RESUMEN
We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single-blind, placebo-controlled study, following once-daily multiple ascending dosing to steady-state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half-life of ~ 60 hours. A dose/concentration-effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady-state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration-dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Peroxidasa/antagonistas & inhibidores , Pirimidinas/efectos adversos , Pirroles/efectos adversos , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Pirroles/administración & dosificación , Pirroles/farmacocinética , Método Simple Ciego , Volumen Sistólico , Función Ventricular Izquierda , Adulto JovenRESUMEN
Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis. FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1-4 weeks before randomization. Stenosis of the left anterior descending coronary artery after percutaneous intervention must be <50%, and Thrombolysis In Myocardial Infarction flow grade must be ≥ 2. Enrolled participants receive standard care plus oral AZD5718 200 mg, 50 mg, or placebo once daily for up to 12 weeks (extended from 4 weeks by protocol amendment). The planned sample size is 100 participants randomized to 12 weeks' treatment. Change in urine leukotriene E4 levels is the primary efficacy outcome. FLAVOUR also aims to evaluate whether AZD5718 can improve coronary microvascular function, as measured by transthoracic colour Doppler-assisted coronary flow velocity reserve. Centrally pretrained study sonographers use standardized protocols and equipment. Additional outcomes include assessment of comprehensive echocardiographic parameters (including coronary flow, global strain, early diastolic strain rate and left ventricular ejection fraction), arterial stiffness, biomarkers, health-related quality of life, and safety. Specific anti-inflammatory therapies may represent novel promising treatments to reduce residual risk in patients with coronary artery disease. By combining primary pharmacodynamic and secondary cardiovascular surrogate efficacy outcomes, FLAVOUR aims to investigate the mechanistic basis and potential benefits of AZD5718 treatment in patients with coronary artery disease.
RESUMEN
Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%-50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).
RESUMEN
AZD5718 is a first-in-class small-molecule anti-inflammatory drug with the potential to reduce the residual risk of cardiovascular events after myocardial infarction in patients receiving lipid-lowering statin therapy. Leukotrienes are potent proinflammatory and vasoactive mediators synthesized in leukocytes via 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP). AZD5718 is a FLAP inhibitor that dose-dependently reduced leukotriene biosynthesis in a first-in-human study. We enrolled 12 healthy men in a randomized, open-label, crossover, single-dose phase 1 pharmacokinetic study of AZD5718 to investigate a potential drug-drug interaction with rosuvastatin, and the effects of formulation and food intake (ClinicalTrials.gov identifier: NCT02963116). Rosuvastatin (10 mg) were absorbed more rapidly when coadministered with AZD5718 (200 mg), probably owing to weak inhibition of hepatic statin uptake, but relative bioavailability was unaffected (geometric least-squares mean ratio [GMR], 100%; 90% confidence interval [CI], 86%-116%). AZD5718 pharmacokinetics were unaffected by coadministration of rosuvastatin. AZD5718 (200 mg) was absorbed less rapidly when formulated as tablets than oral suspension, with reduced relative bioavailability (GMR, 72%; 90%CI, 64%-80%). AZD5718 absorption was slower when 200-mg tablets were taken after a high-fat breakfast than after fasting, but relative bioavailability was unaffected (GMR, 96%; 90%CI, 87%-106%). In post hoc pharmacodynamic simulations, plasma leukotriene B4 levels were inhibited by >90% throughout the day following once-daily AZD5718, regardless of formulation or administration with food. AZD5718 was well tolerated, with no severe or serious adverse events. These data supported the design of a phase 2a efficacy study of AZD5718 in patients with coronary artery disease.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Interacciones Alimento-Droga , Pirazoles/farmacocinética , Rosuvastatina Cálcica/farmacología , Inhibidores de Proteína Activante de 5-Lipoxigenasa/administración & dosificación , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Administración Oral , Adulto , Disponibilidad Biológica , Estudios Cruzados , Interacciones Farmacológicas , Ayuno , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Persona de Mediana Edad , Pirazoles/administración & dosificación , Pirazoles/farmacología , Rosuvastatina Cálcica/administración & dosificación , Adulto JovenRESUMEN
