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Targeting the relief of chronic pain with orally active peroxynitrite decompositi

通过口服活性过氧亚硝酸盐分解物缓解慢性疼痛

基本信息

批准号：
7943926
负责人：
William Neumann
金额：
$ 47.4万
依托单位：
SOUTHERN ILLINOIS UNIV AT EDWARDSVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943926
关键词：
Acute Address Adjuvant Arthritis Adverse effects American Analgesics Animal Model Anti-Inflammatory Agents Anti-inflammatory Area Arthritis Atherosclerosis Bioavailable Biological Assay Biological Availability Cellular Membrane Charge Chemicals Chronic Disease Chronic inflammatory pain Clinic Complex Complex Regional Pain Syndromes Development Diabetes Mellitus Disease Drug Kinetics Drug usage Edema Enzymes Epithelial Equilibrium Follow-Up Studies Goals Health Hyperalgesia In Vitro Inflammation Inflammation Mediators Inflammatory Intestines Ionophores Ions Lipid Bilayers Manganese Measurement Membrane Metalloporphyrins Metals Methotrexate Modeling Morphine Nociception Oral Pain Parkinson Disease Partition Coefficient Pathway interactions Patients Penetration Permeability Peroxonitrite Pharmaceutical Preparations Property Prostaglandins Quality of life Rattus Regimen Relative (related person)Research Resistance Rheumatoid Arthritis Series Solubility Steroids Stress Structure-Activity Relationship Superoxide Dismutase Surface Synthesis Chemistry System Testing Therapeutic Intervention Translating Transmembrane Transport Treatment Protocols Variant analog base catalyst chronic pain cost cytokine design dosage economic impact effective therapy follow-up in vivo inflammatory pain inhibitor/antagonist lipophilicity mimetics multidisciplinary neurotoxic novel passive transport patient population prototype public health relevance scaffold small molecule

项目摘要

DESCRIPTION (provided by applicant): One third of Americans suffer from some form of chronic pain, (30% being resistant to analgesic therapy), making it a significant health problem with serious economic impact (estimated cost of approximately $100 billion annually). Chronic pain associated with complex regional pain syndromes is particularly difficult to manage. Chronic pain associated with inflammatory diseases such as rheumatoid arthritis is often difficult to treat in the clinic due to insufficient understanding of the nociceptive pathways involved. Current drug regimens are marginally effective and often display unacceptable side effects. Over the past decade, our multidisciplinary team has produced experimental results which clearly implicate the overproduction of peroxynitrite as a key mediator of inflammatory and chronic pain states in addition to the development of morphine-induced hyperalgesia and antinociceptive tolerance. Thus, the direct scavenging of this neurotoxic entity by small molecule drugs which act in enzyme-like catalytic fashion provides an unconventional approach to a completely novel analgesic strategy. The overriding goal is a broadly effective treatment for chronic pain associated with inflammatory diseases. Thus, a series of metal-charge-shielded metalloporphyrin and porphyrinoids with membrane penetration properties will be synthesized and screened as peroxynitrite decomposition catalysts. Pharmacokinetic and bioavailability studies will follow. Chemical entities displaying the highest catalytic activity with drug like properties will then be tested for analgesic efficacy and potency in 2 well established animal models of inflammation and arthritis While the main focus our research objective is in the transition of acute to chronic pain and therapeutic intervention to alleviate the chronic pain state, successful identification of orally active peroxynitrite decomposition catalysts will address numerous chronic disease states known to be driven by nitroxidative stress including diabetes, atherosclerosis and Parkinson's disease thus having major impact upon the quality of life for these patient populations. We have also shown that prototype catalysts act in a highly synergistic manner with subtherapeutic levels of selective COXII inhibitors, non-selective COX-I inhibitors, steroids, and methotrexate. Thus, through this approach we may be able to greatly lower the dosages of these important drugs for effective treatment of pain without or with greatly diminished side- effects. PUBLIC HEALTH RELEVANCE: The currently used drug regimens for the treatment of chronic pain associated with inflammatory diseases and arthritis, which encompass a number of varied mechanisms of action, are marginally effective and often display unacceptable side effects. Thus, a broadly effective treatment for chronic pain based upon the catalytic decomposition of the key neurotoxic species, peroxynitrite, would have wide-ranging beneficial effects for patients. In addition, the identification of orally active peroxynitrite decomposition catalysts will address numerous chronic disease states known to be driven by nitroxidative stress including diabetes, atherosclerosis and Parkinson's disease thus having major impact upon the quality of life for these patient populations.

描述（由申请人提供）：三分之一的美国人患有某种形式的慢性疼痛（30%对镇痛治疗有抵抗力），使其成为具有严重经济影响的重大健康问题（估计每年花费约1000亿美元）。与复杂区域疼痛综合征相关的慢性疼痛特别难以管理。与炎性疾病如类风湿性关节炎相关的慢性疼痛通常难以在临床上治疗，这是由于对所涉及的伤害性通路的理解不足。目前的药物治疗方案效果不佳，而且经常显示出不可接受的副作用。在过去的十年中，我们的多学科团队已经产生了实验结果，这些结果清楚地表明，除了吗啡诱导的痛觉过敏和抗伤害性耐受的发展之外，过氧亚硝酸盐的过度产生也是炎症和慢性疼痛状态的关键介质。因此，通过以酶样催化方式起作用的小分子药物直接清除这种神经毒性实体提供了一种全新镇痛策略的非常规方法。压倒一切的目标是广泛有效地治疗与炎症性疾病相关的慢性疼痛。因此，我们将合成并筛选一系列具有膜穿透性能的金属电荷屏蔽金属卟啉和卟啉类化合物作为过氧亚硝酸根分解催化剂。随后将进行药代动力学和生物利用度研究。然后，将在2种建立良好的炎症和关节炎动物模型中测试显示出具有药物样性质的最高催化活性的化学实体的镇痛功效和效力。虽然我们的研究目标的主要焦点是急性疼痛向慢性疼痛的过渡和缓解慢性疼痛状态的治疗干预，口服活性过氧亚硝酸盐分解催化剂的成功鉴定将解决已知由硝基氧化应激驱动的许多慢性疾病状态，动脉粥样硬化和帕金森病，因此对这些患者群体的生活质量具有重大影响。我们还表明，原型催化剂与亚治疗水平的选择性COXII抑制剂、非选择性COX-I抑制剂、类固醇和甲氨蝶呤以高度协同的方式起作用。因此，通过这种方法，我们可能能够大大降低这些重要药物的剂量，以有效治疗疼痛，而没有或大大减少副作用。公共卫生相关性：目前用于治疗与炎性疾病和关节炎相关的慢性疼痛的药物方案包括许多不同的作用机制，其效果不佳，并且经常显示出不可接受的副作用。因此，基于关键神经毒性物质过氧亚硝酸盐的催化分解的广泛有效的慢性疼痛治疗将对患者产生广泛的有益影响。此外，口服活性过氧亚硝酸盐分解催化剂的鉴定将解决已知由硝基氧化应激驱动的许多慢性疾病状态，包括糖尿病、动脉粥样硬化和帕金森病，因此对这些患者群体的生活质量具有重大影响。