report refers to the community pharmacy internship, taking the form of a SWOT analysis.
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Gouveia, Filipa Fontoura Diogo Henriques de. "Liquid chromatographic methods for the determination of direct oral anticoagulant drugs in biological samples: A critical review." Master's thesis, 2019. http://hdl.handle.net/10316/88348.
Full textAbstract:
Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de FarmáciaOs Anticoagulantes orais diretos (DOACs) são os medicamentos de primeira linha usados no tratamento do tromboembolismo venoso e na prevenção de acidentes vasculares cerebrais em doentes com fibrilação auricular, sobretudo porque os DOACs não requerem a monitorização bioquímica tipicamente obrigatória para a varfarina e porque apresentam tempos de meia-vida mais curtos e início de ação mais rápido. Uma vez que estudos recentes na população real evidenciaram uma maior prevalência de efeitos secundários comparativamente aos que estavam previstos nos Ensaios clínicos iniciais, a monitorização plasmática dos DOACs está a começar a ser cada vez mais utilizada de modo a permitir uma personalização da farmacoterapia de acordo com as características individuais do doente e de modo a avaliar a adesão à terapêutica. Para satisfazer as necessidades clínicas mencionadas previamente, estão disponíveis ensaios de coagulação específicos que determinam indiretamente a concentração de DOACs, no entanto estes não são suficientemente precisos e sensíveis. Na verdade, as técnicas de cromatografia líquida, sobretudo associadas à deteção de espetrometria massa, são atualmente consideradas os métodos mais adequados para determinar as concentrações plasmáticas dos DOACs com precisão adequada. Deste modo, esta monografia tem como objetivo fornecer pela primeira vez uma revisão dos métodos analíticos desenvolvidos e validados até à presente data, para a determinação quantitativa do apixabano, dabigatrano, edoxabano, rivaroxabano bem como os seus metabolitos principais em amostras biológicas. Será dado um maior enfase aos métodos cromatográficos e às principais dificuldades sentidas durante a otimização e validação das várias etapas. Para além disso, as caraterísticas físico-químicas, a farmacocinética e a farmacodinâmica dos vários fármacos serão relacionadas com as condições cromatográficas aplicadas, assim como a sua influência nos procedimentos de pré-tratamento da amostra e nas condições de armazenamento dos DOACs, sugerindo estratégias de otimização dos métodos de quantificação dos DOACs.
Direct oral anticoagulant drugs (DOACs) are the first-line drugs used on the treatment of venous thromboembolism and prevention of stroke in patients with atrial fibrillation particularly because DOACs do not require the regular biochemical monitoring that is mandatory for warfarin, and they exhibit shorter half-lives and a faster onset of action. Since recent real-world studies evidence higher prevalence of adverse side effects than it was anticipated in clinical trials, monitoring plasma concentrations of DOACs is starting to be used for personalizing their pharmacotherapy in accordance to individual characteristics and to assess therapy adherence. To attain the aforementioned clinical unmet need, there are specific coagulation assays available that indirectly assess the plasma concentrations of DOACs, however they are not sufficiently accurate or sensitive. Indeed, liquid chromatography techniques, mainly coupled with mass spectrometry detection, are considered the gold standard methods to accurately assess DOACs plasma concentrations. Therefore, the present paper aims at providing, for the first time, a comprehensive review of the current analytical methods that were developed and validated for the quantitative determination of apixaban, dabigatran, rivaroxaban and/or edoxaban and their main metabolites in biological samples. The chromatographic methods will be particularly highlighted and an emphasis will be placed on the major difficulties faced during optimization and development steps. In addition, physicochemical characteristics, pharmacokinetics and pharmacodynamics of each drug will be herein critically related with the employed chromatographic conditions as well as their influence on pre-treatment procedures and storage conditions of DOACs, suggesting strategies that should be employed to accurately quantify DOACs in biological samples.
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Conversy, Bérénice. "Etude d'un anticoagulant oral (le rivaroxaban) sur les paramètres hémostatiques de chiens en santé." Thèse, 2014. http://hdl.handle.net/1866/12613.
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Chez le chien, les thromboses représentent une complication majeure de nombreuses conditions qui sont revues dans ce manuscrit. L’arsenal thérapeutique actuel présente certaines limites: des effets anticoagulants variables d’un patient à l’autre, des hémorragies et une administration par voie sous-cutanée pour l’héparine. Le rivaroxaban est un nouvel anticoagulant oral approuvé pour la prévention et le traitement des thromboses chez l’humain. C’est un inhibiteur direct du facteur Xa.
La présente étude a pour objectif d’évaluer les effets hémostatiques du rivaroxaban chez des chiens en santé, en utilisant les tests de coagulation suivants: temps de prothrombine (PT), temps partiel de thromboplastine (aPTT), activité anti-facteur X, génération de thrombine (GT) et thromboélastographie (TEG®).
