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11. 发明授权

US5545625A Preventing conversion of citrulline to argininosuccinate to limit pathological nitric oxide overproduction 失效
标题翻译：防止瓜氨酸转化为精氨基琥珀酸盐以限制病理性一氧化氮过量产生
公开(公告)号：US5545625A
公开(公告)日：1996-08-13
申请号：US354585
申请日：1994-12-12
申请人： Steven S. Gross , Owen W. Griffith
发明人： Steven S. Gross , Owen W. Griffith
IPC分类号： A61K31/00 , A61K31/198 , A61K45/06 , C07C275/16 , A61K31/70 , A61K31/195
CPC分类号： A61K31/704 , A61K31/00 , A61K31/198 , A61K45/06 , C07C275/16 , Y10S514/93
摘要： Administration of argininosuccinate synthetase activity reducing agents, e.g., argininosuccinate synthetase induction blocking agents (e.g., antibiotics that bind to DNA sequences present in the upstream regulatory region of the argininosuccinate synthetase gene, such as mithramycin) and argininosuccinate synthetase inhibitors (e.g., L-citrulline antagonists such as methyl citrulline and L-aspartate antagonists such as D-aspartate) is useful to prevent or treat sepsis or cytokine-induced systemic hypotension, is useful in the treatment of sepsis or cytokine-induced systemic hypotension to restore vascular sensitivity to the effects of .alpha..sub.1 -adrenergic agonists, and is useful to suppress an immune response, e.g., in treating inflammation. In one embodiment, certain argininosuccinate synthetase activity reducing agents are used together with arginine antagonists to treat sepsis or cytokine induced hypotension.
摘要翻译：精氨基琥珀酸合成酶活性降低剂的施用，例如精氨基琥珀酸合成酶诱导阻断剂（例如，结合存在于精氨基琥珀酸合成酶基因的上游调节区域中的DNA序列的抗生素，例如霉素霉素）和精氨基琥珀酸合成酶抑制剂（例如L-瓜氨酸拮抗剂如瓜氨酸甲酯和L-天冬氨酸拮抗剂如D-天冬氨酸）可用于预防或治疗败血症或细胞因子诱导的全身性低血压，可用于治疗败血症或细胞因子诱导的全身性低血压以恢复对效应的血管敏感性的α1-肾上腺素能激动剂，并且可用于抑制免疫应答，例如治疗炎症。在一个实施方案中，某些精氨基琥珀酸合成酶活性降低剂与精氨酸拮抗剂一起用于治疗败血症或细胞因子诱导的低血压。

12. 发明授权

US06231894B1 Treatments based on discovery that nitric oxide synthase is a paraquat diaphorase 有权
标题翻译：基于发现一氧化氮合酶是百草枯心肌黄酶的治疗
公开(公告)号：US06231894B1
公开(公告)日：2001-05-15
申请号：US09421942
申请日：1999-10-21
申请人： Jonathan S. Stamler , Brian J. Day , Steven S. Gross , Owen W. Griffith
发明人： Jonathan S. Stamler , Brian J. Day , Steven S. Gross , Owen W. Griffith
IPC分类号： A61K3300
CPC分类号： A61K31/44 , A61K31/00 , A61K31/223 , A61K31/4425 , A61K31/444 , A61K31/4985 , A61K33/00 , A61K31/22 , A61K2300/00
摘要： Paraquat has been found to accept electrons from nitric oxide synthase (NOS) whereupon the reduced paraquat generates toxic O2− and prevents NOS from giving electrons to arginine and thereby inhibits NO production. This is generalized for compounds with a redox potential greater than nitric oxide synthase. The compounds inhibit nitric oxide synthase and kill cells including NOS by generating O2− and also by depriving the cells of the NO which they need. Applications include treating paraquat-induced injury and pathologically proliferating cells (tumors, restenosis benign prostatic hypertrophy, pulmonary hypertension, infective pathogens).
摘要翻译：已经发现百草枯接受来自一氧化氮合酶（NOS）的电子，随后还原的百草枯产生有毒的O 2 - 并且防止NOS向精氨酸发电，从而抑制NO产生。这对于具有大于一氧化氮合酶的氧化还原电位的化合物是普遍的。该化合物通过产生O2-抑制一氧化氮合酶并杀死包括NOS的细胞，并且还通过剥夺其所需的NO的细胞。应用包括处理百草枯诱导的损伤和病理增殖细胞（肿瘤，再狭窄良性前列腺肥大，肺动脉高压，感染性病原体）。

