DOXYCYCLINE EFFECT ON OSTEOARTHRITIS PROGRESSION

描述（来自应用程序）： 膝关节骨关节炎（OA）是慢性关节炎最常见的原因。 残疾人在这个国家，并有巨大的社会经济影响。 值得注意的是， 目前OA的治疗仅限于对症治疗。 非类固醇 抗炎药（NSAID）是用于治疗炎症的最常用的药物。 但老年妇女，其中OA是特别常见的，是在最大的风险 非甾体抗炎药的严重副作用 值得注意的是， 药物已被证明可以预防或减缓软骨损伤的进展 在OA的动物模型中，目前正在开发药物来抑制 蛋白酶诱导的软骨损伤，以期其在OA中的应用。 我们有 显示预防性口服给予多西环素（DOXY）显著 降低OA犬模型中软骨损伤的严重程度;即使 治疗开始后，软骨病变建立，保护性 效果明显。 在豚鼠中也观察到了类似的结果， 兔OA模型。 这种效果与降低 胶原酶和明胶酶在OA软骨中的作用。 基于OA动物模型中令人鼓舞的数据，我们建议进行 多西他赛多中心、双盲、安慰剂对照临床试验 OA患者。 我们的假设是，多西他赛会减少 严重程度或进展速度。 因为一种改善疾病的药物 对于OA，大概，更有可能在早期表现出效果， 我们的研究发现， 人口将 2例肥胖女性，45-60岁， X线证据显示单侧胫股OA，其中X线改变 据报告，在2分钟内，近50%的对侧膝关节发生 年 受试者（n=432）将随机接受多西他赛，100 mg bid，或 安慰剂2-1/2年。 不会试图影响NSAID和/或 常规治疗过程中规定的止痛治疗或其他措施 临床护理 将采用几种策略来最大限度地遵守 研究药物和研究中受试者的保留，包括 一种“心脏衰弱”测试，将在一开始用于消除 不遵守，并使用计算机化的药帽，以提供信息 关于访视之间对处方给药方案的依从性， 允许研究人员努力提高依从性， 最能从中受益的人 我们的主要成果 变量将是关节间隙变窄的速率（JSN，通过 膝关节半屈位数字化正位片的计算机系统 采用一种技术，以显着减少放射解剖的变异性， 定位）和OA的个体放射学特征的严重程度， 例如，在一个实施例中，对侧膝盖有骨赘 因为JSN在 对侧膝关节不确定，而已发表的数据表明， 表现出OA骨变化的膝关节（例如，骨赘）它是 足够快，以允许检测合理的药物作用， 在研究期间，索引膝关节的放射学进展也将用于 作为主要的结果变量。 此外，我们还将研究 痛觉功能指数（WOMAC），关节炎活动度，一般健康状况 状态（SF-36）。 两种治疗方式的卫生服务利用情况 组 这项研究应该回答这个问题， doxy -一种相对安全，容易获得和廉价的药物， 几十年的临床经验已经积累-可以改变自然史 OA在人类

DESCRIPTION (from the application): Osteoarthritis (OA) of the knee is the most common cause of chronic disability in this country and has enormous socio-economic impact. Notably, management of OA today is limited to symptomatic therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most popular agents used to treat OA but elderly women, in whom OA is especially common, are at greatest risk of developing serious side effects from NSAIDs. Notablly, however, several drugs have been shown to prevent, or slow progression of, cartilage damage in animal models of 0A, and drugs are currently being developed to inhibit protease-induced cartilage damage, with a view to their use in OA. We have shown that prophylactic oral administration of doxycycline (doxy) markedly reduces the severity of cartilage damage in a canine model of OA; even when therapy was initiated after cartilage lesions were established, a protective effect was apparent. Similar results have been noted in guinea pig and rabbit models of OA. The effect is associated with reduction in the levels of collagenase and gelatinase in the OA cartilage. Based on the encouraging data in animal models of OA, we propose to conduct a multi-center, double-blind, placebo-controlled clinical trial of doxy in subjects with OA. It is our hypothesis that doxy will decrease the severity, or rate of progression, of OA. Because a disease-modifying drug for OA will, presumably, be more likely to show an effect in the early stages of the disease than when OA pathology is more advanced, our study population will be 2 obese females, 45-60 years old, with x-ray evidence of unilateral tibiofemoral OA in whom x-ray changes have been reported to develop in the contralateral knee in nearly 50% within 2 years. Subjects (n=432) will be randomized to receive doxy, 100 mg bid, or placebo for 2-1/2 years. No attempt will be made to influence NSAID and/or analgesic treatment or other measures prescribed in the course of routine clinical care. Several strategies will be employed to maximize compliance with the study medications and retention of subjects in the study, including a "faintness-of-heart" test, which will be used at the outset to eliminate noncompliers, and use of a computerized medicine cap to provide information concerning compliance with the prescribed dosing regimen between visits, permitting study personnel to aim their efforts to enhance compliance at those subjects who can best benefit from them. Our primary outcome variables will be the rate joint space narrowing (JSN, measured by a computerized system on a digitized AP radiograph of the semi-flexed knee taken with a technique to markedly reduce variability in radioanatomic positioning) and the severity of individual radiographic features of OA, e.g., osteophytes, in the contralateral knee. Because the rate of JSN in the contralateral knee is uncertain, whereas published data indicate that in knees which exhibit bony changes of OA (e.g., osteophytes) it is sufficiently rapid to permit detection of a reasonable drug effect during the study period, radiographic progression in the index knee will also serve as a primary outcome variable. In addition, we will examine changes in an algofunctional index (WOMAC), global arthritis activity, general health status (SF-36). and utilization of health services in the two treatment groups. This study should answer the question whether oral treatment with doxy - a relatively safe, readily available and inexpensive drug with which decades of clinical experience have accrued - can modify the natural history of OA in humans.