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1. 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。

2. 发明授权

US5312835A Use of cardiotonic drugs and inhibitors of nitric oxide synthesis to alleviate pathologic hypotension 失效
标题翻译：使用强心药物和一氧化氮合成抑制剂缓解病理性低血压
公开(公告)号：US5312835A
公开(公告)日：1994-05-17
申请号：US890430
申请日：1992-05-29
申请人： Robert G. Kilbourn , Steven S. Gross , Owen W. Griffith
发明人： Robert G. Kilbourn , Steven S. Gross , Owen W. Griffith
IPC分类号： C07D401/04 , A61K31/135 , A61K31/195 , A61K31/198 , A61K31/223 , A61K31/44 , A61K31/4427 , A61P3/00 , A61P9/02 , A61P9/04
CPC分类号： A61K31/195 , A61K31/198 , A61K31/223 , A61K31/44 , Y10S514/93
摘要： The present invention involves a method for prophylaxis or treatment of an animal for systemic hypotension induced by endotoxin and/or a biological response modifier such as the cytokines, IFN, TNF, IL-1 or IL-2 and the like. Said method involves administering, preferably intravascularly, a therapeutically effective amount of dobutamine and an inhibitor of nitric oxide formation from arginine. Although preferable administration is intravascular, it is contemplated that other parenteral administration routes such as intraperitoneal, intramuscular or subdermal injection, for example, may prove useful. Enteral or topical administration of arginine analogs may also prove beneficial under certain clinical conditions.
摘要翻译：本发明涉及一种预防或治疗由内毒素和/或生物反应调节剂如细胞因子，IFN，TNF，IL-1或IL-2等引起的全身性低血压的动物的方法。所述方法包括优选血管内施用治疗有效量的多巴酚丁胺和从精氨酸形成一氧化氮的抑制剂。虽然优选的给药是血管内的，但可以设想，例如腹膜内，肌肉内或皮下注射的其它肠胃外给药途径可证明是有用的。精氨酸类似物的肠内或局部给药在某些临床条件下也可能是有益的。

3. 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。

4. 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。

5. 发明授权

US5770623A Argine antagonists for inhibition of systemic hypotension associated with nitric oxide production or endothelial derived relaxing factor 失效
标题翻译：用于抑制与一氧化氮产生或内皮衍生的松弛因子相关的全身性低血压的Argine拮抗剂
公开(公告)号：US5770623A
公开(公告)日：1998-06-23
申请号：US561717
申请日：1995-11-22
申请人： Robert G. Kilbourn , Steven S. Gross , Roberto Levi , Owen W. Griffith
发明人： Robert G. Kilbourn , Steven S. Gross , Roberto Levi , Owen W. Griffith
IPC分类号： A61K31/195 , A61K31/198 , A61K31/223 , A61K31/44
CPC分类号： A61K31/223 , A61K31/195 , A61K31/198 , A61K31/44 , Y10S514/93
摘要： A method for prophylaxis or treatment of an animal for systemic hypotension induced by internal nitrogen oxide production. The method involves administering a therapeutically effective amount of certain arginine derivatives to inhibit nitrogen oxide formation from arginine. Preferably N.sup.G -substituted arginine or an N.sup.G,N.sup.G -disubstituted arginine (having at least one hydrogen on a terminal guanidino amino group replaced by another atomic species) is administered to an animal possibly developing or already having such induced systemic hypotension. The arginine derivatives are preferably of the L configuration and include pharmaceutically acceptable addition salts. Prophylaxis or treatment of systemic hypotension in a patient which has been induced by chemotherapeutic treatment with biologic response modifiers such as tumor necrosis factor or interleukin-2 may be accomplished. Treatment of an animal for systemic hypotension induced by endotoxin, i.e., septic shock may also be accomplished by treatment with the arginine derivatives.
摘要翻译：一种用于预防或治疗由内部氮氧化物产生引起的全身性低血压的动物的方法。该方法包括施用治疗有效量的某些精氨酸衍生物以抑制由精氨酸形成的氮氧化物。优选将NG取代的精氨酸或NG，NG-二取代的精氨酸（在末端胍基氨基上具有至少一个氢被另一种原子物质取代）给予可能发展或已经具有这种诱发的全身性低血压的动物。精氨酸衍生物优选为L构型，并且包括药学上可接受的加成盐。可以通过生物反应调节剂如肿瘤坏死因子或白细胞介素-2进行化学治疗诱导的患者中预防或治疗全身性低血压。由内毒素引起的系统性低血压的治疗，即败血性休克也可以通过用精氨酸衍生物进行治疗来实现。

