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1. 发明授权

US5028627A Method of using arginine derivatives to inhibit systemic hypotension associated with nitric oxide production or endothelial derived relaxing factor 失效
标题翻译：使用精氨酸衍生物抑制与一氧化氮产生或内皮衍生松弛因子相关的全身性低血压的方法
公开(公告)号：US5028627A
公开(公告)日：1991-07-02
申请号：US406909
申请日：1989-09-13
申请人： Robert G. Kilbourn , Steven Gross , Roberto Levi , Owen W. Griffith
发明人： Robert G. Kilbourn , Steven Gross , Roberto Levi , Owen W. Griffith
IPC分类号： A61K31/00 , A61K31/195 , A61K31/198 , A61K31/223 , A61K38/00 , A61K38/21 , A61K45/00 , A61P9/02 , A61P43/00
CPC分类号： A61K31/00 , A61K31/195 , A61K31/198 , A61K31/223 , Y10S514/93
摘要： A method for prophylaxis of 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. Preferaby 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 induced systemic hypotension. The arginine derivatives are preferably of the L configuration and include pharmaceutically acceptable addition salts. Prophylaxis or treatment or 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：一种用于预防由内部氮氧化物产生引起的全身性低血压的动物治疗的方法。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NG取代的精氨酸或NG，NG-二取代精氨酸（在由另一种原子物质取代的末端胍基氨基上具有至少一个氢）向可能发展或已经具有诱导的全身性低血压的动物施用。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。可以通过用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的预防或治疗或全身性低血压。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。

2. 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。

3. 发明授权

US5374651A Methods and compositions for the treatment of hypotension with arginine free essential and essential amino acids and arginine derivatives 失效
标题翻译：用精氨酸免费的必需和必需氨基酸和非精氨酸衍生物治疗低血压的方法和组合物
公开(公告)号：US5374651A
公开(公告)日：1994-12-20
申请号：US902653
申请日：1992-06-23
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： A61K31/415 , A61K31/715
摘要： Methods and compositions for treating and inhibiting hypotension are provided. A therapeutic regimen useful in the present invention includes an arginine-free parenteral formulation administered concurrently with or followed by an arginine analog. The combination therapy provides an augmentation of the anti-hypotensive effect found by the present inventors with arginine analogs, such as N.sup..omega. -methyl-L-arginine, N.sup..omega. -amino-L-arginine or N.sup..omega. -nitro-L-arginine. These arginine analogs, otherwise described as nitric oxide synthase inhibitors, provide for a decrease in nitric oxide concentrations, and are demonstrated to elicit 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 and tissue levels of arginine in the animal function to augment the hypertensive action of arginine analogs to be administered concurrently or subsequent to administration of the parenteral formulation. This method provides a regiment for treating and/or inhibiting hypotension attendant a variety of conditions, including chemotherapeutic agent therapy (i.e., IFN, TNF), septic shock, trauma, exposure to endotoxins or cytokines, or other condition in which hypotension is attendant. The arginine-free formulations may also include ornithine, citrulline, or both.
摘要翻译：提供了治疗和抑制低血压的方法和组合物。用于本发明的治疗方案包括与精氨酸类似物同时或跟随精氨酸的肠胃外制剂。联合治疗提供本发明人发现的精氨酸类似物如Nω-甲基-L-精氨酸，Nω-氨基-L-精氨酸或N-ω-硝基-L-精氨酸的抗低血压作用的增加。这些精氨酸类似物，另外被描述为一氧化氮合酶抑制剂，提供一氧化氮浓度的降低，并被证明在体内引起血压升高，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和组织水平，以增加在肠胃外制剂的施用同时或之后施用的精氨酸类似物的高血压作用。该方法提供了治疗和/或抑制伴有多种病症的化合物治疗和/或抑制低血压的方法，包括化疗药物治疗（即IFN，TNF），败血性休克，外伤，暴露于内毒素或细胞因子，或其他伴有低血压的病症。不含精氨酸的制剂还可包括鸟氨酸，瓜氨酸或两者。

