抗癌老药进入新的阿尔茨海默病研究

蓓萨罗丁在阿尔茨海默病样病理状态的小鼠体内可清除β淀粉样脑斑块，这种已有十多年应用历史的抗癌药将在9月份开始进行其治疗阿尔茨海默病的首项人体试验。

Gary E. Landreth博士

克利夫兰市凯斯西储大学的Gary E. Landreth博士介绍，这项Ⅰb期试验将随机给予12例健康受试者蓓萨罗丁(Targretin)或安慰剂治疗。研究者将在用药后36 h内每小时收集脑脊液和血液，查看蓓萨罗丁促进淀粉样蛋白自然清除的情况。

 “如果我们的假设是正确的，这种药物应该可以加速载脂蛋白E的合成并保持其稳态水平”，而载脂蛋白E有利于可溶性淀粉样蛋白的分解。饥饿的小胶质细胞是蓓萨罗丁的第二记重拳，在小鼠体内，该药物可激活小胶质细胞，从而促进对β淀粉样斑块的清除。如果这两种事件都能在人体内发生，“我们将有理由进一步开展Ⅱ期试验”。

目前尚不建议对阿尔茨海默病患者处方蓓萨罗丁。Landreth博士说，尽管相对温和，但蓓萨罗丁在癌症患者中可导致甲状腺功能低减和血脂异常。尽管几乎可以确定在即将进行的试验中，志愿者将不会发生这些不良反应，但无法保证在阿尔茨海默病患者中的应用是安全的。

Landreth博士及其同事Paige Cramer拥有蓓萨罗丁作为一种阿尔茨海默病潜在治疗药物的美国临床专利，并得到ReXceptor公司的资助，这家公司拥有大学提供的将蓓萨罗丁用于阿尔茨海默病治疗的批准选择权。

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By: MICHELE G. SULLIVAN, Clinical Neurology News Digital Network

The first human trial of bexarotene, the cancer drug shown to clear beta-amyloid brain plaques in mice with Alzheimer’s-like pathology, will commence sometime in September.

The phase Ib trial will randomize 12 healthy subjects to placebo or bexarotene (Targretin), Gary E. Landreth, Ph.D., said in an interview.
 
Researchers will obtain hourly samples of cerebrospinal fluid and blood for 36 hours after administration of the drug, looking for signs that bexarotene increases natural clearance of the beta-amyloid protein, said Dr. Landreth of Case Western Reserve University, Cleveland.

"If our hypothesis is correct, the drug should accelerate the synthesis and steady-state levels of apolipoprotein E," a protein that helps break down soluble beta-amyloid, he said. Hungry microglia are bexarotene’s second punch; in mice, the drug activated these cells to scavenge beta-amyloid plaques.

If these two events also occur in humans, Dr. Landreth said, "we will have a reason to go forward" into phase II trials.

Media stories about Dr. Landreth’s research sparked a firestorm of dialogue on Alzheimer’s Internet forums and message boards this spring. Families discussed traveling to Canada for bexarotene, and begging their family doctors for a prescription.

Two opinion pieces in the Aug. 9 issue of the New England Journal of Medicine tackled the thorny problem physicians may face when desperate families come looking for answers.

"Writing an off-label prescription is completely permissible and would fulfill family members’ desire to try anything to help their loved ones," wrote Dr. Steven D. Pearson of Massachusetts General Hospital’s Institute for Technology Assessment, Boston, and his colleagues. But in the case of bexarotene, they asked, "is it the right thing to do?"

In the second editorial, Frank M. LaFerla, Ph.D., of the University of California, Irvine, warned against overenthusiasm: "Only a well-designed and carefully executed clinical trial will reveal whether this class of drug lives up to its promise. Until such trials are performed, it would be a mistake to offer this treatment to Alzheimer’s patients."

Dr. Landreth agrees. Although relatively benign, bexarotene can cause hypothyroidism and dyslipidemia in cancer patients. Although volunteers in the upcoming trial will almost certainly experience neither of these, "there is no guarantee at all that it would be safe in an Alzheimer’s population," he said. "I have absolutely no idea what could happen when this drug interacts with a diseased brain. If you remove the plaque, then what happens? Do you end up with holes in the brain? This is the question that keeps me up at night."

Dr. Landreth and his colleague, Paige Cramer, hold a U.S. provisional patent application for bexarotene as a potential therapy for Alzheimer’s disease and have founded ReXceptor Inc., which has licensing options from the university to use bexarotene to treat Alzheimer’s disease.