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11. 发明授权

US07157500B2 Nitrosylation of protein SH groups and amino acid residues as a therapeutic modality 失效
标题翻译：蛋白质SH基团和氨基酸残基的亚硝化作为治疗方式
公开(公告)号：US07157500B2
公开(公告)日：2007-01-02
申请号：US10216865
申请日：2002-08-13
申请人： Jonathan Stamler , Joseph Loscalzo , Daniel Simon , David Singel
发明人： Jonathan Stamler , Joseph Loscalzo , Daniel Simon , David Singel
IPC分类号： A01N33/18
CPC分类号： C12N9/6472 , A61K38/00 , C07K1/1077 , C07K14/3153 , C07K14/4702 , C07K14/76 , C07K14/765 , C07K14/805 , C07K16/00 , C12N9/6459 , C12Y304/21069
摘要： Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoprotein; and S-nitroso-immunoglobulin. The invention also relates to therapeutic use of S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body. The invention also relates to the nitrosylation of oxygen, carbon and nitrogen moieties present on proteins and amino acids, and the use thereof to achieve the above physiological effects.
摘要翻译：蛋白质和氨基酸基团的亚硝化可以选择性调节蛋白质功能，并赋予蛋白质和氨基酸更多的平滑肌松弛剂和血小板抑制能力。因此，本发明涉及通过蛋白质硫醇的亚硝基化实现的新化合物。这些化合物包括：S-亚硝基-t-PA，S-亚硝基组织蛋白酶; S-亚硝基脂蛋白; 和S-亚硝基 - 免疫球蛋白。本发明还涉及S-亚硝基蛋白化合物用于调节蛋白质功能，细胞代谢和影响血管舒张，血小板抑制，非血管平滑肌松弛以及通过血红蛋白和肌红蛋白增加血氧转运的治疗用途。这些化合物也用于以最具生物活性的形式递送一氧化氮，以达到上述效果，或用于身体中存在的分子的体外亚硝基化。本发明还涉及存在于蛋白质和氨基酸上的氧，碳和氮部分的亚硝基化，以及其用于实现上述生理作用的用途。

12. 发明授权

US06589759B1 Compositions and methods for producing platelets and/or proplatelets from megakaryocytes 失效
标题翻译：用于从巨核细胞产生血小板和/或血小板的组合物和方法
公开(公告)号：US06589759B1
公开(公告)日：2003-07-08
申请号：US09937336
申请日：2001-12-05
申请人： Joseph Loscalzo , Elisabeth M. Battinelli
发明人： Joseph Loscalzo , Elisabeth M. Battinelli
IPC分类号： C12Q134
CPC分类号： C12N5/0644 , A61K31/198 , A61K31/401 , A61K31/573 , A61K35/19 , A61K38/06 , A61K38/196 , A61K45/06 , C12N2501/03 , C12N2501/145 , A61K2300/00
摘要： The present invention describes novel compositions and methods to enhance the in vitro and in vivo production of platelets and/or proplatelets from megakaryocytes. The present invention describes compositions comprising megakaryocytes, nitric oxide donors (i.e. compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or are substrates for nitric oxide synthase), and, optionally, at least one thrombopoiesis stimulating factor. The thrombopoiesis stimulating factor is preferably thrombopoietin. The nitric oxide donor is preferable S-nitrosoglutathione. The present invention also describes compositions comprising at least one nitric oxide donor and at least one thrombopoiesis stimulating factor. The present invention also provides methods for treating and/or preventing blood platelet disorders, and for producing platelets and/or proplatelets in vitro and in vivo. The compounds and/or compositions of the present invention can be provided in the form of a pharmaceutical kit.
摘要翻译：本发明描述了增强来自巨核细胞的血小板和/或血小板的体外和体内产生的新型组合物和方法。本发明描述了包含巨核细胞，一氧化氮供体（即捐赠，转移或释放一氧化氮的化合物，提高内源性内源性舒张因子水平，刺激一氧化氮的内源性合成或一氧化氮合酶的底物）的组合物，任选地，至少一种血小板生成刺激因子。血小板生成刺激因子优选为血小板生成素。一氧化氮供体优选S-亚硝基谷胱甘肽。本发明还描述了包含至少一种一氧化氮供体和至少一种血小板生成刺激因子的组合物。本发明还提供了用于治疗和/或预防血小板疾病和用于在体外和体内产生血小板和/或血小板的方法。本发明的化合物和/或组合物可以以药物试剂盒的形式提供。

