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Anticoagulantes/efectos adversos , Bencimidazoles/efectos adversos , Morfolinas/efectos adversos , Pirazoles/efectos adversos , Piridonas/efectos adversos , Procedimientos Quirúrgicos Operativos , Tiofenos/efectos adversos , Heridas y Lesiones/cirugía , beta-Alanina/análogos & derivados , Anticoagulantes/antagonistas & inhibidores , Antídotos/uso terapéutico , Bencimidazoles/antagonistas & inhibidores , Dabigatrán , Urgencias Médicas , Humanos , Morfolinas/antagonistas & inhibidores , Pirazoles/antagonistas & inhibidores , Piridonas/antagonistas & inhibidores , Rivaroxabán , Procedimientos Quirúrgicos Operativos/métodos , Tiofenos/antagonistas & inhibidores , beta-Alanina/efectos adversos , beta-Alanina/antagonistas & inhibidoresAsunto(s)
Anticoagulantes/efectos adversos , Hemorragia/inducido químicamente , Administración Oral , Anticoagulantes/administración & dosificación , Anticoagulantes/antagonistas & inhibidores , Anticoagulantes/farmacocinética , Antídotos/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/antagonistas & inhibidores , Bencimidazoles/farmacocinética , Vías Clínicas , Dabigatrán , Monitoreo de Drogas , Procedimientos Quirúrgicos Electivos , Hemorragia/terapia , Humanos , Morfolinas/administración & dosificación , Morfolinas/efectos adversos , Morfolinas/antagonistas & inhibidores , Morfolinas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/antagonistas & inhibidores , Pirazoles/farmacocinética , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/antagonistas & inhibidores , Piridinas/farmacocinética , Piridonas/administración & dosificación , Piridonas/efectos adversos , Piridonas/antagonistas & inhibidores , Piridonas/farmacocinética , Factores de Riesgo , Rivaroxabán , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Tiofenos/antagonistas & inhibidores , Tiofenos/farmacocinéticaRESUMEN
INTRODUCTION: Anticoagulation therapies carry a risk of bleeding; reversal agents may be beneficial in cases of severe bleeding even for anticoagulants with a relatively short half-life, such as the oral factor Xa inhibitor rivaroxaban. MATERIALS AND METHODS: We investigated the in vitro reversal effect of prothrombin complex concentrate (PCC; 0.2-1.0U/mL), activated PCC (aPCC; 0.2-1.0U/mL) and recombinant activated factor VII (rFVIIa; 5-50µg/mL) on rivaroxaban-induced (200-1000ng/mL) changes in prothrombin time (PT) and thrombin generation (TG) in plasma, and in thromboelastometry (clotting time [CT]) in whole blood from healthy subjects. RESULTS: All three agents were partially effective in reversing rivaroxaban-induced anticoagulation but showed different profiles. rFVIIa and aPCC were more effective than PCC in reversing prolongations of PT, CT and TG lag time; rFVIIa was more effective than aPCC. However, the reversal effect reached a plateau with a maximal effect of approximately 50%. Inhibition of maximum thrombin concentration was slightly reversed by these agents; aPCC was the most effective. In contrast, inhibition of endogenous thrombin potential (ETP) was strongly reversed by aPCC, with significant increases over baseline at low rivaroxaban concentrations. Compared with aPCC, PCC showed a similar but less effective reversal profile. rFVIIa reversed ETP inhibition by approximately 50%. CONCLUSIONS: The extent of reversal by aPCC, PCC and rFVIIa was dependent on the parameter measured in rivaroxaban-anticoagulated plasma or blood. ETP measurements may have predictive power for assessing the reversal potential of PCC or aPCC and may be used to indicate an increased prothrombotic risk.
