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1. 发明授权

US5523084A Enhancing the anti-tumor effect of melphalan by prior administration of L-amino acid oxidase with or without intermediate administration of anti-L-amino acid oxidase antibody 失效
标题翻译：通过事先给予L-氨基酸氧化酶，在或不加中间施用抗L-氨基酸氧化酶抗体的情况下，增强美法仑的抗肿瘤作用
公开(公告)号：US5523084A
公开(公告)日：1996-06-04
申请号：US301769
申请日：1994-09-07
申请人： Darell D. Bigner , Henry S. Friedman , Owen W. Griffith
发明人： Darell D. Bigner , Henry S. Friedman , Owen W. Griffith
IPC分类号： A61K38/44 , A61K37/48 , A61K31/195 , A61K37/50 , A61K39/395
CPC分类号： A61K38/44
摘要： L-amino acid oxidase is utilized to reduce plasma level of large neutral amino acids to allow the opportunity of increased melphalan transport into tumors and melphalan is administered when the plasma level of L-amino acid oxidase is sufficiently low so the gain from increased transport outweighs the loss from L-amino acid oxidase-mediated metabolism of melphalan. Preferably anti L-amino acid oxidase antibody is administered intermediate the L-amino acid oxidase and melphalan administrations to deplete L-amino acid oxidase activity once the L-amino acid oxidase has caused the melphalan transport improving plasma level reduction of large neutral amino acids thereby to reduce or eliminate degrading of melphalan by L-amino acid oxidase.
摘要翻译： L-氨基酸氧化酶被用于降低大中性氨基酸的血浆水平，以便当L-氨基酸氧化酶的血浆水平足够低时，给予美法仑输送到肿瘤中并且美法仑的机会被施用，因此增加运输的增益超过来自L-氨基酸氧化酶介导的美法仑代谢的损失。优选地，抗L-氨基酸氧化酶抗体在L-氨基酸氧化酶和美法仑给药之间施用，以在L-氨基酸氧化酶引起美法仑输送改善大中性氨基酸的血浆水平降低后消耗L-氨基酸氧化酶活性，从而通过L-氨基酸氧化酶降低或消除美法仑降解。

2. 发明授权

US5695751A Enhancing delivery of large neutral amino acid drugs 失效
标题翻译：加强大中性氨基酸药物的输送
公开(公告)号：US5695751A
公开(公告)日：1997-12-09
申请号：US531586
申请日：1995-09-21
申请人： Henry S. Friedman , Darell D. Bigner , Owen W. Griffith
发明人： Henry S. Friedman , Darell D. Bigner , Owen W. Griffith
IPC分类号： A61K38/44 , A61K31/195
CPC分类号： A61K38/44 , A61K31/198 , A61K31/221 , A61K39/3955 , A61K45/06 , C07K16/40 , C12Y104/03002 , A61K2039/545
摘要： L-amino acid oxidase is utilized to reduce the plasma level of large neutral amino acids to allow the opportunity of increased large neutral amino acid drug transport across the blood brain barrier. Preferably anti L-amino acid oxidase antibody is administered intermediate to the L-amino acid oxidase and large neutral amino acid drug administrations to deplete L-amino acid oxidase activity once the L-amino acid oxidase has caused the large neutral amino acid drug transport improving level plasma reduction of large neutral amino acids thereby to reduce or eliminate degrading of large neutral amino acid drugs by L-amino acid oxidase. The large neutral amino acid drugs include levodopa, melphalan, L-DON, azaserine, acivicin, L-alanosine and 3-(phosphonomethyl)phenylalanines. For treatment of brain tumors, the drug administration is preferably preceded by the administration of a large neutral amino acid glutathione depleting agent, e.g., L-buthionine-SR-sulfoximine. L-Amino acid oxidase is also utilized to enhance the transport of large neutral amino acid glutathione depleting agent across the blood brain barrier as an adjunct to radiation therapy of brain tumors.
摘要翻译：利用L-氨基酸氧化酶来降低大的中性氨基酸的血浆水平，以允许增加大的中性氨基酸药物在血脑屏障上的转运的机会。优选地，抗L-氨基酸氧化酶抗体在L-氨基酸氧化酶和大的中性氨基酸药物给药中间给药，以在L-氨基酸氧化酶引起大的中性氨基酸药物转运改善后消耗L-氨基酸氧化酶活性从而降低或消除大中性氨基酸药物由L-氨基酸氧化酶的降解。大的中性氨基酸药物包括左旋多巴，美法仑，L-DON，重氮丝氨酸，acivicin，L-脯氨酸和3-（膦酰基甲基）苯丙氨酸。为了治疗脑肿瘤，药物给药优选之前是施用大量中性氨基酸谷胱甘肽消耗剂，例如L-丁硫氨酸-SR-亚砜亚胺。 L-氨基酸氧化酶还用于增强大中性氨基酸谷胱甘肽消耗剂在血脑屏障上的转运，作为脑肿瘤放射治疗的辅助物质。