6. 发明授权

US5334380A Anti-endotoxin, interleukin-1 receptor antagonist and anti-tumor necrosis factor antibody with arginine-free formulations for the treatment of hypotension 失效
标题翻译：抗内毒素，白细胞介素-1受体拮抗剂和抗肿瘤坏死因子抗体与无精氨酸制剂治疗低血压
公开(公告)号：US5334380A
公开(公告)日：1994-08-02
申请号：US910868
申请日：1992-06-30
申请人： Robert G. Kilbourn , Owen W. Griffith , Steven S. Gross
发明人： Robert G. Kilbourn , Owen W. Griffith , Steven S. Gross
IPC分类号： A61K31/415 , A61K31/715 , A61K38/04 , A61K38/19 , A61K37/02 , A61K37/04 , A61K37/18
CPC分类号： A61K31/415 , A61K31/715 , A61K38/20 , A61K39/395
摘要： Methods and compositions for treating and inhibiting hypotension related to both endotoxin and cytokine-induced shock are provided. A therapeutic regimen useful in the present invention includes an arginine-free parenteral formulation administered with or followed by the administration of an anti-endotoxin antibody, an interleukin-1 or interleukin-2 receptor antagonist, an anti-tumor necrosis factor antibody or a combination thereof. Most preferably, the administration of an arginine-free parenteral formulation augments the anti-hypotensive effect of the various antibodies and antagonist described so as to provide an effective treatment for various forms of hypotension. The therapeutic regimens of the invention are proposed to provide for a decrease in nitric oxide synthase, and thereby an increase in blood pressure in vivo, particularly in animals with cytokine- and/or endotoxin-induced hypotension. The parenteral formulation of the therapeutic regimen and methods of the invention are arginine-free and provide a decrease in plasma arginine levels. Reduced plasma, serum, or tissue levels of arginine in the animal function to augment the hypertensive action of the various antibodies and antagonist to be administered concurrently or subsequent to the administration of the parenteral formulation. Limiting and/or eliminating substrate arginine for nitric oxide synthesis, coupled with limiting and/or eliminating induction of nitric oxide synthase activity with the antibodies and antagonists of the present invention, provides a regimen for treating and/or inhibiting hypotension attendant a variety of conditions and treatments, including chemotherapeutic agent therapy (IFN, TNF, IL-1, IL-2), septic shock, trauma, exposure to endotoxins or cytokines, or other conditions in which hypotension is attendant.
摘要翻译：提供了治疗和抑制与内毒素和细胞因子诱导的休克有关的低血压的方法和组合物。用于本发明的治疗方案包括给予或随后施用抗内毒素抗体，白细胞介素-1或白细胞介素-2受体拮抗剂，抗肿瘤坏死因子抗体或组合的无精氨酸胃肠外制剂其中。最优选地，施用不含精氨酸的肠胃外制剂增加了所描述的各种抗体和拮抗剂的抗低血压作用，以便为各种形式的低血压提供有效的治疗。本发明的治疗方案被提出用于减少一氧化氮合酶，从而提高体内血压，特别是在具有细胞因子和/或内毒素诱导的低血压的动物中。本发明的治疗方案和方法的肠胃外制剂是无精氨酸的并且提供血浆精氨酸水平的降低。在动物功能中降低精氨酸的血浆，血清或组织水平，以增加在肠胃外制剂的同时或之后施用的各种抗体和拮抗剂的高血压作用。限制和/或消除用于一氧化氮合成的底物精氨酸，加上限制和/或消除与本发明的抗体和拮抗剂的一氧化氮合成酶活性的诱导，提供了治疗和/或抑制伴有多种病症的低血压的方案和治疗方法，包括化疗药物治疗（IFN，TNF，IL-1，IL-2），脓毒性休克，创伤，暴露于内毒素或细胞因子，或其他伴有低血压的病症。