Tout d’abord, l’effet anticoagulant du rivaroxaban a été évalué in vitro : le plasma citraté pauvre en plaquettes provenant de 20 Beagle en santé a été aliquoté et enrichi avec des solutions de rivaroxaban à des concentrations de 0 à 1000 mg/L d’anticoagulant. Une prolongation concentration-dépendante de tous les tests de coagulation a été notée. Les concentrations de 0.024 et 0.053 mg/L diminuent respectivement de 50% la vitesse de propagation de la GT et la densité optique de l’activité anti-facteur X. Ces derniers tests sont les plus sensibles et précis pour détecter l’effet anticoagulant du rivaroxaban.
Ensuite, 24 Beagle en santé ont été répartis aléatoirement en 3 groupes (n=8). Chaque groupe a reçu par voie orale un placebo, ou 20 mg de rivaroxaban une ou deux fois à 8h d’intervalle. Quinze échantillons sanguins ont été prélevés pour chaque chien sur 30 heures. Pour tous les tests de coagulation excepté la TEG®, une différence significative a été notée dans les résultats entre les groupes traités et le groupe placebo (p<0.0001). La durée de l’effet anticoagulant du rivaroxaban était de 7.9-18.7h dans le groupe traité une fois; et de 17.5-26.8h dans le groupe traité deux fois. Le pic d’action de l’effet anticoagulant était d’environ 2h. Seul le paramètre R de la TEG® était significativement affecté dans les groupes traités.
En conclusion, le rivaroxaban exerce un effet anticoagulant chez le chien à la dose de 2 mg/kg. Une administration biquotidienne semble appropriée pour un effet de 24h.In dogs, thrombosis is a major complication detected in many conditions. The limits of the current available anticoagulants in veterinary medicine are their variable effects from one patient to another, bleeding complications and subcutaneous injections for heparin administration. Rivaroxaban is a novel oral anticoagulant approved for the prevention and treatment of thrombosis in humans. It is a direct factor Xa inhibitor. The objectives of the study were to determine the haemostatic effects of rivaroxaban in healthy dogs by evaluating the following coagulation assays: prothrombin time (PT), activated partial thromboplastin time (aPTT), anti-factor X activity, thrombin generation (TG) and thromboelastography (TEG®). An in vitro study was conducted: citrated platelet poor plasma from 20 healthy Beagles was aliquoted and mixed with rivaroxaban to obtain solutions ranging from 0 to 1000 mg/L of the anticoagulant. Rivaroxaban exerted a concentration-dependent anticoagulant effect. Rivaroxaban solutions at 0.024 and 0.053 mg/L cause 50% inhibition of the propagation of TG and of the optical density of anti-factor X activity respectively. These assays were the most sensitive to detect the anticoagulant effect of rivaroxaban. Secondly, 24 healthy Beagles were randomly divided in 3 groups (n=8) and received one placebo pill orally, or 20 mg rivaroxaban once or twice at 8h interval. Fifteen citrated blood samples were collected from each dog over 30h. For each coagulation assay except for TEG®, there was a significant difference in assay results between placebo and rivaroxaban groups (p<0.0001). The duration of the rivaroxaban anticoagulant effect was 7.9-18.7h in the group receiving rivaroxaban once, and 17.5-26.8h in the group receiving rivaroxaban twice. The peak of action of rivaroxaban appeared 2h after the dose. Only R parameter of TEG® was significantly affected by rivaroxaban administration. To conclude, rivaroxaban is an efficient anticoagulant in healthy dogs at 2 mg/kg. A twice daily administration seems appropriate to exert a 24h anticoagulation.
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Mao, Yun-Chuan, and 毛雲川. "A study of antithrombotic agent, rivaroxaban, in preventing venous thromboembolism after hip and knee replacement surgery." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/q9t9x6.
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碩士高雄醫學大學
藥學研究所
102
Objectives: Total hip replacement (THR) or total knee replacement (TKR) usually accompanies Venous thromboembolism (VTE). The inci-dence of VTE could be reduced but bleeding increased if preventive an-tithrombotic medicine was used for total joint replacement. Based on the data provided by the Department of National Heath in Taiwan, this study was designed to investigate the prophylactic approach with anticoagula-tion agents, including rivaroxaban prescribed to prevent the occurrence of DVT after THR or TKR by the orthopedic surgeon in Taiwan. Methods: This was a retrospective study of analyses on the data be-tween 2007 and 2013. The analyses were divided into two parts: (1) part I: the antithrombotic drugs prescribed by orthopedic surgeons for the pre-vention of DVT or PE after total joint replacement (including THR, TKR, revision for THR or TKR, partial joint replacement etc) between 2007 and 2011, based on the data provided by the National Health Insurance Administration (NHIA); and (2) part II: the prescription of rivaroxaban based on the same provided data in 2012. Results: Comparing the data between those obtained in 2007~2011 (part I) and in 2012 (part II), there was a tendency that the cost, amount of prescriptions, and number of cases received prescriptions, were in-creased in all 3 categories of medical facilities: medical centers, regional hospitals, and area hospitals. Further analysis indicated that the costs for the use of anticoagulation drugs (including Vitamin K antagonist and heparins) were reduced later. The amount of prescriptions and the total cases with prescriptions were reduced remarkably. From 2007~2011, there were no significant changes in the number of cases with total joint replacement; about 37 % of cases were performed in the medical centers or regional hospitals, and 26 % of cases in the area hospitals. Among them, 45% were performed in the north district, 34% in the south district, 18% in the middle district, and 3% in the east district. However, the total cost and the total amount of antithrombotic prescrip-tions, and total cases with antithrombotic prescriptions were increased progressively the highest cost was that for the prescription of heparins. Comparing the patients with DVT received antithrombotic agents therapy (n = 310) to the patients received total joint replacement treated with prophylactic antithrombotic agents (n = 13600), the occurrence of DVT was significantly reduced (p=0.044). The prescription of the new antico-agulation drug, rivaroxaban, reduced the incidence of venous thrombo-embolism significantly after THR and TKR and also reduced the dates of hospitalization significantly. However, there was no significant difference in the occurrence of bleeding comparing to those treated with other an-tithrombotic agents. Conclusions: The cases of thromboembolic complications after total joint replacements have been reduced gradually since the prescriptions of prophylactic antithrombotic drugs have been increased progressively. The prescription of the oral anticoagulation drug, rivaroxaban, reduced the in-cidence of venous thromboembolism after THR and TKR, but with equal incidence of bleeding and expenditures comparing to those treated with other antithrombotic agents. However, in future, further clinical studies of rivaroxaban in preventing the incidence of venous thrombolism are re-quired in order to confirm the cost-effective principle of National Health Insurance.