3. 发明授权

US5407672A Enhancing the anti-tumor effect of melphalan with L-amino acid oxidase 失效
标题翻译：增强美法仑与L-氨基酸氧化酶的抗肿瘤作用
公开(公告)号：US5407672A
公开(公告)日：1995-04-18
申请号：US46866
申请日：1993-04-08
申请人： Owen W. Griffith , Henry S. Friedman
发明人： Owen W. Griffith , Henry S. Friedman
IPC分类号： A61K38/44 , A61K37/50 , A61K31/195 , A61K37/48
CPC分类号： A61K38/44
摘要： L-amino acid oxidase is utilized to reduce plasma level of large neutral amino acids to allow the opportunity of increased melphalan transport into tumors and melphalan is administered when the plasma level of L-amino acid oxidase is sufficiently low so the gain from increased transport outweighs the loss from L-amino acid oxidase-mediated metabolism of melphalan.
摘要翻译： L-氨基酸氧化酶被用于降低大中性氨基酸的血浆水平，以便当L-氨基酸氧化酶的血浆水平足够低时，给予美法仑输送到肿瘤中并且美法仑的机会被施用，因此增加运输的增益超过来自L-氨基酸氧化酶介导的美法仑代谢的损失。

4. 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）。

5. 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。

6. 发明授权

US5663364A Heme binding compounds and use thereof 失效
标题翻译：血红素结合化合物及其用途
公开(公告)号：US5663364A
公开(公告)日：1997-09-02
申请号：US550645
申请日：1995-10-31
申请人： Owen W. Griffith , Krishnaswamy Narayanan
发明人： Owen W. Griffith , Krishnaswamy Narayanan
IPC分类号： C07D333/20 , A61K31/18 , A61K31/195 , A61K31/198 , A61P9/00 , A61P25/00 , A61P37/06 , A61P43/00 , C07C281/16 , C07C323/25 , C07C335/04 , C07C335/08 , C07D233/64 , C07D333/22 , C07D207/335
CPC分类号： C07C335/08 , C07D333/22
摘要： Inhibitors of nitric oxide formation from arginine useful for treating hypotension, inflammation, stroke and to restore vascular contractile sensitivity to the effects of .alpha..sub.1 adrenergic agonists are physiologically active compounds including N.sup..delta. -substituted ornithine or N.sup..epsilon. -substituted lysine moieties or monoalkyl carbon-substituted N.sup..delta. -substituted ornithine or N.sup..epsilon. -substituted lysine moieties, having the formula ##STR1## wherein R is (CH.sub.2).sub.y CH.sub.3 or H, R' is CH.sub.2 or C(H)(CH.sub.2).sub.y CH.sub.3, and R" is CH.sub.2 or C(H)(CH.sub.2).sub.y CH.sub.3, with y ranging from 0 to 5, and x is 0 or 1 and wherein none or only one of R, R' and R" provides an alkyl substituent on ornithine or lysine moiety, and wherein Q is a heme binding moiety and/or a sulfur-containing binding moiety and Q' is --NH.sub.2 when there is a double bond between the omega carbon and Q and Q' is .dbd.NH when there is a single bond between the omega carbon and Q, and physiologically acceptable acid addition salts thereof.
摘要翻译：用于治疗低血压，炎症，中风和恢复对α1肾上腺素能激动剂的作用的血管收缩敏感性的精氨酸形成一氧化氮的抑制剂是生理活性化合物，包括N-3取代的鸟氨酸或Nε-取代的赖氨酸部分或单烷基碳 - 其中R是（CH 2）y CH 3或H，R'是CH 2或C（H）（CH 2）y CH 3，R“是CH 2 或C（H）（CH 2）y CH 3，y在0至5之间，x是0或1，并且其中R，R'和R“中没有一个或只有一个在鸟氨酸或赖氨酸部分上提供烷基取代基，其中当ω-碳和Q之间存在双键时，Q是血红素结合部分和/或含硫结合部分，Q'是-NH 2，并且当ω碳之间存在单键时，Q'为= NH 和Q，及其生理上可接受的酸加成盐。

