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

基本信息

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
项目类别：
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

项目摘要

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）：类风湿性关节炎 (RA) 是一种慢性疾病，影响着两到三百万美国人，女性患病率是男性的三倍。虽然 RA 通常发生在 20 至 50 岁的人群中，但儿童和老年人也可能患 RA。每年，有 650 亿美元用于治疗 RA 等肌肉骨骼疾病患者的医疗费用、收入损失和生产力损失。关节炎疼痛 (AP) 是 RA 的主要症状。迄今为止，尽管研究表明中枢和外周炎症调节 BBB 功能（即通透性），但中枢神经系统药物跨血脑屏障 (BBB) 吸收的研究仍在幼稚（即未患病）动物中进行。和内皮细胞的细胞结构。拟议的研究将融合我们实验室现有的两个专业领域：向中枢神经系统的药物输送以及血脑屏障的生化和分子改变的评估。本提案的目的是研究 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 通透性）和内皮细胞结构的影响，并最终区分AP 和 RA 对阿片类镇痛药中枢神经系统输送的影响。此外，还将评估 RA（一种涉及关节的慢性疾病状态）对中枢神经系统吸收用于治疗 RA 的药物的影响。这些研究具有临床相关性，因为与疾病相关的血脑屏障通透性增加可能是患者服用阿片类药物和 RA 药物后有时观察到的中枢神经系统毒性的一个因素。我们的假设是，由于 AP 和 RA 期间疼痛/疾病介质的释放导致 BBB 的生化和分子结构发生变化，物质（包括阿片类镇痛药和 RA 药物）转运到大脑的功能会发生变化。这项研究将使我们能够在药物输送和改变输送的机制方面区分急性关节疼痛 (AP) 对 BBB 的影响和慢性疾病 (RA) 对 BBB 的影响。