公开(公告)号：EP3275458A1

公开(公告)日：2018-01-31

申请号：EP16181521.2

申请日：2016-07-27

申请人： Hartis-Pharma Sarl

发明人： Joseph Eric, Niesor ,  Renée, Benghozi ,  François, Lamour

IPC分类号： A61K38/00 ,  A61K31/00 ,  A61P7/06

CPC分类号： C12Y203/01043 ,  A61K31/07 ,  A61K31/216 ,  A61K31/355 ,  A61K31/4439 ,  A61K31/455 ,  A61K38/1709 ,  A61K38/45 ,  A61K2300/00

摘要： Disclosed is a new combination therapy to treat sickle cell disease (SCD) and thalassemia and their vascular acute and chronic complications by a therapy involving the combined administration of a compound improving HDL particle function and activity (i.e. increasing HDL/ ApoA1 levels), and liposoluble antioxidants xanthophylls (such as lutein, zeaxanthin, meso-zeaxanthin, astaxanthin). This method simultaneously and synergistically restores red blood cell function, normalizes red blood cell membrane cholesterol concentration and decreases oxidative stress both parameters being pathologically affected in SCD, thalassemia and diabetes secondary to low levels of plasma HDL and decreased absorption of dietary lipophilic antioxidant.
Although it is known that HDL is involved in the selective and active intestinal uptake of liposoluble vitamins and antioxidants and that HDL uniquely removes excess membrane cholesterol from red blood cells, we discovered that the combination of an HDL therapeutic intervention together with a dietary supplement (as a free or fixed combination) of liposoluble antioxidants act synergistically for treating the rheological complications of sickle cell disease as well as thalassemia and subsequently will contribute to treating and preventing microvascular damages and associated pathologies (retinopathies, kidney failure, leg ulcer, priapism, acute chest syndrome, stroke etc.). Similarly Diabetes, which includes hemorheological abnormalities associated with high red blood cell membrane cholesterol and low plasma HDL antioxidant level will benefit from such combinations. Additional compounds affecting HDL are ApoA1 inducers, HDL and ApoA1 mimetics or (mimicking compounds) ApoA1 and ApoE analogues, Lecithin Cholesterol Acyl Transferase (LCAT) activators, CETP inhibitors and modulators, Peroxisome Proliferator Activated Receptor (PPAR) agonists, ATP Binding Cassette A1 (ABCA1) inducers, Niacin and analogues, Niacin Receptor agonists. Additional lipophilic antioxidants are tocopherols and tocotrienols.

摘要翻译： 本发明公开了一种通过联合给药改善HDL颗粒功能和活性的化合物（即增加HDL / ApoA1水平）和脂溶性治疗来治疗镰状细胞病（SCD）和地中海贫血及其血管急性和慢性并发症的新型组合疗法 抗氧化剂叶黄素（如叶黄素，玉米黄素，内消旋 - 玉米黄质，虾青素）。 该方法同时并协同恢复红细胞功能，使红细胞膜胆固醇浓度正常化并降低氧化应激，这两个参数在SCD，地中海贫血和糖尿病中均受到病理影响，继发于低水平的血浆HDL和降低的膳食亲脂性抗氧化剂的吸收。 虽然已知HDL参与了脂溶性维生素和抗氧化剂的选择性和主动吸收肠内脂质，并且HDL独特地从红细胞中去除了过量的膜胆固醇，但我们发现HDL治疗性干预与膳食补充剂（作为 游离或固定组合）脂溶性抗氧化剂协同作用治疗镰状细胞病以及地中海贫血的流变学并发症，并且随后将有助于治疗和预防微血管损伤和相关病状（视网膜病，肾衰竭，腿部溃疡，阴茎异常勃起，急性胸部 综合征，中风等）。 类似地，包括与高红细胞膜胆固醇和低血浆HDL抗氧化剂水平相关的血液流变学异常的糖尿病将受益于这样的组合。 影响HDL的其他化合物是ApoA1诱导剂，HDL和ApoA1模拟物或（模拟化合物）ApoA1和ApoE类似物，卵磷脂胆固醇酰基转移酶（LCAT）激活剂，CETP抑制剂和调节剂，过氧化物酶体增殖物激活受体（PPAR）激动剂，ATP结合盒A1 ABCA1）诱导剂，烟酸和类似物，烟酸受体激动剂。 另外的亲脂性抗氧化剂是生育酚和生育三烯酚。