Excessive activation of the mineralocorticoid receptor (MR) underlies the pathophysiology of heart failure and chronic kidney disease. Hyperkalemia risk limits the therapeutic use of conventional MR antagonists. AZD9977 is a nonsteroidal, selective MR modulator that may protect nonepithelial tissues without disturbing electrolyte balance. This phase I study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of AZD9977 in healthy volunteers. Twenty-seven male participants aged 23-45 years were randomized 3:1 to receive oral AZD9977 or placebo for 8 days (with twice-daily dosing on days 2-7), in dose cohorts of 50, 150, and 300 mg (AZD9977, n = 6 per cohort; placebo, n = 3 per cohort). Adverse events occurred in 4 of 18 participants receiving AZD9977 (22.2%) and 6 of 9 receiving placebo (66.7%), all of mild or moderate severity; none were serious or led to withdrawal. AZD9977 was rapidly absorbed, with median time of maximum concentration of 0.50-0.84 hours across dose groups. Area under the curve and maximum concentration were approximately dose proportional but elimination and accumulation terminal half-life increased with dose. Steady-state was reached after 3-4 days, with dose-dependent accumulation of 1.2-1.7-fold. Renal clearance was 5.9-6.5 L/hour and 24-37% of AZD9977 was excreted in the urine. Serum aldosterone levels increased dose dependently from days -1 to 7 in participants receiving AZD9977, but serum potassium levels and urinary electrolyte excretion were unchanged. AZD9977 was generally well-tolerated with no safety concerns. Exploratory outcomes suggested reduced hyperkalemia risk compared with MR antagonists. These findings support further clinical development of AZD9977.
Asunto(s)
Benzoatos/efectos adversos , Hiperpotasemia/epidemiología , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Oxazinas/efectos adversos , Receptores de Mineralocorticoides/metabolismo , Administración Oral , Adolescente , Adulto , Aldosterona/sangre , Aldosterona/metabolismo , Área Bajo la Curva , Benzoatos/administración & dosificación , Benzoatos/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Semivida , Voluntarios Sanos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Humanos , Hiperpotasemia/sangre , Hiperpotasemia/inducido químicamente , Hiperpotasemia/diagnóstico , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Oxazinas/administración & dosificación , Oxazinas/farmacocinética , Potasio/sangre , Eliminación Renal , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/etiología , Medición de Riesgo/estadística & datos numéricos , Adulto JovenRESUMEN
Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4-24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.
Asunto(s)
Diabetes Mellitus Tipo 2/terapia , Neovascularización Fisiológica/fisiología , ARN Mensajero/efectos adversos , ARN Mensajero/uso terapéutico , Piel/irrigación sanguínea , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Terapia Genética , Humanos , Inyecciones Intradérmicas , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , ARN Mensajero/genética , Flujo Sanguíneo Regional/genéticaRESUMEN
AIMS: Myeloperoxidase activity can contribute to impaired vascular endothelial function and fibrosis in chronic inflammation-related cardiovascular disease. Here, we investigated the safety, tolerability and pharmacokinetics of the myeloperoxidase inhibitor, AZD4831. METHODS: In this randomized, single-blind, placebo-controlled, phase I, first-in-human study, healthy men in five sequential cohorts were randomized 3:1 to receive a single oral dose of AZD4831 (5, 15, 45, 135 or 405 mg) or placebo, after overnight fasting. After at least 7 days' washout, one cohort additionally received AZD4831 45 mg after a high-calorie meal. RESULTS: Forty men participated in the study (eight per cohort: AZD4831, n = 6; placebo, n = 2). AZD4831 distributed rapidly into plasma, with a half-life of 38.2-50.0 hours. The area under the plasma concentration-time curve (AUC) increased proportionally with dose (AUC0-â slope estimate 1.060; 95% confidence interval [CI] 0.9943, 1.127). Increases in maximum plasma concentration were slightly more than dose proportional (slope estimate 1.201; 95% CI 1.071, 1.332). Food intake reduced AZD4831 absorption rate but did not substantially affect overall exposure or plasma half-life (n = 4). Serum uric acid concentrations decreased by 71.77 (95% CI 29.15, 114.39) and 84.42 (58.90, 109.94) µmol L-1 with AZD4831 135 mg and 405 mg, respectively. Maculopapular rash (moderate intensity) occurred in 4/30 participants receiving AZD4831 (13.3%). No other safety concerns were identified. CONCLUSIONS: AZD4831 was generally well tolerated, rapidly absorbed, had a long plasma half-life and lowered uric acid concentrations after single oral doses in healthy men. These findings support the further clinical development of AZD4831.
