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1. 发明授权

US08372414B2 Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications 有权
标题翻译：治疗窘迫功能障碍并增强特定药物安全性和疗效的方法和组合物
公开(公告)号：US08372414B2
公开(公告)日：2013-02-12
申请号：US13460467
申请日：2012-04-30
申请人： Steven Crain , William E. Crain , Stanley M. Crain , Michael Crain
发明人： Steven Crain , William E. Crain , Stanley M. Crain , Michael Crain
IPC分类号： A61K9/00
CPC分类号： A61K31/485 , A61K31/10 , A61K31/138 , A61K31/167 , A61K31/198 , A61K31/4015 , A61K31/437 , A61K31/439 , A61K31/44 , A61K31/46 , A61K31/522 , A61K31/60 , A61K33/06 , A61K36/16 , A61K36/76 , A61K36/77 , A61K45/06 , A61K2300/00
摘要： The present invention relates to methods and compositions for reducing distress dysfunction, including emotional and physical distress. The invention entails co-administration of at least one Receptor Switcher and at least one Endorphin Enhancer. Additionally, at least one Synergistic Enhance and/or at least one Exogenous Opioid are also administered to enhance or prolong the therapeutic effects.
摘要翻译：本发明涉及用于减少遇难功能障碍的方法和组合物，包括情绪和身体的痛苦。本发明需要共同给予至少一种受体切换器和至少一种内啡肽增强剂。此外，还施用至少一种协同增强和/或至少一种外源性阿片样物质以增强或延长治疗效果。

2. 发明授权

US08202525B2 Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications 失效
标题翻译：治疗窘迫功能障碍并增强特定药物安全性和疗效的方法和组合物
公开(公告)号：US08202525B2
公开(公告)日：2012-06-19
申请号：US12973839
申请日：2010-12-20
申请人： Steven Crain , William E. Crain , Stanley M. Crain , Michael Crain
发明人： Steven Crain , William E. Crain , Stanley M. Crain , Michael Crain
IPC分类号： A61K9/00 , A61K38/00
CPC分类号： A61K31/485 , A61K31/10 , A61K31/138 , A61K31/167 , A61K31/198 , A61K31/4015 , A61K31/437 , A61K31/439 , A61K31/44 , A61K31/46 , A61K31/522 , A61K31/60 , A61K33/06 , A61K36/16 , A61K36/76 , A61K36/77 , A61K45/06 , A61K2300/00
摘要： The present invention relates to methods and compositions for reducing distress dysfunction, including emotional and physical distress. The invention entails co-administration of at least one Receptor Switcher and at least one Endorphin Enhancer. Additionally, at least one Synergistic Enhancer and/or at least one Exogenous Opioid are also administered to enhance or prolong the therapeutic effects.
摘要翻译：本发明涉及用于减少遇难功能障碍的方法和组合物，包括情绪和身体的痛苦。本发明需要共同给予至少一种受体切换器和至少一种内啡肽增强剂。此外，还施用至少一种协同增强剂和/或至少一种外源性阿片样物质以增强或延长治疗效果。