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Ribeiro, Maria João de Castro Martins Oliveira. "Avaliação da adesão à terapêutica com rivaroxabano versus enoxaparina." Master's thesis, 2013. http://hdl.handle.net/10400.6/3121.
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A presente dissertação encontra-se dividida em dois capítulos. O primeiro capítulo é relativo à investigação desenvolvida no âmbito do estudo da adesão à terapêutica anticoagulante oral e subcutânea, em doentes submetidos a artroplastia eletiva da anca (AEA) e artroplastia eletiva do joelho (AEJ) no Centro Hospitalar Cova da Beira (CHCB). O rivaroxabano (Riv) é um inibidor seletivo do fator Xa, indicado para a prevenção do tromboembolismo venoso em adultos submetidos a AEA ou AEJ. Foi introduzido no guia farmacoterapêutico do CHCB em Fevereiro de 2011. É administrado oralmente, o que se torna uma potencial vantagem em termos de adesão à terapêutica, em comparação à enoxaprina (Enox). O objetivo do presente estudo, é comparar a adesão ao Riv versus Enox e determinar os potenciais fatores que podem pôr em causa o não cumprimento da terapêutica. Foi realizado um estudo observacional transversal em relação à adesão à terapêutica com Enox ou Riv em doentes submetidos a AEJ ou AEA no CHCB, de Fevereiro de 2012 a Agosto de 2013. A avaliação da adesão à medicação anticoagulante foi efetuada utilizando um questionário validado que permite classificar os doentes em aderentes ou não aderentes. O estudo incluiu um total de 84 doentes, que foram submetidos a AEJ (45 doentes) ou da anca (39 doentes); 42 dos doentes foram submetidos a terapia com Eno (18 do joelho e 24 da anca) e 42 com Riv (27 do joelho e 15 da anca). No total da amostra, 90,5% dos doentes foram considerados aderentes à medicação, não tendo sido detetada uma diferença significativa (P=0,71) entre doentes a realizarem terapia com Enox a (92,9% aderentes) ou com o Riv (88,1% aderentes). Da mesma forma, não existe diferença significativa (P=1) na adesão à medicação entre doentes submetidos a artroplastia do joelho ou anca. No entanto, houve uma ocorrência significativamente maior de efeitos adversos (P=0,002) em doentes tratados com Enox (38,0% dos doentes referiram efeitos adversos atribuídos à Enox, principalmente hematoma no local da injeção) quando comparados com os doentes tratados com Riv (9,5% dos doentes referiram efeitos adversos atribuídos ao Riv, principalmente problemas gastrointestinais e desordens da pele). A ausência de uma diferença significativa na adesão à Eno subcutânea versus Riv oral pode ser potencialmente atribuído à terapêutica de anticoagulação de curto prazo (2-5 semanas). No entanto, a ocorrência de reações adversas medicamentosas (RAM’s) foi significativamente inferior em doentes tratados com o anticoagulante oral em relação ao subcutâneo. Do ponto de vista metodológico, este é um estudo transversal de pequenas dimensões e os resultados devem ser considerados de natureza exploratória.