Asunto(s)
Inhibidores Enzimáticos/administración & dosificación , Peroxidasa/antagonistas & inhibidores , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Ácido Úrico/sangre , Administración Oral , Adulto , Área Bajo la Curva , Enfermedades Cardiovasculares/prevención & control , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Semivida , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Placebos , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Pirroles/efectos adversos , Pirroles/farmacocinética , Método Simple Ciego , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients. METHODS: We determined the drive on PGD2 secretion by glucose and IL-1beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro. To test if metabolic control would be improved by antagonizing a hyperglycemia-driven increased PGD2 tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m2). The randomized, double-blind, placebo-controlled cross-over study consisted of two three-day treatment periods (AZD1981 or placebo) separated by a three-day wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose infusion (GGI) was performed at start and end of each treatment period. Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, GLP-1, and PGD2 pathway biomarkers were performed. RESULTS: We found (1) that PGD2 is produced in human islet in response to high glucose or IL-1beta, but likely by stellate cells rather than endocrine cells; (2) that PGD2 suppresses both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. However, AZD1981 had no impact on neither glucose nor incretin dependent insulin secretion in humans (GGI AUC C-peptide 1-2h and MMTT AUC Glucose 0-4h LS mean ratios vs placebo of 0.94 (80% CI of 0.90-0.98, p = 0.12) and 0.99 (90% CI of 0.94-1.05, p = 0.45), despite reaching the expected antagonist exposure. CONCLUSION/INTERPRETATION: Pharmacological inhibition of the PGD2-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02367066.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Prostaglandina D2/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Factores de Transcripción/metabolismo , Acetatos/farmacología , Acetatos/uso terapéutico , Glucemia/metabolismo , Péptido C/sangre , Línea Celular , Proteínas de Unión al ADN/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Persona de Mediana Edad , Prostaglandina D2/antagonistas & inhibidores , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
We evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD5718, a novel 5-lipooxygenase activating protein (FLAP) inhibitor, in a randomized, single-blind, placebo-controlled, first-in-human (FIH) study consisting of single and multiple ascending dosing (SAD and MAD) for 10 days in healthy subjects. Target engagement was measured by ex vivo calcium ionophore stimulated leukotriene B (LTB4 ) production in whole blood and endogenous leukotriene E (LTE4 ) in urine. No clinically relevant safety and tolerability findings were observed. The AZD5718 was rapidly absorbed and plasma concentrations declined biphasically with a mean terminal half-life of 10-12 h. Steady-state levels were achieved after â¼3 days. After both SADs and MADs, a dose/concentration-effect relationship between both LTB4 and LTE4 vs. AZD5718 exposure was observed with concentration of half inhibition (IC50 ) values in the lower nM range. Based on obtained result, AZD5718 is considered as a suitable drug candidate for future evaluation in patients with coronary artery disease (CAD).
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Pirazoles/farmacología , Inhibidores de Proteína Activante de 5-Lipoxigenasa/uso terapéutico , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Voluntarios Sanos , Humanos , Concentración 50 Inhibidora , Leucotrieno B4/sangre , Leucotrieno B4/metabolismo , Leucotrieno E4/metabolismo , Leucotrieno E4/orina , Masculino , Placebos , Pirazoles/uso terapéutico , Método Simple CiegoRESUMEN
AIMS: AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977. METHODS: A first-in-human trial explored doses from 5 to 1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross-over four-period clinical trial was performed. Twenty-three healthy volunteers were administered fludrocortisone alone or in combination with AZD9977, eplerenone or both. AZD9977/eplerenone combination was given to assess if AZD9977 can attenuate eplerenone induced natriuresis. RESULTS: AZD9977 at doses from 5 to 1200 mg was safe and well tolerated and pharmacokinetics were compatible with further development. AZD9977 exhibited similar effects on urinary ln [Na+ ]/[K+ ] as eplerenone when using fludrocortisone as mineralocorticoid receptor agonist, and the combination had an additive effect on ln [Na+ K+ ]. CONCLUSIONS: The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients.