3. 发明申请

US20110159048A1 METHODS AND COMPOSITIONS FOR TREATING DISTRESS DYSFUNCTION AND ENHANCING SAFETY AND EFFICACY OF SPECIFIC MEDICATIONS 失效
公开(公告)号：US20110159048A1
公开(公告)日：2011-06-30
申请号：US12973839
申请日：2010-12-20
申请人： Steven Crain , William E. Crain , Stanley M. Crain , Michael Crain
发明人： Steven Crain , William E. Crain , Stanley M. Crain , Michael Crain
IPC分类号： A61K33/06 , A61K31/522 , A61K31/60 , A61K31/439 , A61K31/44 , A61K9/00 , A61P25/00 , A61P15/10 , A61P1/00 , A61P11/00 , B82Y5/00
CPC分类号： A61K31/485 , A61K31/10 , A61K31/138 , A61K31/167 , A61K31/198 , A61K31/4015 , A61K31/437 , A61K31/439 , A61K31/44 , A61K31/46 , A61K31/522 , A61K31/60 , A61K33/06 , A61K36/16 , A61K36/76 , A61K36/77 , A61K45/06 , A61K2300/00
摘要： The present invention relates to methods and compositions for reducing Distress Dysfunction by restoring and maintaining homeostatic balance in the neurotransmitter systems underlying the Stress Response and the experience of distress and hedonic tone. Distress Dysfunction refers to the experience of dysfunctional emotional and physical distress that interferes with the individual's quality of life and functioning. A novel understanding of the bimodal opioid modulation of pain, and its impact, through serotonergic, dopaminergic, epinephrinergic, and norepinephrinergic processes, on hedonic tone, leads directly to new generation pharmaceutical formulations that are remarkably safe and effective for the treatment of a wide variety of Distress Dysfunctions, including anxiety, depression, anger, insomnia, mood disorders, eating disorders, sexual problems, pain, substance and behavioral addictions, gastrointestinal disorders, autistic spectrum disorders, attention-deficit and hyperactivity disorders, and other emotional and physical distress disorders. The foundation of this discovery is the power of Receptor Switchers, such as ultra-low-dose and very-low-dose opioid antagonists and GM1 ganglioside attenuators, in blocking acute and protracted excitatory opioid receptor signaling. Co-administration of Receptor Switchers with Endorphin Enhancers, such as specific cAMP PDE inhibitors and excitatory amino acids, is an excellent formulation for restoring healthy homeostatic balance to the endogenous opioid system, using the body's endorphins to reduce emotional and physical distress, and through synergistic and homeostatic processes, restoring positive hedonic tone. The addition of Synergistic Enhancers, such as amino acids, SSRI and SNRI agents, and non-opioid analgesics, as well as Exogenous Opioids, enhances and prolongs these therapeutic benefits. The novel principles discovered by this invention also teach a new generation of safe and effective formulations for the treatment of respiratory conditions, neuropathy, and nociceptive pain.

4. 发明申请

US20100203084A1 METHOD FOR TREATING PAIN OR OPIOID DEPENDENCE USING A SPECIFIC TYPE OF NON-OPIOID AGENT IN COMBINATION WITH A SELECTIVE EXCITATORY-OPIOID-RECEPTOR INACTIVATOR 审中-公开
标题翻译：使用特定类型的非阿片类药物与选择性激素受体激动剂组合治疗疼痛或阿片依赖性的方法
公开(公告)号：US20100203084A1
公开(公告)日：2010-08-12
申请号：US12312164
申请日：2007-10-12
申请人： Stanley M. Crain , Ke-Fei Shen
发明人： Stanley M. Crain , Ke-Fei Shen
IPC分类号： A61K39/106 , A61K31/195 , A61K31/40 , A61K31/522 , A61K31/352 , A61K31/485 , A61K31/215 , A61K31/35 , A61K33/06 , A61K33/04 , A61P29/00
CPC分类号： A61K31/198 , A61K31/4015 , A61K45/06 , Y02A50/471 , A61K2300/00
摘要： The present invention provides a method for treating pain in a subject in need of treatment, by administering to the subject a non-opioid agent in combination with a selective excitatory-opioid-receptor inactivator, in amounts effective to treat pain in the subject. Also disclosed is a method for treating opioid-withdrawal effects in a subject in need of treatment, by the administration to the subject of a non-opioid agent in combination with a selective excitatory-opioid-receptor inactivator, in amounts effective to treat opioid-withdrawal effects in the subject. Finally, the present invention provides a pharmaceutical composition comprising a non-opioid agent and a selective excitatory-opioid-receptor inactivator, and a pharmaceutically-acceptable carrier.
摘要翻译：本发明提供一种治疗需要治疗的受试者的疼痛的方法，通过以有效治疗受试者的疼痛的量向受试者施用非阿片类药物与选择性兴奋性 - 阿片受体灭活剂组合。还公开了一种治疗需要治疗的受试者中的阿片样物质戒断作用的方法，其通过与选择性兴奋性 - 阿片样物质 - 受体灭活剂组合使用非阿片样物质的受试者，以有效治疗阿片样物质 - 退学效果的主题。最后，本发明提供包含非阿片样物质和选择性兴奋性 - 阿片受体灭活剂的药物组合物和药学上可接受的载体。