7. 发明授权

US5395612A Method for treating systemic hypotension caused by sepsis or cytokine using arginase in combination with an .alpha..sub.1 adrenergic agonist 失效
标题翻译：使用精氨酸酶与α1肾上腺素能激动剂组合治疗由败血症或细胞因子引起的全身性低血压的方法
公开(公告)号：US5395612A
公开(公告)日：1995-03-07
申请号：US814808
申请日：1991-12-31
申请人： Owen W. Griffith , Steven S. Gross , Roberto Levi
发明人： Owen W. Griffith , Steven S. Gross , Roberto Levi
IPC分类号： A61K38/50 , A61K38/46
CPC分类号： A61K38/50
摘要： Reducing plasma levels of endogenous arginine by parenteral administration of arginine depleting agent limits nitric oxide formation and results in blood pressure increase. Preferably arginase is administered intravenously to raise blood pressure. The arginine depleting agent can be administered in conjunction with arginine antagonists to potentiate the effect of these. The arginine depleting agent can be used concurrently with .alpha..sub.1 adrenergic agonists in treating systemic hypotension caused by induced production of nitric oxide, to restore vascular contractile sensitivity to the effect of the .alpha..sub.1 adrenergic agonists. Duration of action and avoidance of antigenicity may be obtained by use in conjunction with a carrier or modifier.
摘要翻译：通过肠外给药精氨酸消耗剂降低内源性精氨酸的血浆水平限制了一氧化氮的形成并导致血压升高。优选静脉内给予精氨酸酶以提高血压。精氨酸消耗剂可以与精氨酸拮抗剂一起施用以增强这些作用。精氨酸消耗剂可以与α1肾上腺素能激动剂同时使用，用于治疗由诱导的一氧化氮产生引起的全身性低血压，以恢复对α1肾上腺素能激动剂的作用的血管收缩敏感性。通过与载体或改性剂结合使用可以获得作用的持续时间和抗原性的避免。

8. 发明授权

US5273875A N.sup.6 -(hydrazinoiminomethyl)lysine and method of inhibiting nitric oxide formation in body 失效
标题翻译： N6-（肼基亚氨基甲基）赖氨酸和抑制体内一氧化氮形成的方法
公开(公告)号：US5273875A
公开(公告)日：1993-12-28
申请号：US865060
申请日：1992-04-08
申请人： Owen W. Griffith
发明人： Owen W. Griffith
IPC分类号： C07C281/16 , C12N5/00 , A01N1/02
CPC分类号： C07C281/16
摘要： Physiologically active N.sup.6 -(hydrazinoiminomethyl)lysine or pharmaceutically acceptable acid addition salt thereof is administered in a nitric oxide synthesis inhibiting amount to a subject in need of such inhibition (e.g., a subject with low blood pressure, e.g., due to sepsis or to therapeutic administration of cytokines, or needing immunosuppressive effect) or is added to a medium containing isolated organs, intact cells, cell homogenates or tissue homogenates in an amount sufficient to inhibit nitric oxide formation to elucide or control the biosynthesis, metabolism or physiological role of nitric oxide. CompThis invention was made at least in part with Government support under National Institutes of Health grant number DK 37116. The Government has certain rights in the invention.
摘要翻译：生理活性N6-（肼基亚氨基甲基）赖氨酸或其药学上可接受的酸加成盐以一氧化氮合成抑制量施用于需要这种抑制的受试者（例如，低血压受试者，例如由于败血症或治疗性或需要免疫抑制作用），或加入含有足以抑制一氧化氮形成以分离或控制一氧化氮的生物合成，代谢或生理作用的量的分离器官，完整细胞，细胞匀浆或组织匀浆的培养基。与已知的一氧化氮合成抑制剂相比，N6-（肼基亚氨基甲基）赖氨酸及其酸加成盐对一氧化氮合酶的诱导型异构体显示出比对一氧化氮合酶的组成型异构体更大的相对活性。 N6-（肼基亚氨基甲基）赖氨酸及其药学上可接受的酸加成盐的含量远低于NG-氨基精氨酸及其药学上可接受的酸加成盐。