O segundo capítulo descreve as competências adquiridas durante o estágio de final de curso, necessárias ao exercício da profissão farmacêutica em farmácia comunitária. O estágio é um elo de ligação fundamental entre os conhecimentos adquiridos e a prática profissional e proporciona ao estudante o contacto com as tarefas e atividades que poderá vir a desempenhar no futuro. O referido estágio decorreu na Farmácia Vitória e teve como objetivo a consolidação dos conhecimentos adquiridos durante a formação académica e o contacto com a realidade da profissão farmacêutica.The following thesis is divided in two chapters. The first one is about the investigation developed in the study of adherence to oral anticoagulant therapy and intravenous, in patients submitted to elective hip arthroplasty (EHA) and elective knee arthroplasty (EKA) in Centro Hospitalar Cova da Beira (CHCB). Rivaroxaban (Riv) is a selective inhibitor of factor Xa, indicated in the prevention of venous thromboembolism on adults submitted to EHA or EKA. It was introduced in the pharmacotherapeutic guide of CHCB in February 2011. It is orally administrated, which is a potential advantage in terms of adherence to therapy, compared to Enoxaparin (Enox). The goal of this study is to compare the adherence to Riv versus Enox and to analyze the potential factors that may jeopardize the non-compliance to pharmacological therapy. It was realized a cross-sectional observational study related to the therapeutic adherence with Eno or Riv in patients submitted to EKA or EHA in CHCB, from February 2012 to August 2013. The evaluation of anticoagulant medication adherence was made by using a validated questionnaire that allows the classification of patients in adherent or non-adherent. The study included a total of 84 patients, who underwent elective knee (45 patients) or hip (39 patients) surgery; 42 patients were subjected to therapy with Eno (18 knee + 24 hip) and 42 with Riv (27 knee + 15 hip). In all, 90.5% patients were considered adherent to medication, but it was not observed a significant difference (P=0.71) between patients anticoagulated with Eno (92.9% adherent) or Riv (88.1% adherent). Similarly, there was no significant difference (P=1) in medication adherence between patients undergoing knee or hip surgery. However, there was a significantly higher occurrence of adverse drug reactions (ADRs) (P=0.002) in patients treated with Eno (38.0% patients reported ADRs attributable to this drug, mainly hematoma in the site of injection) when compared to patients treated with Riv (9.5% patients reported ADRs attributable to this drug, mainly gastrointestinal and skin disorders). Although it was not observed a significant difference in adherence to subcutaneous Eno vs oral Riv, which may be potentially attributed to the shortterm anticoagulation therapy (2 to 5 weeks), the occurrence of ADRs was significantly lower in patients treated with the oral anticoagulant. From a methodological point of view, this is a small cross-sectional study and these results must be considered exploratory in nature. The second chapter describes the skills acquired during the final training, necessary to the exercise of the pharmaceutical profession in community pharmacy. The training is a crucial link between the acquired knowledge and professional practice and provides the student contact with the tasks and activities to be performed in the future. That training took place in Farmácia Vitória and aimed to consolidate the knowledge acquired during the academic formation and to provide contact with the reality of pharmaceutical profession.
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Cheng, Yu-Han, and 鄭羽含. "Determination of Rivaroxaban in Human Urine and Serum by Surface-Assisted Laser Desorption/Ionization Mass Spectrometry with Dispersive Liquid-Liquid Microextraction." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/87903660345033914618.
Full textAbstract:
碩士國立高雄師範大學
化學系
103
A method for the determination of rivaroxaban (RIV) using dispersive liquid-liquid microextraction (DLLME) coupled to surface-assisted laser desorption/ionization mass spectrometric (SALDI-MS) detection was developed. A mixture of 50 μL of chloroform (extraction solvent) and 260 μL of tetrahydrofuran (dispersive solvent) was injected rapidly into the aqueous sample to form a cloudy solution. After the extraction, RIV was detected through SALDI-MS using colloidal Pd as SALDI matrix. Under optimum conditions, the limits of detection (LOD) at a signal-to-noise ratio of 3 was 2 nM for RIV. With a sample-to-extract volume ratio of 200, the enrichment factor for RIV was calculated to be 141. This developed method was successfully applied to the determination of RIV in human urine and serum samples. The linear ranges were 0.02-1μM for urine sample and 0.2-5.0 μM for serum sample. The LODs for urine and serum were 6 and 60 nM, respectively. Recoveries of RIV in urine and serum sample were 50.6% and 29.8%, respectively. This method provides simplicity, rapidity, low cost, and high reproducibility for the determination of RIV in human urine and serum sample.
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Ferreira, João Pedro Rosa. "Análise custo-efectividade dos novos anticoagulantes orais." Master's thesis, 2014. http://hdl.handle.net/10437/4711.
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Orientação: Ana MircoOs novos anticoagulantes orais são opções emergentes para a prevenção e tratamento das doenças tromboembólicas. São cada vez mais usados na prática clínica pela facilidade do seu uso e pelos seus benefícios clínicos mas a sua utilização mais generalizada carece de demonstração de custo efetividade. O objectivo consistiu na realização de uma revisão sistemática dos estudos de custo-efetividade dos novos anticoagulantes orais, dabigatrano, rivaroxabano e apixabano, em todas as suas indicações clínicas e descrever os resultados principais. Foi realizada uma revisão sistemática da literatura nas bases de dados Pubmed, Embase, Scopus, Cochrane e Web of Knowledge, para identificar todos os estudos de custo-efetividade dos novos anticoagulantes orais em todas as suas indicações clínicas. A pesquisa selecionou 42 estudos, 15 relacionados com a tromboprofilaxia na artroplastia total da anca ou na artroplastia total do joelho e 27 na prevenção do acidente vascular cerebral na fibrilhação auricular. Não foram identificados estudos para as indicações de tratamento e prevenção secundária do tromboembolismo venoso ou para a prevenção secundária após síndromes coronários agudos. Os resultados principais incluíram os rácios custo-efetividade incremental por anos de vida ajustados pela qualidade, comparações com o limite pré-fixado à disponibilidade a pagar e análises de sensibilidade que revelaram custo-efetividade ou dominância dos novos anticoagulantes orais. A presente revisão sistemática demonstra que os novos anticoagulantes orais são custo-efetivos para a tromboprofilaxia em cirurgia ortopédica major e para a prevenção do acidente vascular cerebral na fibrilhação auricular.