5. 发明申请

US20100015147A1 Methods for increasing analgesic potency and attenuating adverse excitatory effects of bimodally-acting opioid agonists by inhibiting GM1-ganglioside 审中-公开
标题翻译：通过抑制GM1神经节苷脂增加镇痛效力和减轻双模作用阿片激动剂的不利兴奋作用的方法
公开(公告)号：US20100015147A1
公开(公告)日：2010-01-21
申请号：US12586518
申请日：2009-09-23
申请人： Stanley M. Crain , Ke-Fei Shen
发明人： Stanley M. Crain , Ke-Fei Shen
IPC分类号： A61K39/395 , A61K31/485 , A61K33/04
CPC分类号： A61K33/00 , A61K31/00 , A61K31/215 , A61K38/33 , A61K2039/505 , A61K2300/00
摘要： The present invention provides a method for increasing analgesic potency of a bimodally-acting opioid agonist in a subject, by inhibiting GM1-ganglioside in nociceptive neurons. The present invention further provides a method for treating pain in a subject in need of treatment thereof. Also provided in the present invention is a method for treating chronic pain in a subject in need of treatment thereof. Additionally, the present invention provides a method for treating tolerance to or an addiction to a bimodally-acting opioid agonist in a subject in need of treatment thereof. Finally, the present invention provides a pharmaceutical composition of analgesic agents and a pharmaceutically-acceptable carrier.
摘要翻译：本发明提供一种通过抑制伤害感受神经元中的GM1-神经节苷脂来增加受试者中双模型作用的阿片样物质激动剂的镇痛效力的方法。本发明还提供了治疗需要治疗的受试者的疼痛的方法。本发明还提供了治疗需要治疗的受试者的慢性疼痛的方法。另外，本发明提供了治疗需要治疗的受试者对双峰作用的阿片样物质激动剂的耐受性或成瘾性的方法。最后，本发明提供了止痛剂和药学上可接受的载体的药物组合物。

6. 发明授权

US06765010B2 Compositions and methods for enhancing analgesic potency of tramadol and attenuating its adverse side effects 失效
标题翻译：用于增强曲马多镇痛效力并减弱其不良副作用的组合物和方法
公开(公告)号：US06765010B2
公开(公告)日：2004-07-20
申请号：US10095802
申请日：2002-03-12
申请人： Stanley M. Crain , Ke-Fei Shen , Barry Sherman , Mary Remien , Remi Barbier , Nadav Friedmann
发明人： Stanley M. Crain , Ke-Fei Shen , Barry Sherman , Mary Remien , Remi Barbier , Nadav Friedmann
IPC分类号： A61R3114
CPC分类号： A61K31/135 , A61K9/2018 , A61K9/2054 , A61K9/4858 , A61K9/4866 , A61K9/5042 , A61K9/5084 , A61K31/00 , A61K31/445 , A61K31/455 , A61K31/485 , A61K2300/00
摘要： The invention generally relates to compositions and methods with tramadol and an opioid antagonist to enhance analgesic potency and/or attenuate one or more adverse effects of tramadol, including adverse side effect(s) in humans such as nausea, vomiting, dizziness, headache, sedation (somnolence) or pruritis. This invention relates to compositions and methods for selectively enhancing the analgesic potency of tramadol and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of tramadol. The methods of the present invention comprise administering to a subject an analgesic or subanalgesic amount of tramadol and an amount of excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of tramadol and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of tramadol.
摘要翻译：本发明一般涉及具有曲马多和阿片样物质拮抗剂以增强止痛效力和/或减弱曲马多的一种或多种副作用的组合物和方法，包括人类的不良副作用，例如恶心，呕吐，头晕，头痛，镇静（嗜睡）或瘙痒症。本发明涉及用于选择性增强曲马多镇痛效力的组合物和方法，并且同时减轻与施用曲马多相关的抗镇痛，痛觉过敏，过度兴奋，身体依赖和/或耐受性作用。本发明的方法包括对受试者施用止痛剂或亚麻痛剂量的曲马多和一定量的兴奋性阿片样物质受体拮抗剂如纳曲酮或纳美芬，其有效地增强曲马多的镇痛效力并减弱镇痛，痛觉过敏，兴奋性过高，曲马多的身体依赖和/或耐受性影响。