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Anticoagulantes/administración & dosificación , Factores de Coagulación Sanguínea/farmacología , Pruebas de Coagulación Sanguínea/métodos , Coagulación Sanguínea/efectos de los fármacos , Factor VIIa/farmacología , Morfolinas/farmacología , Tiofenos/farmacología , Trombina/farmacología , Interacciones Farmacológicas , Factor VIIa/metabolismo , Humanos , Morfolinas/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Rivaroxabán , Tiofenos/antagonistas & inhibidores , TromboelastografíaAsunto(s)
Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea/uso terapéutico , Hematoma Subdural/tratamiento farmacológico , Hematoma Subdural/cirugía , Morfolinas/efectos adversos , Tiofenos/efectos adversos , Accidentes por Caídas , Anciano , Anticoagulantes/antagonistas & inhibidores , Coagulación Sanguínea/efectos de los fármacos , Coma/etiología , Coma/terapia , Femenino , Escala de Coma de Glasgow , Hematoma Subdural/inducido químicamente , Humanos , Morfolinas/antagonistas & inhibidores , Rivaroxabán , Tiofenos/antagonistas & inhibidores , Ultrasonografía Doppler TranscranealRESUMEN
PURPOSE OF REVIEW: Warfarin has been the sole oral anticoagulant used in the management of thromboembolic disorders for over 60 years. Target-specific oral anticoagulants (TSOAs) have recently emerged as alternatives to warfarin, because they do not require laboratory monitoring. Nevertheless, with the rising use of TSOAs, there is growing concern among clinicians regarding management of bleeding in patients taking them. Unlike warfarin, there is no antidote or reversal agent for TSOAs. This review summarizes recent developments and attempts to provide a systematic approach to patients on TSOAs presenting with bleeding complications. RECENT FINDINGS: Currently, data involving clinical management of TSOAs are limited and primarily based on ex-vivo or animal models using hemostatic agents with uncertain implications in bleeding patients. There is a pressing need for randomized clinical trials evaluating the safety and efficacy of hemostatic agents. SUMMARY: Without evidence-based guidelines for TSOA management, appropriate patient care requires an understanding of TSOA pharmacology, their effect on coagulation tests and, hence, a correct interpretation of test results, as well as a systematic approach to bleeding complications.
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Antitrombinas/farmacología , Inhibidores del Factor Xa , Trastornos Hemorrágicos/tratamiento farmacológico , Anticoagulantes/antagonistas & inhibidores , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapéutico , Antitrombinas/antagonistas & inhibidores , Bencimidazoles/antagonistas & inhibidores , Bencimidazoles/farmacología , Ensayos Clínicos como Asunto , Dabigatrán , Humanos , Morfolinas/antagonistas & inhibidores , Morfolinas/farmacología , Pirazoles/antagonistas & inhibidores , Pirazoles/farmacología , Piridonas/antagonistas & inhibidores , Piridonas/farmacología , Rivaroxabán , Tiofenos/antagonistas & inhibidores , Tiofenos/farmacología , beta-Alanina/análogos & derivados , beta-Alanina/antagonistas & inhibidores , beta-Alanina/farmacologíaRESUMEN
Warfarin has been the mainstay of oral anticoagulation for more than half a century. Within the last several years, 2 new classes of oral anticoagulants have been introduced as potential alternatives to warfarin for certain indications. The oral direct thrombin inhibitor, dabigatran, and 2 factor Xa inhibitors, rivaroxaban and apixaban, are the newest agents approved for use in the United States. These agents have been studied in various areas including stroke prophylaxis in atrial fibrillation, prevention and treatment of venous thromboembolism, and for reduction of ischemic events following acute coronary syndromes. While these agents do not require routine monitoring of international normalized ratio, these agents may be more challenging to reverse than traditional warfarin therapy. The following review will focus on describing the areas where the new oral anticoagulant agents have been studied, the basic pharmacologic characteristics of each agent, and how to appropriately manage the reversal of these agents when indicated.
