Blood-to-CNS Drug Uptake in Pain/Rheumatoid Arthritis

疼痛/类风湿关节炎中血液至中枢神经系统的药物摄取

• 批准号: 7190580
• 负责人: THOMAS Paul DAVIS
• 金额: $ 32.82万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-05 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7190580
• 关键词: ABCC1 gene; Actins; Acute; Acute Pain; Affect; Alkaline Phosphatase; American; Amino Acid Substitution; Analgesics; Animals; Anions; Area; Arthralgia; Arthritis; Biochemical; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Carrier Proteins; Cellular Structures; Cerebrovascular Circulation; Cerebrum; Characteristics; Chemicals; Child; Chronic; Chronic Disease; Codeine; Condition; Confocal Microscopy; Cytoskeletal Proteins; D-Phe-Cys-Tyr-D-Trp-Arg-Pen-Thr-NH2; Data; Diffusion; Disease; Drug Delivery Systems; Drug Efflux; Drug Kinetics; Drug Transport; Drug usage; Elderly; Endothelial Cells; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Enzyme-Linked Immunosorbent Assay; Ethylene Glycols; FOS gene; Goals; Hour; Immunoblotting; In Situ; Income; Indomethacin; Inflammation; Inflammatory; Investigation; Joints; Knee joint; Laboratories; Lead; Mediator of activation protein; Medical; Messenger RNA; Methodology; Methods; Methotrexate; Modeling; Modification; Molecular; Molecular Structure; Morphine; Multidrug Resistance Gene; Multidrug Resistance-Associated Proteins; Musculoskeletal; Neutral Amino Acids; Numbers; OATP Transporters; Opioid; Opioid Analgesics; Opioid Peptide; P-Glycoprotein; P-Glycoproteins; Pain; Patients; Penicillamine; Peptides; Perfusion; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phosphorylation; Prodrugs; Productivity; Proteins; RNase protection assay; Radioactive Tracers; Rattus; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Route; Serum; Signal Transduction; Stereoisomer; Sucrose; Symptoms; System; Testing; Therapeutic; Tight Junctions; Time; Tissues; Toxic effect; Western Blotting; Woman; biphalin; capillary; clinically relevant; connective tissue-activating peptide; copolymer; cost; cytokine; day; ethylene glycol; glycosylation; halogenation; improved; intracellular protein transport; men; occludin; programs; protein localization location; transcription factor; uptake

DESCRIPTION (provided by applicant): RHEUMATOID ARTHRITIS (RA) is a chronic disease that affects two to three million Americans and is three times more prevalent in women than in men. While RA typically occurs in people twenty to fifty years old, children and the elderly can also develop RA. Every year, $65 billion is spent on medical costs, lost income, and lost productivity for patients suffering from musculoskeletal conditions such as RA. ARTHRITIC PAIN (AP) is a dominant symptom of RA. To date, studies of CNS drug uptake across the blood-brain barrier (BBB) have been carried out in naive (i.e., nondiseased) animals, despite the fact that studies have shown that central and peripheral inflammation modulates BBB function (i.e., permeability) and endothelial cell cytoarchitecture. The proposed studies will meld two areas of expertise already present in our laboratory: drug delivery to the CNS and assessment of biochemical and molecular alterations of the blood-brain barrier. The goal of this proposal is to investigate the effects of AP (using an acute arthritis pain rat model) versus RA (using a chronic RA rat model) on CNS drug uptake (i.e., BBB permeability) and endothelial cell structure and to ultimately differentiate between the effects of AP and RA on CNS delivery of opioid analgesics. Additionally, the influence of RA (a chronic disease state involving the joints) on CNS uptake of drugs used to treat RA itself will be assessed. These studies are clinically relevant since disease-associated BBB permeability increases could be a factor in the CNS toxicity sometimes observed following administration of opioids and RA drugs to patients. Our hypothesis is that functional changes in the transport of substances (including opioid analgesics and RA drugs) into the brain will occur due to alterations in the biochemical and molecular structure of the BBB caused by the release of pain/disease mediators during AP and RA. This study will allow us to differentiate between acute joint pain (AP) effects on the BBB and chronic disease (RA) effects on the BBB in terms of drug delivery and the mechanisms by which delivery is altered.

描述（由申请人提供）：类风湿关节炎（RA）是一种慢性疾病，影响了2至300万美国人，而女性的普遍性是男性的三倍。虽然RA通常发生在二十至五十岁的人中，但儿童和老年人也可以发展RA。每年，650亿美元用于医疗费用，收入损失和肌肉骨骼状况（例如RA）的患者的生产力降低。关节炎疼痛（AP）是RA的主要症状。 迄今为止，尽管研究表明中心炎症调节了BBB功能（即通透性），但在NAIVE（即非疾病）动物中对CNS药物摄取（BBB）的摄取（BBB）已经进行了。和内皮细胞细胞结构。拟议的研究将融合我们的实验室中已经存在的两个专业知识领域：将药物输送到中枢神经系统中，并评估血脑屏障的生化和分子改变。该建议的目的是研究AP（使用急性关节炎疼痛大鼠模型）与RA（使用慢性RA大鼠模型）对CNS药物摄取（即BBB渗透性）和内皮细胞结构的影响，并最终区分AP和RA对中枢神经系统递送阿片类镇痛药的影响。此外，将评估RA（涉及关节的慢性疾病状态）对用于治疗RA本身的药物摄取的影响。这些研究在临床上是相关的，因为与疾病相关的BBB渗透性增加可能是CNS毒性的一个因素，有时会在对患者进行阿片类药物和RA药物后观察到。 我们的假设是，由于AP和RA期间，由于AP和RA期间疼痛/疾病介体的释放，BBB的生化和分子结构的改变，物质转运（包括阿片类镇痛药和RA药物）的功能变化将发生。这项研究将使我们在药物输送方面对BBB的急性关节疼痛（AP）对BBB的影响和慢性疾病（RA）影响进行区分。