4. 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。

5. 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。

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

US5776979A Method of 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的方法
公开(公告)号：US5776979A
公开(公告)日：1998-07-07
申请号：US338591
申请日：1995-03-31
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. The method involves administering, preferably intravascularly, a therapeutically effective amount of dobutamine and an inhibitor of nitric oxide formation from arginine.
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。该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。

9. 发明授权

US5216025A Nitric oxide synthesis inhibitors for potentiating the action of pressor agents in certain hypotensive patients 失效
标题翻译：一氧化氮合成抑制剂用于增强某些低血压患者的加压剂的作用
公开(公告)号：US5216025A
公开(公告)日：1993-06-01
申请号：US723480
申请日：1991-07-01
申请人： Steven S. Gross , Robert G. Kilbourn , Roberto Levi
发明人： Steven S. Gross , Robert G. Kilbourn , Roberto Levi
IPC分类号： A61K31/13 , A61K31/195 , A61K31/198 , A61K31/223 , A61K38/04 , A61K38/19 , A61K38/20 , A61K38/21 , A61K45/06 , A61P9/02
CPC分类号： A61K38/085 , A61K31/195 , A61K31/198 , A61K31/223 , A61K45/06 , Y10S514/93
摘要： A method for treatment of an animal for systemic hypotension induced by internal nitric oxide production caused by endotoxin or cytokines. The method involves administering an .alpha..sub.1 adrenergic agonist and an amount of an inhibitor of nitric oxide formation from argiResearch relating to the development of this invention was supported by the United States Public Health Service grants which gives the United States government certain rights to use of the present invention.
摘要翻译：由内毒素或细胞因子引起的内部一氧化氮产生诱导的全身性低血压动物的治疗方法。该方法包括从精氨酸施用α1肾上腺素能激动剂和一定量的一氧化氮形成抑制剂以恢复对α1肾上腺素能激动剂的血管收缩敏感性。一氧化氮形成的优选抑制剂是在胍基氨基上具有至少一个氢原子的NG取代的精氨酸，其被另一个原子或分子物质替代，包括NG-氨基精氨酸，NG-硝基精氨酸和NG-烷基精氨酸如NG-甲基精氨酸， NG-乙精氨酸，NG-丙精氨酸和NG-精氨酸。精氨酸衍生物抑制剂优选为L构型，并且包括药学上可接受的加成盐。用生物反应调节剂如肿瘤坏死因子或白细胞介素-2进行化疗诱导的患者的系统性低血压的治疗可以同样完成。治疗由内毒素或其他细菌毒素（例如败血性休克）引起的全身性低血压的动物也可以通过用α1肾上腺素能激动剂和抑制剂如精氨酸衍生物进行治疗来实现，其恢复对α1肾上腺素能的血管收缩敏感性激动剂。

10. 发明授权

US5480866A Hemoproteins for inhibition of nitric oxide-mediated hypotension and septic shock 失效
标题翻译：用于抑制一氧化氮介导的低血压和败血性休克的血液蛋白
公开(公告)号：US5480866A
公开(公告)日：1996-01-02
申请号：US184637
申请日：1994-01-18
申请人： Joseph Bonaventura , Joseph DeAngelo , Robert G. Kilbourn
发明人： Joseph Bonaventura , Joseph DeAngelo , Robert G. Kilbourn
IPC分类号： A61K38/16 , A61K38/42 , A61P9/00 , A61P9/12
CPC分类号： A61K38/42
摘要： The invention is directed to a method for the prophylaxis or treatment of an animal for deleterious physiological effects such as systemic hypotension caused by nitric oxide production induced by a biological response modifier. Examples of such biological response modifiers include but are not limited to a cytokine and an endotoxin. The invention is also directed to a method for the treatment of septic shock. Hemoproteins such as hemoglobin, myoglobin, hemalbumin and methemalbumin, for example, are useful when administered to a hypotensive patient.
摘要翻译：本发明涉及一种用于预防或治疗由生物反应调节剂引起的一氧化氮产生引起的全身性低血压的有害生理作用的动物的方法。这种生物反应调节剂的实例包括但不限于细胞因子和内毒素。本发明还涉及一种治疗败血性休克的方法。例如血红蛋白，肌红蛋白，白蛋白和白蛋白等血液蛋白在给予低血压患者时是有用的。

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