13. 发明授权

US06489290B2 Antiplatelet agent 失效
标题翻译：抗血小板药
公开(公告)号：US06489290B2
公开(公告)日：2002-12-03
申请号：US09381261
申请日：1999-12-07
申请人： Joseph Loscalzo , Aida Inbal
发明人： Joseph Loscalzo , Aida Inbal
IPC分类号： A61K3800
CPC分类号： C07K14/355 , A61K38/00
摘要： This invention combines the unique antiplatelet effects of S-nitrosothiols and the antiadhesive properties of fragments of von Willebrand (vWF) in the A1 domain to provide unique molecules that exploit both of these properties. Preferred molecules comprise a fragment of A1 (Ala 444-Asn 730) in which arginine at position 545 is replaced by cysteine (the most frequent von Willebrand disease type 2b mutation) that has been discovered to impair platelet adhesion, and to inhibit an antithrombotic activity in vivo. This cysteine residue may be S-nitrosated to produce a novel molecule that has the potential for impairing platelet adhesion as well as activation/aggregation, and such molecules form the basis of a novel therapeutic method for impairing platelet responses following vascular injury or in other thrombotic disorders according to this invention.
摘要翻译：本发明结合了S-亚硝基硫醇的独特的抗血小板作用和缬沙坦（vWF）片段在A1结构域中的抗粘附性，以提供独特的分子，利用这两种特性。优选的分子包含A1（Ala 444-Asn 730）的片段，其中545位的精氨酸被已被发现损伤血小板粘附的半胱氨酸（最常见的血管性血友病血型B型突变）代替，并且抑制抗血栓形成活性体内。该半胱氨酸残基可以被S-亚硝基化以产生具有损害血小板粘附和活化/聚集的潜力的新分子，并且这些分子形成用于损伤血管损伤或其它血栓形成后血小板反应的新型治疗方法的基础根据本发明的病症。

14. 发明授权

US06291424B1 Nitrosated and nitrosylated heme proteins 失效
标题翻译：亚硝化和亚硝基化血红素蛋白
公开(公告)号：US06291424B1
公开(公告)日：2001-09-18
申请号：US09092622
申请日：1998-06-05
申请人： Johnathan Stamler , Joseph Loscalzo , David J. Singel
发明人： Johnathan Stamler , Joseph Loscalzo , David J. Singel
IPC分类号： A61K3814
CPC分类号： A61K38/42 , C07K1/1077 , C07K14/3153 , C07K14/4702 , C07K14/76 , C07K14/765 , C07K14/775 , C07K14/805 , C07K16/00 , C12N9/6459 , C12N9/6472 , C12Y304/21069 , Y10S514/832 , Y10S530/829 , A61K2300/00
摘要： Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoprotein; and S-nitroso-immunoglobulin. The invention also relates to therapeutic use if S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body. The invention also relates to the nitrosylation of oxygen, carbon and nitrogen moieties present on proteins and amino acids, and the use thereof to achieve the above physiological effects.
摘要翻译：蛋白质和氨基酸基团的亚硝化可以选择性调节蛋白质功能，并赋予蛋白质和氨基酸更多的平滑肌松弛剂和血小板抑制能力。因此，本发明涉及通过蛋白质硫醇的亚硝基化实现的新化合物。这些化合物包括：S-亚硝基-t-PA，S-亚硝基组织蛋白酶; S-亚硝基脂蛋白; 和S-亚硝基 - 免疫球蛋白。本发明还涉及用于调节蛋白质功能，细胞代谢和影响血管舒张，血小板抑制，非血管平滑肌松弛以及通过血红蛋白和肌红蛋白增加血氧转运的S-亚硝基蛋白化合物的治疗用途。这些化合物也用于以最具生物活性的形式递送一氧化氮，以达到上述效果，或用于身体中存在的分子的体外亚硝基化。本发明还涉及存在于蛋白质和氨基酸上的氧，碳和氮部分的亚硝基化，以及其用于实现上述生理作用的用途。