13. 发明授权

US06784178B2 Pharmacotherapy for vascular dysfunction associated with deficient nitric oxide bioactivity 失效
标题翻译：与一氧化氮缺乏生物活性相关的血管功能障碍的药物治疗
公开(公告)号：US06784178B2
公开(公告)日：2004-08-31
申请号：US10240729
申请日：2002-10-09
申请人： Steven S. Gross , Caroline L. Jones
发明人： Steven S. Gross , Caroline L. Jones
IPC分类号： A61K3150
CPC分类号： A61K31/44 , A61K31/155 , A61K31/198 , A61K31/445 , A61K31/495 , A61K31/505 , A61K31/519 , A61K31/525 , A61K31/70 , A61K2300/00
摘要： A patient with a disorder involving endothelial dysfunction associated with deficient nitric oxide bioactivity, e.g., coronary artery disease, atherosclerosis, hypertension, diabetes or neurodegenerative condition stemming from ischemia and/or inflammation, is treated by administering nitric oxide bioactivity increasing hydroxyguanidine.
摘要翻译：通过施用增加羟基胍的一氧化氮生物活性来治疗患有与缺血性一氧化氮生物活性相关的内皮功能障碍的病症，例如冠状动脉疾病，动脉粥样硬化，高血压，糖尿病或由缺血和/或炎症引起的神经变性病症。

14. 发明授权

US5877176A Blocking induction of tetrahydrobiopterin to block induction of nitric oxide synthesis 失效
标题翻译：四氢生物喋呤的阻断诱导阻断一氧化氮合成的诱导
公开(公告)号：US5877176A
公开(公告)日：1999-03-02
申请号：US151889
申请日：1993-11-15
申请人： Steven S. Gross
发明人： Steven S. Gross
IPC分类号： A61K45/00 , A61K31/135 , A61K31/165 , A61K31/195 , A61K31/198 , A61K31/40 , A61K31/4045 , A61K31/405 , A61K31/495 , A61K31/505 , A61K31/513 , A61K31/519 , A61K45/06 , A61P9/00 , A61P9/02 , A61P17/00 , A61P19/02 , A61P29/00 , A61P37/00
CPC分类号： A61K45/06 , A61K31/165 , A61K31/198 , A61K31/40 , A61K31/4045 , A61K31/405 , A61K31/495 , A61K31/505 , A61K31/513 , A61K31/519
摘要： Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonists are administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylactic or curative effect for endotoxin- or cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension). The tetrahydrobiopterin synthesis antagonist may be administered with .alpha..sub.1 -adrenergic agonist or with nitric oxide synthase inhibitor. The tetrahydrobiopterin synthesis antagonists are also administered to attenuate inflammation caused by induced nitric oxide production in immune cells. Unwanted counterproductive or side effects can be eliminated or ameliorated by administration additionally of levodopa with or without carbidopa and L-5-hydroxytryptophane.
摘要翻译：给予鸟苷三磷酸途径四氢生物喋呤合成拮抗剂和/或蝶呤补救途径四氢生物喋呤合成拮抗剂以抑制需要这种抑制的受试者的血管细胞中精氨酸的一氧化氮合成（例如，对于内毒素或细胞因子诱导的预防或治疗作用低血压或恢复对加压剂的血管收缩敏感性，以治疗这种低血压）。四氢生物喋呤合成拮抗剂可与α1-肾上腺素能激动剂或一氧化氮合酶抑制剂一起施用。还给予四氢生物喋呤合成拮抗剂以减轻由免疫细胞中诱导的一氧化氮产生引起的炎症。通过另外施用具有或不含卡比多巴和L-5-羟色氨酸的左旋多巴可以消除或改善不利的副作用或改善。