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Anticoagulantes/farmacología , Bencimidazoles/farmacología , Cuidados Críticos , Morfolinas/farmacología , Pirazoles/farmacología , Piridonas/farmacología , Tiofenos/farmacología , beta-Alanina/análogos & derivados , Administración Oral , Anticoagulantes/antagonistas & inhibidores , Bencimidazoles/antagonistas & inhibidores , Dabigatrán , Enoxaparina/antagonistas & inhibidores , Enoxaparina/farmacología , Humanos , Morfolinas/antagonistas & inhibidores , Pirazoles/antagonistas & inhibidores , Piridonas/antagonistas & inhibidores , Rivaroxabán , Tiofenos/antagonistas & inhibidores , Warfarina/antagonistas & inhibidores , Warfarina/farmacología , beta-Alanina/antagonistas & inhibidores , beta-Alanina/farmacologíaRESUMEN
PURPOSE: To describe the pharmacologic agents and strategies used for urgent reversal of warfarin and the target-specific oral anticoagulants dabigatran, rivaroxaban, and apixaban. SUMMARY: To reverse the anticoagulant effects of warfarin in patients who are bleeding or need surgery, exogenous vitamin K (phytonadione) may be used in combination with another, shorter-acting intervention, such as fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa, or activated PCC (aPCC). Three-factor PCC contains factors II, IX, and X in an inactivated form, and four-factor PCC also includes factor VII in an inactivated form. No four-factor PCC products are available in the United States, but aPCC, which contains the same four factors with factor VII provided in an activated form, is available. The intervention depends on the International Normalized Ratio, presence of bleeding, and need for and timing of surgery. Research suggests that clotting factor concentrates are more effective than FFP alone for warfarin reversal. These products also may be useful for reversing the effects of target-specific oral anticoagulants, but limited efficacy and safety data are available to support their use. The risks and benefits associated with these products need to be weighed before their use for reversal of dabigatran, rivaroxaban, or apixaban. Additional clinical data are needed to clearly define the role of concentrated clotting factor products in reversal and to determine the optimal clotting factor concentrate product and dose for urgent reversal of oral anticoagulation. CONCLUSION: Phytonadione and clotting factor concentrates appear to have a role for reversal of warfarin, and limited evidence suggests that clotting factor concentrates could have a role in reversal of target-specific oral anticoagulants in an emergency situation.
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Anticoagulantes/efectos adversos , Anticoagulantes/antagonistas & inhibidores , Antifibrinolíticos/administración & dosificación , Factores de Coagulación Sanguínea/administración & dosificación , Pérdida de Sangre Quirúrgica/prevención & control , Hemorragia/prevención & control , Plasma , Vitamina K 1/administración & dosificación , Administración Oral , Anticoagulantes/administración & dosificación , Antitrombinas/efectos adversos , Antitrombinas/antagonistas & inhibidores , Bencimidazoles/efectos adversos , Bencimidazoles/antagonistas & inhibidores , Dabigatrán , Quimioterapia Combinada , Urgencias Médicas , Hemorragia/inducido químicamente , Humanos , Relación Normalizada Internacional , Morfolinas/efectos adversos , Morfolinas/antagonistas & inhibidores , Pirazoles/efectos adversos , Pirazoles/antagonistas & inhibidores , Piridonas/efectos adversos , Piridonas/antagonistas & inhibidores , Rivaroxabán , Procedimientos Quirúrgicos Operativos/efectos adversos , Tiofenos/efectos adversos , Tiofenos/antagonistas & inhibidores , Tromboembolia/etiología , Tromboembolia/prevención & control , Resultado del Tratamiento , Warfarina/efectos adversos , Warfarina/antagonistas & inhibidores , beta-Alanina/efectos adversos , beta-Alanina/análogos & derivados , beta-Alanina/antagonistas & inhibidoresRESUMEN
BACKGROUND: Rivaroxaban has been approved as an antithrombotic agent for prevention of venous thromboembolism with specific indications. At present no antidote is appointed and no guidelines have been formulated for the measurement of Rivaroxaban reversal. OBJECTIVES: In the present study, we have evaluated the influence of prothrombin complex concentrate (PCC) on the anticoagulant effects of Rivaroxaban as measured by prothrombin time (PT) and thrombin generation tests (TGTs). METHODS: Plasma and whole blood samples from healthy volunteers were spiked with Rivaroxaban (up to 800 µg L(-1) ) and PCC was added to these samples in concentration ranges as used clinically to reverse the effects of vitamin K antagonists. PT, endogenous thrombin potential (ETP) and calibrated automated thrombography (CAT) assays were performed with varying tissue factor (TF) concentrations. RESULTS: Addition of PCC to Rivaroxaban-spiked samples did not result in normalization of PT and TGT lag time/T-Lag in ETP and CAT, respectively. In contrast, normalization of ETP and CAT area under the curve did occur. However, the response to PCC addition was strongly TF concentration dependent and in whole blood less PCC was required for Rivaroxaban reversal as compared with plasma. CONCLUSIONS: Prothrombin complex concentrate does not neutralize the lengthening effect on PT and TGT lag time/T-Lag of Rivaroxaban anticoagulated blood in vitro; however, total thrombin potential could be normalized. Response of the different TGTs in this respect is assay condition dependent. Therefore, prospective studies are needed to clarify which assay condition and parameter describes in vivo hemostasis best in patients on Rivaroxaban who are treated with PCC.
