[发明专利]用罗达司他乙酯治疗肺动脉高压的给药方案和方法

说明书

提出了用于治疗肺动脉高压的每日给药方案。所述方案采用两种不同的剂型形式。每个剂型包括约600mg至约800mg量的(S)‑乙基8‑(2‑氨基‑6‑((R)‑1‑(5‑氯‑[1,1'‑联苯]‑2‑基)‑2,2,2‑三氟乙氧基)嘧啶‑4‑基)‑2,8‑二氮杂螺[4.5]癸烷‑3‑羧酸酯。还存在提供每日给药方案的其他方法。还提出了用于治疗肺动脉高压的数种方法。提出了一种将血清素生物合成水平降低至少50％的方法。还提出了实现AUC_0‑tau≥2530ng.hr/mL(S)‑8‑(2‑氨基‑6‑((R)‑1‑(5‑氯‑[1.1'‑联苯]‑2‑基)‑2,2,2‑三氟乙氧基)嘧啶‑4‑基)‑2,8‑二氮杂螺[4.5]癸烷‑3‑羧酸的一种方法。提出了一种将尿5‑HIAA降低50％的方法。

本公开的背景

1.本公开的领域

本公开涉及用于治疗肺动脉高压的每日给药方案。本公开还涉及用于治疗肺动脉高压的方法。本公开进一步涉及在一段时间内降低血清素生物合成水平的方法。本公开还进一步涉及在一段时间内实现AUC_0-tau水平提高的方法。本公开进一步涉及在一段时间内实现尿中5-HIAA降低的方法。