Asunto(s)
Benzoatos/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Natriuresis/efectos de los fármacos , Oxazinas/administración & dosificación , Potasio/orina , Sodio/orina , Adulto , Benzoatos/efectos adversos , Benzoatos/farmacocinética , Estudios Cruzados , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Eplerenona/administración & dosificación , Eplerenona/efectos adversos , Eplerenona/farmacocinética , Fludrocortisona/administración & dosificación , Fludrocortisona/efectos adversos , Fludrocortisona/farmacocinética , Voluntarios Sanos , Humanos , Masculino , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Oxazinas/efectos adversos , Oxazinas/farmacocinética , Potasio/metabolismo , Receptores de Mineralocorticoides/metabolismo , Eliminación Renal/efectos de los fármacos , Método Simple Ciego , Sodio/metabolismoRESUMEN
ICH E9 Statistical Principles for Clinical Trials was issued in 1998. In October 2014, an addendum to ICH E9 was proposed relating to estimands and sensitivity analyses. In preparation for the release of the addendum, Statisticians in the Pharmaceutical Industry held a 1-day expert group meeting in February 2015. Topics debated included definition, development, implementation, education and communication challenges associated with estimands and sensitivity analyses. The topic of estimands is an important and relatively new one in clinical development. A clear message from the meeting was that estimands bridge the gap between study objectives and statistical methods. When defining estimands, an iterative process linking trial objectives, estimands, trial design, statistical and sensitivity analysis needs to be established. Each objective should have at least one distinct estimand, supported by sensitivity analyses. Because clinical trials are multi-faceted and expensive, it is unrealistic to restrict a study to a single objective and associated estimand. The actual set of estimands and sensitivity analyses for a study will depend on the study objectives, the disease setting and the needs of the various stakeholders. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Ensayos Clínicos como Asunto/métodos , Industria Farmacéutica/métodos , Modelos Estadísticos , Proyectos de Investigación , Interpretación Estadística de Datos , Diseño de Fármacos , HumanosRESUMEN
The metabotropic glutamate receptor 5 (mGluR5) has been suggested to modulate energy balance. For example, mGluR5 antagonists inhibit food intake in rodents and mGluR5 knockout mice resist diet-induced obesity. However, nonspecific effects can reduce food intake. Thus, to further support the role of mGluR5 in feeding behaviour, we evaluated if the mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) would induce the opposite effect, i.e. increased food intake in rats. Intracerebroventricularly injected CHPG (0.5-1.5 micromol) induced a dose-dependent stimulation of food intake (349% increase at 2 h with 1.5 micromol). The mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (10 mg/kg intraperitoneally) reduced 24 h food intake, without altering CHPG-induced feeding. These findings further support a physiologically relevant role of mGluR5 in appetite regulation.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Glicina/análogos & derivados , Fenilacetatos/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Animales , Cateterismo , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/fisiología , Agonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Ayuno , Glicina/administración & dosificación , Glicina/farmacología , Inyecciones Intraperitoneales , Masculino , Fenilacetatos/administración & dosificación , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Tiazoles/farmacología , Factores de TiempoRESUMEN
The effect of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran, on thrombin generation was investigated in vitro and ex vivo using a thrombin generation assay. In-vitro thrombin generation was triggered in human platelet-poor plasma by the addition of tissue factor, and the endogenous thrombin potential (ETP) was measured. The ETP IC(50) values for melagatran and the low-molecular-weight heparin dalteparin were 0.44 micromol/l and 0.06 IU/ml, respectively. In contrast to dalteparin, melagatran increased the time-to-thrombin peak in a concentration-dependent manner. ETP was also studied ex vivo in platelet-poor plasma collected from healthy male subjects (n = 54) at pre-dose and 2 h post-dose, with ximelagatran (60 mg) orally, dalteparin (120 IU/kg) subcutaneously, or control (water) orally. After ximelagatran or dalteparin administration, the time-to-thrombin peak was prolonged by 41 and 95%, and the ETP was decreased by 61 and 77%, respectively. Thus, melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, efficiently delays and inhibits the generation of thrombin in plasma both in vitro and ex vivo.