Reines S A, Block G A, Morris J C, Liu G, Nessly M L, Lines C R, Norman B A, Baranak C C
Merck Research Laboratories, 10 Sentry Parkway, Blue Bell, PA 19422, USA.
Neurology. 2004 Jan 13;62(1):66-71. doi: 10.1212/wnl.62.1.66.
Inflammatory mechanisms have been implicated in the pathogenesis of Alzheimer's disease (AD) and may be mediated via the cyclo-oxygenase-2 enzyme. This study sought to evaluate the effect of rofecoxib, a nonsteroidal anti-inflammatory drug that selectively inhibits cyclo-oxygenase-2, in slowing the progression of dementia in patients with established AD.
A double-blinded, multicenter trial was conducted in which 692 patients with mild or moderate AD aged 50 years or older were randomly assigned to receive 25 mg rofecoxib or placebo daily for 12 months. The key efficacy measures were mean change from baseline at month 12 on the cognitive subscale of the AD Assessment Scale (ADAS-cog) and score on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+).
Four hundred eighty-one patients (70%) completed assessments and remained on treatment at 12 months. No significant differences between treatments were found on the mean change from baseline error score for the ADAS-cog (rofecoxib = 4.84; placebo = 5.44; difference = -0.60) or mean score on the CIBIC+ (rofecoxib = 4.90; placebo = 4.87; difference = 0.03) over 12 months. This result persisted after adjusting for severity of dementia at baseline, presence of the APOE-epsilon4 allele, and donepezil use. Secondary analyses did not reveal any significant differences on any other measures.
The failure of selective cyclo-oxygenase-2 inhibition to slow the progression of AD may indicate either that the disease process is too advanced to modify in patients with established dementia or that cyclo-oxygenase-2 does not play a significant role in the pathogenesis of the disorder.
炎症机制与阿尔茨海默病（AD）的发病机制有关，可能通过环氧化酶-2 酶介导。本研究旨在评估罗非昔布（一种选择性抑制环氧化酶-2 的非甾体抗炎药）对已确诊 AD 患者痴呆进展的延缓作用。
进行了一项双盲、多中心试验，将 692 例年龄在 50 岁及以上的轻度或中度 AD 患者随机分配，每天接受 25 毫克罗非昔布或安慰剂治疗，为期 12 个月。关键疗效指标为第 12 个月时阿尔茨海默病评估量表认知分量表（ADAS-cog）相对于基线的平均变化以及基于临床医生访谈印象变化并结合照料者意见的评分（CIBIC+）。
481 例患者（70%）完成评估并在 12 个月时仍在接受治疗。在 12 个月期间，ADAS-cog 的相对于基线误差评分（罗非昔布 = 4.84；安慰剂 = 5.44；差值 = -0.60）或 CIBIC+的平均评分（罗非昔布 = 4.90；安慰剂 = 4.87；差值 = 0.03）在治疗组之间未发现显著差异。在对基线时痴呆严重程度、APOE-ε4 等位基因的存在情况以及多奈哌齐的使用情况进行校正后，该结果依然成立。二次分析在任何其他指标上均未发现显著差异。
选择性抑制环氧化酶-2 未能延缓 AD 的进展，这可能表明对于已确诊痴呆的患者，疾病进程过于晚期而无法改变，或者环氧化酶-2 在该疾病的发病机制中未发挥重要作用。