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Anticoagulantes/antagonistas & inhibidores , Factores de Coagulación Sanguínea/uso terapéutico , Morfolinas/antagonistas & inhibidores , Morfolinas/química , Tiofenos/antagonistas & inhibidores , Tiofenos/química , Trombina/química , Anticoagulantes/química , Área Bajo la Curva , Coagulación Sanguínea/efectos de los fármacos , Pruebas de Coagulación Sanguínea , Calibración , Fibrinolíticos/química , Humanos , Plasma/efectos de los fármacos , Protrombina/química , Tiempo de Protrombina , Rivaroxabán , Tromboplastina/química , Factores de Tiempo , Vitamina K/antagonistas & inhibidoresRESUMEN
Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.
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Anticoagulantes/antagonistas & inhibidores , Antídotos/farmacología , Inhibidores del Factor Xa , Proteínas Recombinantes/farmacología , Animales , Benzamidas/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Enoxaparina/antagonistas & inhibidores , Factor Xa/farmacología , Fondaparinux , Hemorragia/tratamiento farmacológico , Hemostasis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Morfolinas/antagonistas & inhibidores , Polisacáridos/antagonistas & inhibidores , Pirazoles/antagonistas & inhibidores , Piridinas/antagonistas & inhibidores , Piridonas/antagonistas & inhibidores , Conejos , Ratas , Ratas Sprague-Dawley , Rivaroxabán , Tiofenos/antagonistas & inhibidoresRESUMEN
Biomarkers are becoming increasingly important when considering the efficacy, toxicology, mechanism of action, and risk of adverse events in certain drugs. As availability of bio-genomic information increases, more treatments can be tailored to specific individuals, with a net effect of improved health outcomes. Many dermatology drugs have pharmacogenomic information on their labels. Knowing the risks and benefits associated with genomic biomarkers can aid physicians to make more knowledgeable decisions when identifying treatments for their patients.
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Biomarcadores/metabolismo , Fármacos Dermatológicos/metabolismo , Androstenos/efectos adversos , Androstenos/metabolismo , Hidrocarburo de Aril Hidroxilasas/efectos de los fármacos , Cloroquina/efectos adversos , Cloroquina/metabolismo , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6/deficiencia , Citocromo P-450 CYP2D6/metabolismo , Dapsona/efectos adversos , Dapsona/metabolismo , Fármacos Dermatológicos/efectos adversos , Deficiencia de Dihidropirimidina Deshidrogenasa/metabolismo , Etinilestradiol/efectos adversos , Etinilestradiol/metabolismo , Fluorouracilo/efectos adversos , Fluorouracilo/metabolismo , Deficiencia de Glucosafosfato Deshidrogenasa/metabolismo , Humanos , Naftalenos/efectos adversos , Naftalenos/metabolismo , Primaquina/efectos adversos , Primaquina/metabolismo , Quinuclidinas/efectos adversos , Quinuclidinas/antagonistas & inhibidores , Quinuclidinas/metabolismo , Terbinafina , Tiofenos/efectos adversos , Tiofenos/antagonistas & inhibidores , Tiofenos/metabolismoAsunto(s)
Anticoagulantes/antagonistas & inhibidores , Antídotos/farmacología , Bencimidazoles/antagonistas & inhibidores , Factores de Coagulación Sanguínea/farmacología , Coagulación Sanguínea/efectos de los fármacos , Morfolinas/antagonistas & inhibidores , Tiofenos/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Humanos , MasculinoAsunto(s)
Anticoagulantes/antagonistas & inhibidores , Antídotos/farmacología , Bencimidazoles/antagonistas & inhibidores , Factores de Coagulación Sanguínea/farmacología , Coagulación Sanguínea/efectos de los fármacos , Morfolinas/antagonistas & inhibidores , Tiofenos/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Humanos , MasculinoRESUMEN
BACKGROUND: As a potent anticoagulant agent, rivaroxaban exposes a risk of bleeding. An effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa) and prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of an overdose of rivaroxaban in a rabbit model of bleeding and thrombosis. METHODS: First, a dose-ranging study assessed the minimal rivaroxaban dose that increased bleeding. Then, 48 anesthetized and ventilated rabbits were randomized into four groups: control (saline), rivaroxaban (rivaroxaban and saline), rFVIIa (rivaroxaban and rFVIIa), and PCC (rivaroxaban and PCC). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis, detected as cyclic flow reductions, which were recorded over 20 min. Then the following were measured: ear immersion bleeding time, clotting times, anti-Xa activity, thrombelastometric parameters, and thrombin generation test. Ultimately, a hepatosplenic section was performed and the total amount of blood loss after 15 min was evaluated as primary endpoint. RESULTS: Rivaroxaban increased blood loss (17 g [8-32] vs. 7 g [5-18] for control (median [range]), P = 0.0004), ear bleeding time, clotting times, thrombelastographic clotting time, and decreased thrombin generation. In contrast, rFVIIa decreased ear bleeding time (92 s [65-115] vs. 140 s [75-190], P < 0.02), but without efficacy on blood loss. PCC and rFVIIa decreased activated partial thromboplastin time as well as thrombelastographic clotting time. Regarding safety, neither rFVIIa nor PCC increased cyclic flow reductions. CONCLUSION: rFVIIa and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding.