7. 再颁专利

USRE36547E Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists 失效
标题翻译：同时增强镇痛效力和减轻由外源性和内源性阿片样物质激动剂引起的依赖责任的方法
公开(公告)号：USRE36547E
公开(公告)日：2000-02-01
申请号：US782452
申请日：1996-01-13
申请人： Stanley M. Crain , Ke-Fei Shen
发明人： Stanley M. Crain , Ke-Fei Shen
IPC分类号： A61K31/00 , A61K31/485 , A61K38/33 , G01N33/94 , A61K31/14
CPC分类号： G01N33/9486 , A61K31/00 , A61K31/485 , A61K38/33 , G01N33/94 , G01N2500/10
摘要： This invention relates to a method of selectively enhancing the analgesic potency of morphine and other clinically used bimodally-acting opioid agonists and simultaneously attenuating development of physical dependence, tolerance and other undesirable side effects caused by the chronic administration of said bimodally-acting opioid agonists comprising the co-administration of a bimodally-acting opioid agonist which activates both inhibitory and excitatory opioid receptor-mediated functions of neurons in the nociceptive (pain) pathways of the nervous system and an opioid receptor antagonist which selectively inactivates excitatory opioid receptor-mediated side effects. This invention also relates to a method of using excitatory opioid receptor antagonists alone to block the undesirable excitatory side effects of endogenous bimodally-acting opioid agonists which may be markedly elevated during chronic pain. This invention further relates to a method of long-term treatment of previously detoxified opiate, cocaine and alcohol addicts utilizing said excitatory opioid receptor antagonists, either alone or in combination with low-dose methadone, to prevent protracted physical dependence, and to compositions comprising an excitatory opioid receptor antagonist of the invention and a bimodally-acting opioid agonist.
摘要翻译：本发明涉及选择性增强吗啡和其它临床使用的双峰作用阿片样物质激动剂的止痛效力的方法，同时减轻由慢性施用所述双模型作用的阿片样物质激动剂引起的物理依赖性，耐受性和其它不良副作用的发展，包括共同施用双功能阿片样物质激动剂，其激活神经系统的伤害感受（疼痛）途径中的神经元的抑制性和兴奋性阿片受体介导的功能，以及选择性地使兴奋性阿片受体介导的副作用失活的阿片受体拮抗剂。本发明还涉及一种单独使用兴奋性阿片样物质受体拮抗剂来阻断内源性双重作用的阿片样物质激动剂的不期望的兴奋性副作用的方法，其在慢性疼痛中可能显着升高。本发明还涉及一种利用所述兴奋性阿片受体拮抗剂单独或与低剂量美沙酮组合来长期治疗先前解毒的阿片剂，可卡因和酒精成瘾者的方法，以防止持久的物理依赖性，以及包含本发明的兴奋性阿片受体拮抗剂和双峰作用的阿片样物质激动剂。