15. 发明授权

US5502050A Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis 失效
公开(公告)号：US5502050A
公开(公告)日：1996-03-26
申请号：US158829
申请日：1993-11-29
申请人： Steven S. Gross
发明人： Steven S. Gross
IPC分类号： C07D211/70 , A61K31/44 , A61K31/4409 , A61K31/4418 , A61K31/4425 , A61K45/00 , A61P9/02 , A61P43/00 , C07D213/46 , A61K31/54 , A61K31/495 , A61K31/525
CPC分类号： A61K31/44
摘要： Inhibitor of the use of tetrahydrobiopterin as a cofactor for nitric oxide synthase, e.g., substituted 4-phenyl(hydropyridines) such as 1-methyl-4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine or, 4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine) or tetrahydropterin analog which does not replace tetrahydrobiopterin as a substrate for nitric oxide synthase such as (6R,S)-6,7-dimethyl-tetrahydropterin or (6R,S)-tetrahydrofolic acid or 2,4-diamino-, 2,6-diamino, or 4,6-diamino mono- or disubstituted pyrimidines or the corresponding pyrimidine-3-oxides such as 2,4-diamino-6-(diethylamino)pyrimidine, 2,4-diamino-6-piperidino-pyrimidine-3-oxide, 2,4-diamino-6-hydroxypyrimidine, 4,6-diamino-2-hydroxypyrimidine or 2,5-diamino-4,6-dihydroxypyrimidine is administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylaxis or treatment of cytokine- or endotoxin-induced hypotension (e.g., septic shock). The latter two types are advantageously administered with nitric oxide synthase inhibitors (concurrent therapy) or to potentiate the effect of .alpha..sub.1 -adrenergic agonists in the prophylaxis or treatment of induced hypotension.

16. 发明授权

US06274581B1 Blocking induction of tetrahydrobiopterin to block induction of nitric oxide synthesis 失效
标题翻译：四氢生物喋呤的阻断诱导阻断一氧化氮合成的诱导
公开(公告)号：US06274581B1
公开(公告)日：2001-08-14
申请号：US08063067
申请日：1993-05-20
申请人： Steven S. Gross
发明人： Steven S. Gross
IPC分类号： A61K31495
CPC分类号： A61K31/519 , A61K31/40 , A61K31/4045 , A61K31/405 , A61K31/495 , A61K31/505 , A61K31/513 , A61K2300/00
摘要： Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonist are administered to inhibit nitric oxide synthesis from arginine in vascular smooth muscle cells in a subject in need of such inhibition (e.g. for prophylactic or curative effect for cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension).
摘要翻译：给予鸟苷三磷酸途径四氢生物喋呤合成拮抗剂和/或蝶呤补救途径四氢生物喋呤合成拮抗剂以抑制需要这种抑制的受试者的血管平滑肌细胞中精氨酸的一氧化氮合成（例如用于细胞因子诱导的低血压的预防或治疗作用用于恢复对加压剂的血管收缩敏感性，用于治疗这种低血压）。