7. 发明授权

US5286739A Parenteral formulations for the inhibition of systemic hypotension associated with nitric oxide production or endothelial derived relaxing factor 失效
标题翻译：用于抑制与一氧化氮产生或内皮衍生的松弛因子相关的全身性低血压的肠胃外制剂
公开(公告)号：US5286739A
公开(公告)日：1994-02-15
申请号：US767265
申请日：1991-09-27
申请人： Robert G. Kilbourn , Owen W. Griffith , Steven S. Gross
发明人： Robert G. Kilbourn , Owen W. Griffith , Steven S. Gross
IPC分类号： A61K31/415 , A61K31/715 , A61K38/04 , A61K38/19 , A61K31/195
CPC分类号： A61K31/715 , A61K31/415 , Y10S514/921 , Y10S514/929
摘要： An anti-hypotensive formulation comprising an essentially arginine-free or low arginine (less than about 0.1%, most preferably, about 0.01%) containing mixture of amino acids is provided. The invention in particular embodiments of the anti-hypotensive formulation includes ornithine, citrulline or both. A method for prophylaxis and treatment of systemic hypotension in an animal is provided. Most particularly, a method for treating hypotension caused by nitric oxide synthesis through administering a low or essentially arginine-free parenteral formulation to an animal, so as to reduce or eliminate nitric oxide synthesis is described. A method for treating an animal in septic shock is also disclosed, comprising administering to the animal an anti-hypotensive formulation comprising a mixture of amino acids, which is essentially arginine free. Prophylaxis or treatment of systemic hypotension, particularly that hypotension incident to chemotherapeutic treatment with biologic response modifiers, such as tumor necrosis factor or interleukin-1 or -2, may be accomplished through the administration of the defined anti-hypotensive formulations until physiologically acceptable systolic blood pressure levels are achieved in the animal. Treatment of an animal for septic shock induced by endotoxin may also be accomplished by administering to the animal the arginine-free formulations described.
摘要翻译：提供包含基本上不含精氨酸或低精氨酸（小于约0.1％，最优选约0.01％）的包含氨基酸混合物的抗低血压制剂。本发明在抗低血压制剂的具体实施方案中包括鸟氨酸，瓜氨酸或两者。提供了一种预防和治疗动物体内低血压的方法。最特别地，描述了一种通过向动物施用低或基本上不含精氨酸的肠胃外制剂以治疗由一氧化氮合成引起的低血压以减少或消除一氧化氮合成的方法。还公开了一种用于治疗脓毒性休克的动物的方法，包括向动物施用包含基本上不含精氨酸的氨基酸混合物的抗低血压制剂。预防或治疗全身性低血压，特别是生物反应调节剂如肿瘤坏死因子或白细胞介素-1或-2的化学治疗引起的低血压可以通过给予定义的抗低血压制剂直至生理学上可接受的收缩血在动物体内实现压力水平。内毒素引起的脓毒性休克动物的治疗也可以通过向动物施用所述的不含精氨酸的制剂来实现。

8. 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。

9. 发明授权

US5723448A Preventing conversion of citrulline to argininosuccinate to limit pathological nitric oxide overproduction 失效
公开(公告)号：US5723448A
公开(公告)日：1998-03-03
申请号：US618810
申请日：1996-03-20
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 , C07C241/00
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.

10. 发明授权

US5534545A Parenteral amino acid formulations for the inhibition of systemic hypotension associated with nitric oxide production 失效
标题翻译：用于抑制与一氧化氮产生相关的全身低血压的肠胃外氨基酸制剂
公开(公告)号：US5534545A
公开(公告)日：1996-07-09
申请号：US152050
申请日：1993-11-12
申请人： Robert G. Kilbourn , Owen W. Griffith , Steven S. Gross
发明人： Robert G. Kilbourn , Owen W. Griffith , Steven S. Gross
IPC分类号： A61K31/415 , A61K31/715 , A61K38/04 , A61K38/19 , A61K31/195 , A61K31/385 , A61K31/40
CPC分类号： A61K31/715 , A61K31/415 , Y10S514/921 , Y10S514/929
摘要： An anti-hypotensive formulation comprising an essentially arginine-free or low arginine (less than about 0.1%, most preferably, about 0.01%) containing mixture of amino acids is provided. The invention in particular embodiments of the anti-hypotensive formulation includes ornithine, citrulline or both. A method for prophylaxis and treatment of systemic hypotension in an animal is provided. Most particularly, a method for treating hypotension caused by nitric oxide synthesis through administering a low or essentially arginine-free parenteral formulation to an animal, so as to reduce or eliminate nitric oxide synthesis is described. A method for treating an animal in septic shock is also disclosed, comprising administering to the animal an anti-hypotensive formulation comprising a mixture of amino acids, which is essentially arginine free.
摘要翻译：提供包含基本上不含精氨酸或低精氨酸（小于约0.1％，最优选约0.01％）的包含氨基酸混合物的抗低血压制剂。本发明在抗低血压制剂的具体实施方案中包括鸟氨酸，瓜氨酸或两者。提供了一种预防和治疗动物体内低血压的方法。最特别地，描述了一种通过向动物施用低或基本上不含精氨酸的肠胃外制剂以治疗由一氧化氮合成引起的低血压以减少或消除一氧化氮合成的方法。还公开了一种用于治疗脓毒性休克的动物的方法，包括向动物施用包含基本上不含精氨酸的氨基酸混合物的抗低血压制剂。

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