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Anticoagulantes/antagonistas & inhibidores , Factor VIIa/uso terapéutico , Morfolinas/antagonistas & inhibidores , Protrombina/uso terapéutico , Tiofenos/antagonistas & inhibidores , Anestesia , Animales , Anticoagulantes/farmacología , Tiempo de Sangría , Pruebas de Coagulación Sanguínea , Presión Sanguínea/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Factor VIIa/administración & dosificación , Hemorragia/sangre , Hígado/irrigación sanguínea , Masculino , Monitoreo Fisiológico , Morfolinas/farmacología , Protrombina/administración & dosificación , Conejos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Respiración Artificial , Rivaroxabán , Bazo/irrigación sanguínea , Tiofenos/farmacología , Tromboelastografía , Trombina/biosíntesis , Trombosis/sangre , Trombosis/tratamiento farmacológicoAsunto(s)
Anticoagulantes/antagonistas & inhibidores , Bencimidazoles/antagonistas & inhibidores , Hemorragia/prevención & control , beta-Alanina/análogos & derivados , Anticoagulantes/uso terapéutico , Bencimidazoles/uso terapéutico , Factores de Coagulación Sanguínea/farmacología , Dabigatrán , Humanos , Morfolinas/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Rivaroxabán , Tiofenos/antagonistas & inhibidores , Warfarina/antagonistas & inhibidores , beta-Alanina/antagonistas & inhibidores , beta-Alanina/uso terapéuticoRESUMEN
The synthesis and glucosidase inhibitory activities of two C-3'- and C-5'-ß-maltose-extended analogues of the naturally occurring sulfonium-ion inhibitor, de-O-sulfonated ponkoranol, are described. The compounds are designed to test the specificity towards four intestinal glycoside hydrolase family 31 (GH31) enzyme activities, responsible for the hydrolysis of terminal starch products and sugars into glucose, in humans. The target sulfonium-ion compounds were synthesized by means of nucleophilic attack of benzyl protected 1,4-anhydro-4-thio-D-arabinitol at the C-6 position of 6-O-trifluoromethanesulfonyl trisaccharides as alkylating agents. The alkylating agents were synthesized from D-glucose by glycosylation at C-4 or C-2 with maltosyl trichloroacetimidate. Deprotection of the coupled products by using a two-step sequence, followed by reduction afforded the final compounds. Evaluation of the target compounds for inhibition of the four glucosidase activities indicated that selective inhibition of one enzyme over the others is possible.
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Mucosa Intestinal/metabolismo , Intestinos/enzimología , Maltosa/antagonistas & inhibidores , Maltosa/química , Maltosa/síntesis química , Almidón/química , Complejo Sacarasa-Isomaltasa/antagonistas & inhibidores , Complejo Sacarasa-Isomaltasa/metabolismo , Compuestos de Sulfonio/antagonistas & inhibidores , Compuestos de Sulfonio/química , Tiofenos/antagonistas & inhibidores , Tiofenos/síntesis química , alfa-Glucosidasas/química , alfa-Glucosidasas/síntesis química , Catálisis , Inhibidores Enzimáticos/farmacología , Humanos , Estructura Molecular , Estereoisomerismo , Tiofenos/químicaAsunto(s)
Anticoagulantes/antagonistas & inhibidores , Antídotos/farmacología , Bencimidazoles/antagonistas & inhibidores , Factores de Coagulación Sanguínea/farmacología , Coagulación Sanguínea/efectos de los fármacos , Morfolinas/antagonistas & inhibidores , Tiofenos/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Dabigatrán , Humanos , Masculino , Rivaroxabán , beta-Alanina/antagonistas & inhibidoresRESUMEN
BACKGROUND: Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P<0.001) that was immediately and completely reversed by PCC (12.8±1.0; P<0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P=0.002) and normalized with PCC (114±26%; P<0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. CONCLUSION: Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration- URL: http://www.trialregister.nl. Unique identifier: NTR2272.