Novel oral anticoagulants are emerging options for the prevention and treatment of thromboembolic diseases. They are increasingly used in clinical practice due to simplicity of use and clinical benefits but an important step is to evaluate their cost-effectiveness. We aimed to perform a systematic review of cost-effectiveness studies of novel oral anticoagulants, dabigatran, rivaroxaban and apixaban, in all their clinical indications and describe key findings. A systematic review of the literature was conducted searching Pubmed, Embase, Scopus, Cochrane and Web of Knowledge databases to identify all cost-effectiveness studies of novel oral anticoagulants in all their clinical indications. The research selected 42 studies, 15 related to thromboprophylaxis in total hip arthroplasty or total knee arthroplasty and 27 to stroke prevention in non-valvular atrial fibrillation. No studies were identified for the indications of treatment and secondary prevention of venous thromboembolism or for the secondary prevention after acute coronary syndromes. Key findings included incremental cost-effectiveness ratios per quality-adjusted life-years, comparisons with appropriate willingness-to-pay thresholds and sensitivity analysis that revealed cost-effectiveness or dominance for the novel oral anticoagulants. This present systematic review demonstrates that novel oral anticoagulants are cost-effective for the thromboprophylaxis in major orthopedic surgery and for stroke prevention in atrial fibrillation.
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Costa, Joana Catarina Quadros Bebiano da Providência e. "Terapêutica antitrombótica na fibrilhação auricular não valvular: novos anticoagulantes orais." Master's thesis, 2014. http://hdl.handle.net/10316/37297.
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Petrák, Ondřej. "Elektroforetické stanovení rivaroxabanu." Master's thesis, 2021. http://www.nusl.cz/ntk/nusl-437912.
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Capillary electrophoresis is a method used in pharmaceutical analysis because of its low cost, speed and environmental friendliness. This diploma thesis deals with development of electrophoretic method for rivaroxaban determination. After several optimizations, a method suitable for rivaroxaban determination inside its dosage forms was developed. Optimizations involved change of background electrolyte's composition from aqueous solution of low molecular weight organic acids to non-aqueous solution of acetic acid and cetyltrimethylammoniumbromide in acetonitrile in multiple steps. Final conditions of analysis included background electrolyte composed of 1M acetic acid and 40mM cetyltrimethylammoniumbromide in acetonitrile, sample injection carried out hydrodynamically by pressure of 5,0 kPa for period of 3 s and subsequent insertion of separation voltage of 30,0 kV for entire duration of analysis. Capillary content was mobilized by pressure of 0,50 kPa for entire duration of analysis. With aforementioned optimizations a selective method for determination of dosage forms of rivaroxaban was obtained. This method provides limit of detection 0,0056 mg/ml and limit of quantification 0,019 mg/ml and is linear in 0,01 - 0,40 mg/ml range with a recovery of 93,2 %. Keywords capillary electrophoresis,...
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Fernandes, Marta Sofia Gomes. "Análise do Consumo de Novos Anticoagulantes Orais no Centro Hospitalar Universitário Cova da Beira." Master's thesis, 2018. http://hdl.handle.net/10400.6/8748.
Full textAbstract:
Sendo o farmacêutico um profissional de saúde muito próximo da população e que integra equipas multidisciplinares, o Mestrado Integrado em Ciências Farmacêuticas está organizado de forma a permitir o contacto dos futuros farmacêuticos com as principais vertentes da profissão. Assim, o presente trabalho divide-se em três capítulos: Capítulo I – projeto de investigação desenvolvido; Capítulo II e III – relatórios dos estágios em farmácia hospitalar e comunitária, respetivamente.
No Capítulo I foi feita uma abordagem sobre os novos anticoagulantes orais, de forma a expor as vantagens dos inibidores da trombina (dabigatrano) e do fator Xa (rivaroxabano, apixabano e edoxabano). Estes são administrados por via oral, em doses fixas, sem haver necessidade de monitorização regular e apresentam poucas interações medicamentosas. Por estes motivos começaram a ser considerados uma alternativa viável à varfarina – anticoagulante mais prescrito.
Os ensaios clínicos publicados compararam cada um dos fármacos às terapêuticas convencionais. Os resultados revelam uma eficácia equivalente na prevenção de acidentes vasculares cerebrais e tromboembolismos e um perfil de segurança bastante favorável, notando-se que, em alguns casos, os novos anticoagulantes causam menos hemorragias.
Foi objetivo deste trabalho, também, o estudo das prescrições dos novos fármacos em doentes internados no Centro Hospitalar Universitário Cova da Beira, sendo possível afirmar que a sua utilização é crescente e ultrapassou o consumo de varfarina, no período de estudo.