9. 发明授权

US06359004B1 Manipulating nitrosative stress to upregulate nitrosative stress defenses 失效
标题翻译：控制亚硝化压力以上调亚硝酸胁迫防御
公开(公告)号：US06359004B1
公开(公告)日：2002-03-19
申请号：US09690989
申请日：2000-10-18
申请人： Jonathan S. Stamler , Owen W. Griffith
发明人： Jonathan S. Stamler , Owen W. Griffith
IPC分类号： A61K31195
CPC分类号： A61K31/00 , A61K31/195 , A61K31/255 , C07C381/10 , Y02A50/473
摘要： Mammals are treated for infections or for conditions associated with pathologically proliferating mammalian cell growth (for example, certain cancers, restenosis, benign prostatic hypertrophy) by administration of a manipulator of nitrosative stress to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells. Novel agents include &agr;-alkyl-S-alkyl-homocysteine sulfoximines wherein the &agr;-alkyl contains 2 to 8 carbon atoms, and the S-alkyl- contains 1 to 10 carbon atoms. In another invention herein, mammals in need of increased nitrosative stress defenses are treated, e.g., humans at risk for a stroke because of having had a transient ischemic attack, are treated. Treatments to increase nitrosative stress defenses include, for example, repeated administrations of low doses of manipulators of nitrosative stress so that the subject treated has increased tolerance to nitrosative stress. In still another invention, mammals are treated for protozoal infections by systemic administration of L-buthionine-S-sulfoximine and agent that increases nitrosative stress.
摘要翻译：哺乳动物通过施用亚硝化应激的机械手来治疗感染或与病理性增殖的哺乳动物细胞生长（例如某些癌症，再狭窄，良性前列腺肥大）相关的病症，以选择性地杀死或减少微生物或蠕虫的生长，从而导致感染或用微生物或病理增殖的哺乳动物细胞感染的宿主细胞。新型药剂包括α-烷基-S-烷基 - 高半胱氨酸亚砜，其中α-烷基含有2-8个碳原子，并且S-烷基含有1-10个碳原子。在本文的另一发明中，需要治疗需要增加的亚硝酸应激防御的哺乳动物被治疗，例如由于具有短暂性脑缺血发作而处于卒中风险的人。增加亚硝化应激防御的治疗包括例如重复施用低剂量的亚硝化应激的操纵者，使得所治疗的受试者具有增加的对亚硝化应激的耐受性。在另一个发明中，哺乳动物通过全身施用L-丁硫氨酸-S-亚磺酰亚胺和增加亚硝化压力的试剂来治疗原生动物感染。

10. 发明授权

US06180824B2 Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically, proliferating cells or to upregulate nitrosative stress defenses 有权
标题翻译：控制亚硝化压力以杀死病理微生物，病理性蠕虫和病理性增殖细胞或上调亚硝化应激防御
公开(公告)号：US06180824B2
公开(公告)日：2001-01-30
申请号：US09361167
申请日：1999-07-27
申请人： Jonathan S. Stamler , Owen W. Griffith
发明人： Jonathan S. Stamler , Owen W. Griffith
IPC分类号： C07C6108
CPC分类号： A61K31/00 , A61K31/195 , A61K31/255 , C07C381/10 , Y02A50/473
摘要： Mammals are treated for infection or for conditions associated with pathologically proliferating mammalian cell growth (for example, certain cancers, restenosis, benign prostatic hypertrophy) by administration of a manipulator of nitrosative stress to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells. Novel agents include &agr;-alkyl-S-alkyl-homocysteine sulfoximines wherein the &agr;-alkyl contains 2 to 8 carbon atoms, and the S-alkyl- contains 1 to 10 carbon atoms. In another invention herein, mammals in need of increased nitrosative stress defenses are treated, e.g., humans at risk for a stroke because of having had a transient ischemic attack, are treated. Treatments to increase nitrosative stress defenses include, for example, repeated administrations of low doses of manipulators of nitrosative stress so that the subject treated has increased tolerance to nitrosative stress. In still another invention, mammals are treated for protozoal infections by systemic administration of L-buthionine-S-sulfoximine and agent that increases nitrosative stress.
摘要翻译：哺乳动物通过施用亚硝化胁迫的操纵者来治疗感染或与病理增殖的哺乳动物细胞生长（例如某些癌症，再狭窄，良性前列腺肥大）相关的病症，以选择性地杀死或减少微生物或蠕虫的生长，从而导致感染或用微生物或病理增殖的哺乳动物细胞感染的宿主细胞。新型药剂包括α-烷基-S-烷基 - 高半胱氨酸亚砜，其中α-烷基含有2-8个碳原子，并且S-烷基含有1-10个碳原子。在本文的另一发明中，需要治疗需要增加的亚硝酸应激防御的哺乳动物被治疗，例如由于具有短暂性脑缺血发作而处于卒中风险的人。增加亚硝化应激防御的治疗包括例如重复施用低剂量的亚硝化应激的操纵者，使得所治疗的受试者具有增加的对亚硝化应激的耐受性。在另一个发明中，哺乳动物通过全身施用L-丁硫氨酸-S-亚磺酰亚胺和增加亚硝化压力的试剂来治疗原生动物感染。

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