8. 发明授权

US06395705B2 Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists 失效
标题翻译：使用低剂量的阿片受体拮抗剂治疗肠易激综合征的方法和组合物
公开(公告)号：US06395705B2
公开(公告)日：2002-05-28
申请号：US09754840
申请日：2001-01-04
申请人： Stanley M. Crain , Ke-fei Shen , Gerald M. Fleischner
发明人： Stanley M. Crain , Ke-fei Shen , Gerald M. Fleischner
IPC分类号： A61K3800
CPC分类号： A61K31/485 , A61K31/00
摘要： This invention relates to a method for treating a subject with irritable bowel syndrome (“IBS”) which comprises long-term administration of an opioid receptor antagonist at an appropriately low dose which will selectively antagonize excitatory opioid receptor functions, but not inhibitory opioid receptor functions, in myenteric neurons in the intestinal tract as well as in neurons of the central nervous system (“CNS”). The administration of the opioid receptor antagonist at a low dose enhances the potency of the inhibitory effects of endogenous opioid peptides present in the intestinal tract and the CNS, thereby reducing abdominal pain and stool frequency resulting from abnormally supersensitized excitatory opioid receptor functions. The invention also relates to a composition for treating a subject with IBS, which comprises an effective dose of an opioid receptor antagonist, and a pharmaceutically acceptable carrier.
摘要翻译：本发明涉及用于治疗肠易激综合征（“IBS”）的受试者的方法，其包括以适当低剂量长期施用阿片受体拮抗剂，其将选择性拮抗兴奋性阿片受体功能，但不抑制阿片受体功能，在肠道的肠系膜神经元以及中枢神经系统的神经元（“CNS”）中。以低剂量施用阿片样物质受体拮抗剂增强了存在于肠道和CNS中的内源性阿片样物质肽的抑制作用的效力，从而降低了由异常超敏刺激性阿片受体功能引起的腹痛和大便频率。本发明还涉及用IBS治疗受试者的组合物，其包含有效剂量的阿片受体拮抗剂和药学上可接受的载体。

9. 发明授权

US06194382B1 Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists 失效
标题翻译：使用低剂量的阿片受体拮抗剂治疗肠易激综合征的方法和组合物
公开(公告)号：US06194382B1
公开(公告)日：2001-02-27
申请号：US09261361
申请日：1999-03-03
申请人： Stanley M. Crain , Ke-fei Shen , Gerald M. Fleischner
发明人： Stanley M. Crain , Ke-fei Shen , Gerald M. Fleischner
IPC分类号： A61K3800
CPC分类号： A61K31/485 , A61K31/00
摘要： This invention relates to a method for eating a subject with irritable bowel syndrome (“IBS”) which comprises long-term administration of an opioid receptor antagonist at an appropriately low dose which will selectively antagonize excitatory opioid receptor functions, but not inhibitory opioid receptor functions, in myenteric neurons in the intestinal tract as well as in neurons of the central nervous system (“CNS”). The administration of the opioid receptor antagonist at a low dose enhances the potency of the inhibitory effects of endogenous opioid peptides present in the intestinal tract and the CNS, thereby reducing abdominal pain and stool frequency resulting from abnormally supersensitized excitatory opioid receptor functions. The invention also relates to a composition for treating a subject with IBS, which comprises an effective dose of an opioid receptor antagonist, and a pharmaceutically acceptable carrier.
摘要翻译：本发明涉及一种吃肠易激综合征（“IBS”）的方法，其包括以适当低剂量长期施用阿片样物质受体拮抗剂，其将选择性拮抗兴奋性阿片受体功能，但不抑制阿片受体功能，在肠道的肠系膜神经元以及中枢神经系统的神经元（“CNS”）中。以低剂量施用阿片样物质受体拮抗剂增强了存在于肠道和CNS中的内源性阿片样物质肽的抑制作用的效力，从而降低了由异常超敏刺激性阿片受体功能引起的腹痛和大便频率。本发明还涉及用IBS治疗受试者的组合物，其包含有效剂量的阿片受体拮抗剂和药学上可接受的载体。

10. 发明授权

US5580876A Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists 失效
公开(公告)号：US5580876A
公开(公告)日：1996-12-03
申请号：US552296
申请日：1995-11-03
申请人： Stanley M. Crain , Ke-fei Shen
发明人： Stanley M. Crain , Ke-fei Shen
IPC分类号： A61K31/00 , A61K31/485 , A61K38/33 , G01N33/94
CPC分类号： A61K31/00 , A61K31/137 , A61K31/485 , A61K38/33 , G01N33/94 , G01N33/9486 , G01N2500/10 , Y10S514/811 , Y10S514/812
摘要： This invention relates to a method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist such as morphine and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist. The method of the present invention comprises administering to a subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist such as morphine and an amount of an excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist.

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