17. 发明授权

US5880124A Blocking induction of tetrahydrobiopterin to block induction of nitric oxide synthesis 失效
公开(公告)号：US5880124A
公开(公告)日：1999-03-09
申请号：US642883
申请日：1996-05-06
申请人： Steven S. Gross
发明人： Steven S. Gross
IPC分类号： A61K45/00 , A61K31/135 , A61K31/165 , A61K31/195 , A61K31/198 , A61K31/40 , A61K31/4045 , A61K31/405 , A61K31/495 , A61K31/505 , A61K31/513 , A61K31/519 , A61K45/06 , A61P9/00 , A61P9/02 , A61P17/00 , A61P19/02 , A61P29/00 , A61P37/00 , A61K31/50
CPC分类号： A61K45/06 , A61K31/165 , A61K31/198 , A61K31/40 , A61K31/4045 , A61K31/405 , A61K31/495 , A61K31/505 , A61K31/513 , A61K31/519
摘要： Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonists are administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylactic or curative effect for endotoxin- or cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension). The tetrahydrobiopterin synthesis antagonist may be administered with .alpha..sub.1 -adrenergic agonist or with nitric oxide synthase inhibitor. The tetrahydrobiopterin synthesis antagonists are also administered to attenuate inflammation caused by induced nitric oxide production in immune cells. Unwanted counterproductive or side effects can be eliminated or ameliorated by administration additionally of levodopa with or without carbidopa and L-5-hydroxytryptophane.

18. 发明授权

US6153615A Blocking induction of tetrahydrobioterin to block induction of nitric oxide synthesis 有权
标题翻译：阻断四氢生物素诱导阻断一氧化氮合成的诱导
公开(公告)号：US6153615A
公开(公告)日：2000-11-28
申请号：US228977
申请日：1999-01-12
申请人： Steven S. Gross
发明人： Steven S. Gross
IPC分类号： A61K45/00 , A61K31/135 , A61K31/165 , A61K31/195 , A61K31/198 , A61K31/40 , A61K31/4045 , A61K31/405 , A61K31/495 , A61K31/505 , A61K31/513 , A61K31/519 , A61K45/06 , A61P9/00 , A61P9/02 , A61P17/00 , A61P19/02 , A61P29/00 , A61P37/00
CPC分类号： A61K45/06 , A61K31/165 , A61K31/198 , A61K31/40 , A61K31/4045 , A61K31/405 , A61K31/495 , A61K31/505 , A61K31/513 , A61K31/519
摘要： Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonists are administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylactic or curative effect for endotoxin- or cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension). The tetrahydrobiopterin synthesis antagonist may be administered with .alpha..sub.1 -adrenergic agonist or with nitric oxide synthase inhibitor. The tetrahydrobiopterin synthesis antagonists are also administered to attenuate inflammation caused by induced nitric oxide production in immune cells. Unwanted counterproductive or side effects can be eliminated or ameliorated by administration additionally of levodopa with or without carbidopa and L-5-hydroxytryptophane.
摘要翻译：给予鸟苷三磷酸途径四氢生物喋呤合成拮抗剂和/或蝶呤补救途径四氢生物喋呤合成拮抗剂以抑制需要这种抑制的受试者的血管细胞中精氨酸的一氧化氮合成（例如，对于内毒素或细胞因子诱导的预防或治疗作用低血压或恢复对加压剂的血管收缩敏感性，以治疗这种低血压）。四氢生物喋呤合成拮抗剂可与α1-肾上腺素能激动剂或一氧化氮合酶抑制剂一起施用。还给予四氢生物喋呤合成拮抗剂以减轻由免疫细胞中诱导的一氧化氮产生引起的炎症。通过另外施用具有或不含卡比多巴和L-5-羟色氨酸的左旋多巴可以消除或改善不利的副作用或改善。