O Capítulo II relata as diferentes funções do farmacêutico em meio hospitalar, desempenhadas no estágio no Centro Hospitalar de Trás-os-Montes e Alto Douro, desde dia 22 de janeiro a 16 de março. Como futura profissional, o contacto com o ambiente hospitalar foi importante para aprofundar conhecimentos acerca de terapias farmacológicas específicas e exclusivas de hospitais.
No Capítulo III são descritas as ações desenvolvidas enquanto estagiária na Farmácia Barreira, durante o período de 19 de março a 1 de junho. Estas permitiram-me percecionar a relevância da interação farmacêutico-utente e do acompanhamento das terapêuticas, tendo sempre presente o espírito de missão e humanidade que a profissão acarreta.Being the pharmacist a health professional in close contact with the population and integrated in multidisciplinary teams, the Integrated Master’s Degree in Pharmaceutical Sciences is organized to allow the contact of future professionals with the main dimensions of the profession. Therefore, this work is divided in three chapters: Chapter I – investigation project carried out; Chapters II and III – internship reports in hospital and community pharmacy, respectively. In Chapter I, an approach to novel oral anticoagulants has been made, in order to show the advantages of the thrombin inhibitors (dabigatran) and factor Xa (rivaroxaban, apixaban and edoxaban). These are administered orally, in fixed doses, without the need for regular monitoring and they present few drug interactions. For these reasons, they started to be considered a viable alternative to warfarin – the most prescribed anticoagulant. The published clinical trials compare each of the drugs to conventional therapeutics. The results reveal an equivalent efficiency in the prevention of stroke and thromboembolisms and a quite favourable security profile showing that, in some cases, the novel anticoagulants cause fewer bleedings. The study of the prescription of these new medicines in the Centro Hospitalar Universitário da Cova da Beira was also a goal of this work and it is possible to say that its use is increasing and has exceeded the consumption of warfarin, in the period studied. Chapter II describes the different duties of the pharmacist in hospital setting, carried out during the internship in the Centro Hospitalar de Trás-os-Montes e Alto Douro, from January 22nd to March 25th. As a future professional, the contact with hospital environment was important to deepen knowledge about specific pharmaceutical therapies exclusive to hospitals. In Chapter III are described the activities undertaken as a trainee at Farmácia Barreira during the period between March 19th and June 1st. These activities allowed me to realize the relevance of the interaction pharmacist-user and therapy follow up, always bearing in mind the sense of commitment and humanity that the profession entails.
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Plácido, Ana Isabel Pereira. "Anticoagulantes orais: terapêutica clássica versus novos anticoagulantes." Master's thesis, 2016. http://hdl.handle.net/10284/5835.
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Os novos anticoagulantes orais representam uma inovação terapêutica anticoagulante, tendo obtido recentemente aprovação para várias indicações clínicas. A varfarina foi um dos primeiros anticoagulantes orais a ser desenvolvido, no entanto acarreta inúmeras inconveniências tais como, interações medicamentosas e alimentares, margem terapêutica reduzida, monitorização frequente e variações de resposta entre indivíduos, que comprometem a eficácia do tratamento. Consequentemente, foi necessário investigar outras alternativas surgindo assim os novos anticoagulantes orais, dabigatrano, apixabano e rivaroxabano que detêm menos limitações e a mesma eficácia que os AVK. Estes anticoagulantes são eficientes na profilaxia e tratamento tromboembolismo venoso e na prevenção de AVC em pacientes com fibrilação auricular, contudo também apresentam as suas desvantagens como custo elevado e ausência de antídoto específico.
Nesta revisão bibliográfica serão abordadas as propriedades farmacológicas, mecanismos de ação, vantagens e desvantagens, custos terapêuticos dos anticoagulantes clássicos e novos anticoagulantes, sendo feita uma comparação entre estes de modo a perceber qual será a melhor opção terapêutica.The new oral anticoagulants represent an innovation in anticoagulant therapy, which has been recently approved for various clinical indications. Warfarin was the first oral anticoagulants to be developed, however entails numerous drawbacks such as drug and food interactions, narrow therapeutic index, frequent monitoring and interindividual response variations that compromise the effectiveness of treatment. Consequently, it was necessary to investigate other alternatives that lead to the discover of new oral anticoagulants, dabigatran, rivaroxaban and apixaban who hold fewer limitations and the same efficacy as the AVK. These anticoagulants are effective in the treatment and prevention of venous thromboembolism and for the prevention of stroke in patients with atrial fibrillation, but also have their disadvantages such as high cost and lack of specific antidote. In this literature review the pharmacological properties will be addressed as well as mechanisms of action, advantages and disadvantages, therapeutic costs of classic and new anticoagulants and a comparison between them in order to understand what the best treatment option is.
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Cordeiro, Ana Catarina Soares Rodrigues. "Recorrência de tromboembolismo pulmonar varfarina versus rivaroxabano : estudo retrospetivo." Master's thesis, 2017. http://hdl.handle.net/10451/30747.