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Anticoagulantes/antagonistas & inhibidores , Antídotos/farmacología , Bencimidazoles/antagonistas & inhibidores , Factores de Coagulación Sanguínea/farmacología , Coagulación Sanguínea/efectos de los fármacos , Morfolinas/antagonistas & inhibidores , Tiofenos/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Adulto , Estudios Cruzados , Dabigatrán , Método Doble Ciego , Endopeptidasas , Inhibidores del Factor Xa , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Rivaroxabán , Trombina/antagonistas & inhibidores , Tiempo de Trombina , Adulto Joven , beta-Alanina/antagonistas & inhibidoresRESUMEN
Acute intermittent hypoxia (AIH) facilitates phrenic motor output by a mechanism that requires spinal serotonin (type 2) receptor activation, NADPH oxidase activity and formation of reactive oxygen species (ROS). Episodic spinal serotonin (5-HT) receptor activation alone, without changes in oxygenation, is sufficient to elicit NADPH oxidase-dependent phrenic motor facilitation (pMF). Here we investigated: (1) whether serotonin 2A and/or 2B (5-HT2A/B) receptors are expressed in identified phrenic motor neurons, and (2) which receptor subtype is capable of eliciting NADPH-oxidase-dependent pMF. In anesthetized, artificially ventilated adult rats, episodic C4 intrathecal injections (3×6 µl injections, 5 min intervals) of a 5-HT2A (DOI) or 5-HT2B (BW723C86) receptor agonist elicited progressive and sustained increases in integrated phrenic nerve burst amplitude (i.e. pMF), an effect lasting at least 90 min post-injection for both receptor subtypes. 5-HT2A and 5-HT2B receptor agonist-induced pMF were both blocked by selective antagonists (ketanserin and SB206553, respectively), but not by antagonists to the other receptor subtype. Single injections of either agonist failed to elicit pMF, demonstrating a need for episodic receptor activation. Phrenic motor neurons retrogradely labeled with cholera toxin B fragment expressed both 5-HT2A and 5-HT2B receptors. Pre-treatment with NADPH oxidase inhibitors (apocynin and diphenylenodium (DPI)) blocked 5-HT2B, but not 5-HT2A-induced pMF. Thus, multiple spinal type 2 serotonin receptors elicit pMF, but they act via distinct mechanisms that differ in their requirement for NADPH oxidase activity.
Asunto(s)
Potenciales de Acción/fisiología , NADPH Oxidasas/fisiología , Nervio Frénico/fisiología , Receptor de Serotonina 5-HT2A/fisiología , Receptor de Serotonina 5-HT2B/fisiología , Acetofenonas/administración & dosificación , Acetofenonas/farmacología , Potenciales de Acción/efectos de los fármacos , Anfetaminas/administración & dosificación , Anfetaminas/antagonistas & inhibidores , Anfetaminas/farmacología , Animales , Indoles/administración & dosificación , Indoles/antagonistas & inhibidores , Indoles/farmacología , Inyecciones Espinales , Ketanserina/administración & dosificación , Ketanserina/farmacología , Masculino , NADPH Oxidasas/antagonistas & inhibidores , Compuestos Onio/farmacología , Nervio Frénico/efectos de los fármacos , Nervio Frénico/enzimología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Tiofenos/administración & dosificación , Tiofenos/antagonistas & inhibidores , Tiofenos/farmacologíaRESUMEN
Thienopyridines are a class of drug targeting the platelet adenosine diphosphate 2 receptor. They have been shown to significantly reduce platelet activity exerting an important role in those clinical settings in which such an effect is beneficial. Ticlopidine was first to be introduced several years ago but it was quickly replaced by clopidogrel as it had a better risk/benefit profile. Recently, prasugrel has been developed and tested in several ex vivo studies and clinical trials showing able to provide a more powerful antiplatelet effect at the expense of a higher risk of bleeding complications. Great debate rose around its recent approval in the US as well as in Europe. This review aims at exploring the development and available clinical data of this third-generation thienopyridine while discussing its practical implementation in routine practice.