15. 发明授权

US5648393A Treatment of male impotence with s-nitrosylated compounds 失效
标题翻译：用s-亚硝基化化合物治疗男性阳。
公开(公告)号：US5648393A
公开(公告)日：1997-07-15
申请号：US297698
申请日：1994-08-29
申请人： Jonathan Stamler , Joseph Loscalzo , Adam Slivka , Daniel Simon , Robert Brown , Jeffrey Drazen
发明人： Jonathan Stamler , Joseph Loscalzo , Adam Slivka , Daniel Simon , Robert Brown , Jeffrey Drazen
IPC分类号： A61K38/00 , C07C381/00 , C07K5/02 , A61K31/195 , A61K31/13
CPC分类号： C07C381/00 , C07K5/0215 , A61K38/00
摘要： Methods of relaxing corpus cavernosum smooth muscle, treating disease states responsive to prevention or relaxation of undesirable contractions of corpus cavernosum smooth muscle and of treating male impotence by administering an S-nitrosothiol such as a low molecular weight S-nitrosothiol, S-nitroso-ACE-inhibitor or S-nitroso-protein.
摘要翻译：放松海绵体平滑肌的方法，通过施用S-亚硝基硫醇如低分子量S-亚硝基硫醇，S-亚硝基ACE，治疗响应于预防或放松海绵体平滑肌不期望的收缩和治疗男性阳states的疾病状态抑制剂或S-亚硝基蛋白。

16. 发明授权

US5593876A Nitrosylation of protein SH groups and amino acid residues as a therapeutic modality 失效
标题翻译：蛋白质SH基团和氨基酸残基的亚硝化作为治疗方式
公开(公告)号：US5593876A
公开(公告)日：1997-01-14
申请号：US287830
申请日：1994-08-09
申请人： Jonathan Stamler , Joseph Loscalzo , Daniel Simon , David Singel
发明人： Jonathan Stamler , Joseph Loscalzo , Daniel Simon , David Singel
IPC分类号： A61K35/14 , A61K38/00 , A61K38/02 , A61K38/16 , A61K38/38 , A61K38/42 , A61K38/46 , A61K38/49 , A61K39/395 , A61P9/00 , C07K1/06 , C07K1/107 , C07K14/00 , C07K14/315 , C07K14/47 , C07K14/76 , C07K14/765 , C07K14/805 , C07K16/00 , C07K16/18 , C12N9/00 , C12N9/48 , C12N9/64 , C12N9/70 , C12N9/72 , C12N9/96
CPC分类号： C12N9/6472 , C07K1/1077 , C07K14/3153 , C07K14/4702 , C07K14/76 , C07K14/765 , C07K14/805 , C07K16/00 , C12N9/6459 , C12Y304/21069 , A61K38/00
摘要： Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoprotein; and S-nitroso-immunoglobulin. The invention also relates to therapeutic use of S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body. The invention also relates to the nitrosylation of oxygen, carbon and nitrogen moieties present on proteins and amino acids, and the use thereof to achieve the above physiological effects.
摘要翻译：蛋白质和氨基酸基团的亚硝化可以选择性调节蛋白质功能，并赋予蛋白质和氨基酸更多的平滑肌松弛剂和血小板抑制能力。因此，本发明涉及通过蛋白质硫醇的亚硝基化实现的新化合物。这些化合物包括：S-亚硝基-t-PA，S-亚硝基组织蛋白酶; S-亚硝基脂蛋白; 和S-亚硝基 - 免疫球蛋白。本发明还涉及S-亚硝基蛋白化合物用于调节蛋白质功能，细胞代谢和影响血管舒张，血小板抑制，非血管平滑肌松弛以及通过血红蛋白和肌红蛋白增加血氧转运的治疗用途。这些化合物也用于以最具生物活性的形式递送一氧化氮，以达到上述效果，或用于身体中存在的分子的体外亚硝基化。本发明还涉及存在于蛋白质和氨基酸上的氧，碳和氮部分的亚硝基化，以及其用于实现上述生理作用的用途。