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Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2017Introdução: Este trabalho teve como objetivo comparar as recorrências de TEP nos doentes com o diagnóstico de TEP medicados inicialmente com varfarina ou rivaroxabano. Assim, pretendeu-se testar a afirmação que, de acordo com os estudos realizados, os anticoagulantes orais diretos são não-inferiores à varfarina. Materiais e métodos: Foram analisados 108 doentes da base de dados da consulta de Tromboembolismo Venoso/ Medicina Interna do HGO. As recorrências de TEP foram analisadas e os doentes caracterizados com base em características demográficas, antecedentes, fatores de risco e características da doença. A análise estatística foi efetuada com recurso ao software IBM®SPSS® versão 22. Resultados: Apenas foram registadas duas recorrências até aos três meses, o que não permitiu comparar a eficácia dos dois fármacos. Até aos seis meses 12% dos doentes recorreram: do grupo medicado inicialmente com varfarina verificaram-se 8,2% de recorrências, contra 15,3% do grupo inicialmente medicado com rivaroxabano. A varfarina obteve melhores resultados em todas as análises subsequentes, à exceção de: género masculino, doentes sem trombofilia, doentes com dislipidémia e doentes sem TVP anterior. De realçar o género feminino onde não existiram recorrências no grupo da varfarina, contra 21,1% no grupo do rivaroxabano. Os doentes que realizaram switch de varfarina para rivaroxabano apresentaram maus resultados em variados grupos. Discussão: O grupo de doentes que realiza switch é o que apresenta mais recorrências, sendo recomendável um estudo dirigido a este grupo. Entre os dois fármacos, a varfarina revelou-se, de um modo geral, superior ao rivaroxabano, contrariando a bibliografia que aponta este fármaco como sendo não inferior à terapêutica clássica.
Introduction: The aim of this work was to compare pulmonary thromboembolism recurrences in patients to whom was prescribed warfarin and rivaroxaban. According to different studies, the direct oral anticoagulants are non-inferior to warfarin. Materials and methods: 108 patients from Garcia de Orta Hospital database were analyzed. The recurrences of pulmonary thromboembolism were noted and the patients characterized according to personal, demographic and disease related data. IBM®SPSS® 22 software was used to do the statistical analysis. Results: There were only two recurrences until three months after the index event which unable the comparison between therapies. Until six months after the index event, 12% of the patients fell back on. From those using warfarin, 8,2% had a new event against 15,3%, using rivaroxaban. Warfarin achieved better results in all groups except in males, patients without thrombophilia, patients with dyslipidemia and patients without prior deep venous thrombosis. In the female group, there weren’t any recurrences using warfarin despite 21,1% with rivaroxaban. Patients who switched from warfarin to rivaroxaban presented worse outcomes in several groups. Discussion: Patients who switched therapies are the group with higher recurrences and, for that reason, a more directed study is recommended. Between both drugs, warfarin revealed itself superior to rivaroxaban, contradicting the bibliography that stands rivaroxaban to be non-inferior to the classic therapy.
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Calvão, Catarina Duarte. "Cuidados peri-operatórios em cirurgia oral de pacientes submetidos a terapêutica anticoagulante : revisão bibliográfica." Master's thesis, 2020. http://hdl.handle.net/10400.26/33981.
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Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas MonizO aumento da prevalência de pacientes hipocoagulados na consulta de Medicina Dentária e a necessidade de intervenções cirúrgicas pressionam a necessidade de se estabelecer normas de orientação clínicas peri-operatórias, para uma abordagem terapêutica segura e correta dos mesmos. Os Novos Anticoagulantes Orais (Dabigatrano, Rivaroxabano e Edoxabano) surgiram como alternativa à Varfarina, apresentando eficácia semelhante e segurança superior, com menos interações alimentares, medicamentosas e menor risco de hemorragia. Os Médicos Dentistas devem conhecer os mecanismos de coagulação sanguínea para melhor entenderem o mecanismo de ação dos anticoagulantes orais. A avaliação do risco hemorrágico é fulcral no planeamento da cirurgia oral de um paciente submetido a terapêutica anticoagulante. Permanece sobre os profissionais de saúde uma controvérsia acerca da necessidade de suspensão ou manutenção da terapêutica, associada ao risco de tromboembolismo e hemorragia, respetivamente. A opção de manter ou suspender a terapia anticoagulante depende do risco hemorrágico individual e do procedimento cirúrgico a realizar. Esta decisão deve ser discutida com o Médico Assistente, sempre que necessário. A presente revisão bibliográfica visa esclarecer quais as medidas pré, trans e pósoperatórias a tomar, de forma a diminuir as complicações cirúrgicas associadas a pacientes submetidos a terapêutica anticoagulante oral.