2.现有技术说明

血清素(5-羟色胺、5-HT)是一种神经递质，其通过作用于神经元、平滑肌和其他细胞类型来调节中枢和外周功能。5-HT参与多种生理和心理过程的控制和调节。在中枢神经系统(CNS)中，5-HT调节情绪、食欲和其他行为功能。在胃肠(GI)系统中，5-HT具有一般的促动力作用，是胃肠道和大脑之间感觉(例如，恶心和饱腹感)的重要介体。根据报告，外周5-HT信号传导系统失调与多种病症的病因有关(例如，参见：Mawe,G.M.Hoffman,J.,Serotonin Signalling in the Gut-functions,Dysfunctions and TherapeuticTargets.Nature Reviews.GastroenterologyHepatology 10,473-486(2013)；Gershon,M.D.5-hydroxytryptamine(serotonin)in the Gastrointestinal Tract.CurrentOpinion in Endocrinology,Diabetes,and Obesity 20,14-21(2013)；Lesurtel,M.,Soll,C,Graf,R.Ciavien,P.-A.Role of Serotonin in the Hepato-gastrointestinalTract:An Old Molecule for New Perspectives.Cellular and Molecular LifeSciences:CMLS 65,940-52(2008)。这些包括骨质疏松症(例如，Kode,A,et al.,FOXO1Orchestrates the Bone-suppressing Function of Gut-derived Serotonin,TheJournal of Clinical Investigation 122,3490-503(2012)；Yadav,V,K.et al.,Pharmacological Inhibition of Gut-derived Serotonin Synthesis is a PotentialBone Anabolic Treatment for Osteoporosis.Nature Medicine 16,308-12(2010)；Yadav,V.K,et al.,Lrp5 Controls Bone Formation by Inhibiting SerotoninSynthesis in the Duodenum,Cell 135,825-37(2008)、癌症(例如，Liang,C,et al.,Serotonin Promotes the Proliferation of Serum-deprived HepatocellularCarcinoma Cells Via Upregulation of FOX03a.Molecular Cancer 12,14(2013)；Soil,C.et al.,Serotonin Promotes Tumor Growth in Human HepatocellularCancer.Hepatology 51,1244-1254(2010)；Pai,V.P et al.,Altered SerotoninPhysiology in Human Breast Cancers Favors Paradoxical Growth and CellSurvival.Breast Cancer Research:BCR 11,R81(2009)；Engelman,K.,Lovenberg,W.Sjoerdsma,A.Inhibition of Serotonin Synthesis by Para-chlorophenylalanine inPatients with The Carcinoid Syndrome.The New England Journal of Medicine 277,1103-8(1967)、心血管疾病(例如，Robiolio,P.A,et al.,Carcinoid Heart Disease:Correlation of High Serotonin Levels with Valvular Abnormalities Detected byCardiac Catheterization and Echocardiography.Circulation 92,790-795(1995)、糖尿病(例如，Sumara,G.,Sumara,O.,Kim,J.K.Karsenty,G.Gut-derived Serotonin is aMultifunctional Determinant to Fasting Adaptation.Cell Metabolism 16,588-600(2012)、动脉粥样硬化(例如，Ban,Y.et al.,Impact of Increased Plasma SerotoninLevels and Carotid Atherosclerosis on Vascular Dementia.Atherosclerosis 195,153-9(2007))以及胃肠道疾病(例如，Manocha,M.Khan,W.I.Serotonin and GIDisorders:An Update on Clinical and Experimental Studies.Clinical andTranslational Gastroenterology 3,el 3(2012)；Ghia,J.-E.et al.,Serotonin has aKey Role in Pathogenesis of Experimental Colitis.Gastroenterology 137,1649-60(2009)；Sikander,A.,Rana,S.V.Prasad,K.K.,Role of Serotonin inGastrointestinal Motility and Irritable Bowel Syndrome.Clinica Chimica Acta；International Journal of Clinical Chemistry403,47-55(2009)；Spiller,R,RecentAdvances in Understanding the Role of Serotonin in Gastrointestinal Motilityin Functional Bowel Disorders:Alterations In 5-HT Signalling and Metabolismin Human Disease.Neurogastroenterology and Motility:The Official Journal ofThe European Gastrointestinal Motility Society 19Suppl 2,25-31(2007)；Costedio,M.M.,Hyman,N.Mawe,G,M,Serotonin and its Role in Colonic Functionand In Gastrointestinal Disorders.Diseases of the Colon and Rectum 50,376-88(2007)；Gershon,M.D.Tack,J.,The Serotonin Signalling System:From BasicUnderstanding to Drug Development for Functional GIDisorders.Gastroenterology 132,397-14(2007)；Mawe,G.M.,Coates,M.D.Moses,P.L.Review Article:Intestinal Serotonin Signalling In Irritable BowelSyndrome.Alimentary PharmacologyTherapeutics 23,1067-76(2006)；Crowell,M.D.Role of Serotonin in the Pathophysiology of The Irritable BowelSyndrome.British Journal of Pharmacology 141,1285-93(2004)、肺病(例如，Lau,W.K.W.et al.,The Role of Circulating Serotonin in the Development of ChronicObstructive Pulmonary Disease.PloS One 7,e31617(2012)；Egermayer,P.,Town,G.I.Peacock,A.J.Role of Serotonin in the Pathogenesis of Acute and ChronicPulmonary Hypertension.Thorax 54,161-168(1999)、炎症性疾病(例如，Margolis,K.G.et al.,Pharmacological Reduction of Mucosal but Not Neuronal SerotoninOpposes Inflammation in Mouse Intestine.Gut doi:10.1 136/gutjnl-2013-304901(2013)；Duerschmied,D.et al.,Platelet Serotonin Promotes the Recruitment ofNeutrophils to Sites of Acute Inflammation in Mice.Blood 121,1008-15(2013)；Li,N.et al.,Serotonin Activates Dendritic Cell Function in the Context of GutInflammation.The American Journal of Pathology 178,662-71(2011)或肝脏疾病或失调(例如，Ebrahimkhani,M.R.et al.,Stimulating Healthy Tissue Regeneration byTargeting The 5-HT2B Receptor in Chronic Liver Disease.Nature Medicine 17,1668-73(2011)。阻断或刺激各种5-HT受体的大量药剂也提示了与5-HT失调有关的广泛医学疾病(例如，参见：Wacker,D.et al.,Structural Features for FunctionalSelectivity at Serotonin Receptors,Science(New York N Y.)340,615-9(2013)。