17. 发明授权

US5427797A Systemic effects of nitric oxide inhalation 失效
标题翻译：一氧化氮吸入的全身效应
公开(公告)号：US5427797A
公开(公告)日：1995-06-27
申请号：US43653
申请日：1993-04-06
申请人： Claes G. Frostell , Goran Hedenstierna , Marieann E. Hogman , Joseph Loscalzo , Jonathan S. Stamler
发明人： Claes G. Frostell , Goran Hedenstierna , Marieann E. Hogman , Joseph Loscalzo , Jonathan S. Stamler
IPC分类号： A61K38/00 , A61K33/00 , A61K33/04 , A61K33/26 , A61K38/06 , A61K38/38 , A61P7/02 , A61P9/08 , A61P9/10 , A61P11/00 , A61L9/04 , A61K9/12
CPC分类号： A61K38/063 , A61K33/00 , A61K38/38 , Y10S514/826 , Y10S514/957
摘要： Nitric oxide or nitric oxide releasing or delivering compounds administered by the inhalation route to humans and animals in need thereof have a systemic and pulmonary effect of preventing or treating blood platelet aggregation and coagulation and thus, are useful for the prevention or treatment of systemic platelet aggregation, pulmonary emboli, angina pectoris and acute respiratory distress syndrome.
摘要翻译：将通过吸入途径给药的化学物质的一氧化氮或一氧化氮释放给需要其的人和动物具有预防或治疗血小板聚集和凝血的全身和肺部作用，因此可用于预防或治疗系统性血小板聚集，肺栓塞，心绞痛和急性呼吸窘迫综合征。

18. 发明授权

US5025001A S-nitroso derivatives of ACE inhibitors and the use thereof 失效
标题翻译： ACE抑制剂的S-亚硝基衍生物及其用途
公开(公告)号：US5025001A
公开(公告)日：1991-06-18
申请号：US328397
申请日：1989-03-24
申请人： Joseph Loscalzo , John Cooke
发明人： Joseph Loscalzo , John Cooke
IPC分类号： C07D207/16
CPC分类号： C07D207/16
摘要： The invention relates to novel S-nitroso derivatives of ACE inhibitors and to pharmaceutical compositions comprising the S-nitrosothiol derivatives of the invention together with a pharmaceutically acceptable carrier.The invention also relates to methods for treating various pathophysiological conditions including acute myocardial infarction, left ventricular dysfunction without overt heart failure, hypertension, pulmonary hypertension, congestive heart failure, angina pectoris, vascular thrombosis, Raynauds syndrome, scleroderma, toxemia of pregnancy, acute renal failure, diabetic nephropathy, and renal artery stenosis, and to methods of inhibiting ACE and effecting vasodilation comprising administering the S-nitrosothiol derivatives of the ACE inhibitors of the invention to an animal.
摘要翻译：本发明涉及ACE抑制剂的新S-亚硝基衍生物和包含本发明的S-亚硝基硫醇衍生物与药学上可接受的载体的药物组合物。本发明还涉及用于治疗各种病理生理状况的方法，包括急性心肌梗塞，无明显心力衰竭的左心室功能障碍，高血压，肺动脉高压，充血性心力衰竭，心绞痛，血管血栓形成，雷诺氏综合征，硬皮病，怀孕毒血症，急性肾脏失败，糖尿病性肾病和肾动脉狭窄，以及抑制ACE和影响血管舒张的方法，包括将本发明的ACE抑制剂的S-亚硝基硫代衍生物施用于动物。