The increase in the prevalence of hipocoagulated patients at the dental appointment and the need of surgical intervention, drive the need of setting clinical peri-operative guidelines, for a safe and correct therapeutic approach. The new oral anticoagulants (Dabigatran, Rivaroxaban and Edoxaban) appeared as an alternative to Warfarin, presenting similar effectiveness and increased security, with less food and drug interactions and lower bleeding scores. Dentists should recognize the mechanisms involved in coagulation, in order to better understand the mechanism of action of oral anticoagulants. The evaluation of the bleeding risk is crucial in the planning of the oral surgery of a patient submitted to anticoagulation therapy. There remains a controversy associated with health professionals, regarding the need of suspending or maintaining the therapeutic approach related to the risk of developing thromboembolisms and hemorrhage, respectively. The option of whether to keep or suspend anticoagulant therapy depends on the individual bleeding risk and the surgical procedure to be made. This decision should be discussed with the assisting doctor, as much as needed. The present literature review aims to clarify which measures should be taken before, during and after surgery, in order to decrease surgical complications associated with patients submitted to oral anticoagulation therapy.
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Pereira, Ana Sofia França Fernandes. "Caracterização da Prescrição e do Consumo de Anticoagulantes Orais." Master's thesis, 2017. http://hdl.handle.net/10451/27965.
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Tese de mestrado, Farmacoterapia e Farmacoepidemiologia, Universidade de Lisboa, Faculdade de Farmácia, 2017As Doenças Cardiovasculares (DCV) constituem uma das principais causas de morte em Portugal e, apesar de existir atualmente uma forte evidência de que a anticoagulação oral reduz o risco tromboembólico, mais de metade dos doentes com Fibrilhação Auricular (FA), elegíveis para a toma de anticoagulação oral, não estão a ser medicados. A varfarina apesar de estar associada a um elevado risco de hemorragias, de apresentar muitas interações medicamentosas e de requerer uma avaliação periódica da Razão Normalizada Internacional (INR), continua a ser o Anticoagulante Oral (ACO) melhor conhecido, com início e duração de ação previsíveis, com antídoto específico em caso de hemorragia e o mais prescrito e consumido no nosso país. No entanto tem-se verificado um consumo crescente dos novos ACO, principalmente desde o ano de 2015, em que foi alargada a comparticipação do rivaroxabano, dabigatrano e apixabano para novas indicações terapêuticas. Estes apresentam como vantagens maior comodidade posológica, uma larga margem terapêutica e previsibilidade do efeito anticoagulante. Contudo, ainda não dispõem nem de testes laboratoriais padronizados para avaliar a sua atividade, nem de antídotos específicos em caso de hemorragia. Com o objetivo de caracterizar a prescrição e o consumo de ACO realizaram-se dois estudos. No primeiro caracterizou-se a evolução da prescrição e do consumo de ACO, no período de 2012 a 2015, em Portugal Continental, através da análise de uma base de dados relativa ao consumo de ACO em ambulatório. No segundo estudo caracterizou-se o consumo de ACO numa amostra não aleatória de utentes de Farmácias Comunitárias do Distrito de Setúbal, mediante a realização de inquéritos aos utentes que adquiriam ACO com receita médica. No primeiro estudo verificou-se que o consumo de ACO cresceu de forma significativa em Portugal Continental, tendo sido a varfarina o ACO mais consumido e o rivaroxabano o que registou uma maior evolução. No segundo estudo verificou-se que o ACO mais consumido foi a varfarina, mesmo nos doentes com idade mais avançada. Constatou-se que metade dos utentes que mudaram de ACO tinham estado a tomar a varfarina, sugerindo uma transferência de prescrição para os novos ACO, sendo que destes o dabigatrano foi o mais prescrito. O aumento do consumo da terapêutica anticoagulante oral permite inferir que se está a assistir a uma melhor prevenção, controlo e tratamento das doenças tromboembólicas em Portugal.
Cardiovascular Diseases (CVD) are one of the main causes of death in Portugal and although there is strong evidence that oral anticoagulation reduces thromboembolic risk, more than half of patients with atrial fibrillation (AF), eligible for oral anticoagulation, are not being medicated. Despite warfarin being associated with a high risk of hemorrhage, having many interactions and requiring a periodic evaluation of the International Normalized Ratio (INR), it is still the best known Oral Anticoagulant (OAC), with predictable onset and duration of action, with specific antidote in case of bleeding, and the most prescribed and consumed in our country. However, there has been an increase in the use of new OAC, especially since 2015, when rivaroxaban, dabigatran and apixaban were approved for new therapeutic indications. These have some advantages, such as, fixed and convenient dosing regiments, wide therapeutic window and predictable anticoagulant response. However, they do not have a standardized laboratory test to evaluate their activity and lack a specific antidote. Two studies were carried out to characterize the use and prescription of OAC. The first one, between 2012 and 2015, in Continental Portugal, used the analysis of a database relating to the use of OAC by outpatients, to characterize the use and prescription of OAC. The second study based its findings on a non-random sample of users of Community Pharmacies, in the District of Setubal. In order to characterize the consumption of OAC, users who purchased these drugs with medical prescription answered a survey. The first study indicated a significant increase in the use of OAC in Portugal. Warfarin was the most consumed and rivaroxaban was the new OAC with the best evolution. The second study indicated that warfarin was the most consumed, even by older age patients. Half of the patients that changed OAC had been taking warfarin, suggesting a transfer of prescription for the new OAC, of which dabigatran is the most prescribed. The increase of OAC consumption allows us to infer that better prevention, control and treatment of thromboembolic diseases are being observed in Portugal.