19. 发明授权

US5874433A Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis 失效
标题翻译：四氢生物喋呤的阻断利用阻断一氧化氮合成的诱导
公开(公告)号：US5874433A
公开(公告)日：1999-02-23
申请号：US574654
申请日：1995-12-19
申请人： Steven S. Gross
发明人： Steven S. Gross
IPC分类号： C07D211/70 , A61K31/44 , A61K31/4409 , A61K31/4418 , A61K31/4425 , A61K45/00 , A61P9/02 , A61P43/00 , C07D213/46 , A01N43/66 , A61K31/495 , A61K31/53
CPC分类号： A61K31/44
摘要： Inhibitor of the use of tetrahydrobiopterin as a cofactor for nitric oxide synthase, e.g., substituted 4-phenyl(hydropyridines) such as 1-methyl-4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine or, 4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine) or tetrahydropterin analog which does not replace tetrahydrobiopterin as a substrate for nitric oxide synthase such as (6R,S)-6,7-dimethyl-tetrahydropterin or (6R,S)-tetrahydrofolic acid or 2,4-diamino-, 2,6-diamino, or 4,6-diamino mono- or disubstituted pyrimidines or the corresponding pyrimidine-3-oxides such as 2,4-diamino-6-(diethylamino)pyrimidine, 2,4-diamino-6-piperidino-pyrimidine-3-oxide, 2,4-diamino-6-hydroxypyrimidine, 4,6-diamino-2-hydroxypyrimidine or 2,5-diamino-4,6-dihydroxypyrimidine is administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylaxis or treatment of cytokine- or endotoxin-induced hypotension (e.g., septic shock). The latter two types are advantageously administered with nitric oxide synthase inhibitors (concurrent therapy) or to potentiate the effect of .alpha..sub.1 -adrenergic agonists in the prophylaxis or treatment of induced hypotension.
摘要翻译：使用四氢生物喋呤作为一氧化氮合成酶的辅因子的抑制剂，例如取代的4-苯基（氢吡啶）如1-甲基-4-（3'，4'-二羟基苯基）-1,2,3,6-四氢吡啶或者不代替四氢生物蝶呤作为一氧化氮合成酶如（6R，S）-6,7的底物的4-（3'，4'-二羟基苯基）-1,2,3,6-四氢吡啶）或四氢蝶呤类似物（6R，S） - 四氢叶酸或2,4-二氨基 - ，2,6-二氨基或4,6-二氨基单或二取代嘧啶或相应的嘧啶-3-氧化物如2， 4-二氨基-6-（二乙基氨基）嘧啶，2,4-二氨基-6-哌啶子基 - 嘧啶-3-氧化物，2,4-二氨基-6-羟基嘧啶，4,6-二氨基-2-羟基嘧啶或2,5- 施用二氨基-4,6-二羟基嘧啶以抑制需要这种抑制的受试者的血管细胞中的精氨酸的一氧化氮合成（例如，用于预防或治疗细胞因子或内毒素诱发的低血压（例如败血性休克）。后者tw o类型有利地与一氧化氮合酶抑制剂（并发治疗）一起施用或增强α1-肾上腺素能激动剂在预防或治疗诱导性低血压中的作用。

20. 发明授权

US06967219B2 Reversing or preventing premature vascular senescence 有权
标题翻译：逆转或预防血管老化过早
公开(公告)号：US06967219B2
公开(公告)日：2005-11-22
申请号：US10268106
申请日：2002-10-10
申请人： Steven S. Gross , Michael S. Goligorsky
发明人： Steven S. Gross , Michael S. Goligorsky
IPC分类号： A61K31/155 , A61K31/195
CPC分类号： A61K31/155
摘要： Premature vascular senescence is reversed or prevented in tissue or cells by contacting the tissue or cells with a hydroxyguanidine. This finds application in treatment of patients with a disorder associated with elevated levels of advanced glycation end products in blood or tissue, e.g., patients with end stage renal disease or poorly controlled diabetes, and in contacting vascular tissue or cells ex vivo to prevent occurrence of premature senescence.
摘要翻译：早期血管衰老在组织或细胞中通过使组织或细胞与羟基胍接触来逆转或预防。这可用于治疗与血液或组织中高级糖基化终产物水平升高相关的疾病的患者，例如终末期肾病或控制不良的糖尿病患者，以及离体接触血管组织或细胞以预防发生过早衰老

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