19. 发明授权

US07708989B2 Methods of treating vascular diseases characterized by nitric oxide insufficiency 失效
标题翻译：治疗以一氧化氮不足为特征的血管疾病的方法
公开(公告)号：US07708989B2
公开(公告)日：2010-05-04
申请号：US10692724
申请日：2003-10-27
申请人： Joseph Loscalzo , Joseph A. Vita , Michael D. Loberg , Manuel Worcel
发明人： Joseph Loscalzo , Joseph A. Vita , Michael D. Loberg , Manuel Worcel
IPC分类号： A61K38/43 , A01N43/04
CPC分类号： A61K31/135 , A61K9/0056 , A61K9/7023 , A61K31/19 , A61K31/34 , A61K31/355 , A61K31/415 , A61K31/495 , A61K31/50 , A61K31/535 , A61K45/06 , A61K2300/00
摘要： The invention provides methods of treating and/or preventing vascular diseases characterized by nitric oxide insufficiency by administering a therapeutically effective amount of at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated beta-adrenergic blocker, nitrosated cholesterol reducer, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist, nitrosated renin inhibitor, and optionally at least one compound used to treat cardiovascular diseases and/or at least one antioxidant, or a pharmaceutically acceptable salt thereof, and/or at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The antioxidant may preferably be a hydralazine compound or a pharmaceutically acceptable salt thereof. The compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase may preferably be isosorbide dinitrate and/or isosorbide mononitrate. The vascular diseases characterized by nitric oxide insufficiency include a cardiovascular disease and a disease resulting from oxidative stress.
摘要翻译：本发明提供治疗和/或预防以一氧化氮不足为特征的血管疾病的方法，其通过施用治疗有效量的至少一种亚硝化血管紧张素转换酶抑制剂，亚硝化β-肾上腺素能阻断剂，亚硝化胆固醇降低剂，亚硝化钙通道阻断剂，亚硝化内皮素拮抗剂，亚硝化血管紧张素II受体拮抗剂，亚硝化肾素抑制剂和任选的至少一种用于治疗心血管疾病的化合物，和/或至少一种抗氧化剂或其药学上可接受的盐，和/或至少一种可以转移的化合物或释放一氧化氮，提高内源性内源性舒张因子水平，刺激一氧化氮的内源性合成，或是一氧化氮合成酶的底物。抗氧化剂可优选为肼屈嗪化合物或其药学上可接受的盐。捐赠，转移或释放一氧化氮的化合物提高内源性内皮衍生的松弛因子水平，刺激一氧化氮的内源性合成，或者是一氧化氮合酶的底物可优选为硝酸异山梨酯和/或一硝酸异山梨酯。以一氧化氮不足为特征的血管疾病包括心血管疾病和由氧化应激引起的疾病。

20. 发明申请

US20100068267A1 COMPOSITIONS FOR TREATING VASCULAR DISEASES CHARACTERIZED BY NITRIC OXIDE INSUFFICIENCY 审中-公开
标题翻译：用于治疗由氮氧化物缺乏症表征的血管疾病的组合物
公开(公告)号：US20100068267A1
公开(公告)日：2010-03-18
申请号：US12564550
申请日：2009-09-22
申请人： Joseph LOSCALZO , Joseph A. VITA , Michael D. LOBERG , Manuel WORCEL
发明人： Joseph LOSCALZO , Joseph A. VITA , Michael D. LOBERG , Manuel WORCEL
IPC分类号： A61K9/54 , A61K9/26 , A61K9/14 , A61K31/502
CPC分类号： A61K31/135 , A61K9/0056 , A61K9/7023 , A61K31/19 , A61K31/34 , A61K31/355 , A61K31/415 , A61K31/495 , A61K31/50 , A61K31/535 , A61K45/06 , A61K2300/00
摘要： The invention provides methods of treating a cardiovascular disease comprising administering a sustained release formulation of hydralazine hydrochloride and at least one of isosorbide dinitrate and/or isosorbide mononitrate in therapeutically effective dosage of each of the aforementioned compounds.
摘要翻译：本发明提供治疗心血管疾病的方法，其包括给予盐酸肼屈嗪的缓释制剂和硝酸异山梨酯和/或一硝酸异山梨酯中的至少一种治疗有效剂量的每种上述化合物。

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