Restenosis often occurs without symptoms

SCIENCE AND MEDICINE

New mechanism proposed for NSAID reduction of Alzheimer’s disease incidence

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ome non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of Alzheimer’s disease by decreasing brain concentrations of the 42-residue isoform of the peptide amyloid-␤ (A␤42), claim Edward Koo (University of California, San Diego, CA, USA) and colleagues. “This effect is independent of ability to inhibit cyclo-oxygenase [COX] activity”, says Koo, “and if our data are correct, it may be possible to develop a compound that looks like a NSAID, has no COX-related side-effects, yet still reduces the risk of developing Alzheimer’s disease”. Considerable epidemiological evidence shows an inverse relation between sustained NSAID use and the risk of developing Alzheimer’s disease. However, although a small clinical trial of indomethacin for the treatment of Alzheimer’s disease provided

supporting data for these epidemiological studies, a larger trial on the COX-2 inhibitor celecoxib failed, and a small trial on diclofenac was inconclusive. NSAIDs are generally thought to work in Alzheimer’s disease by reducing brain inflammatory responses, but Koo and colleagues now suggest a different mechanism. They have found that in tissue culture cells engineered to produce large amounts of amyloid precursor protein (APP), high doses of some, but not all, NSAIDs preferentially reduce the concentration of the highly amyloidogenic A␤42 peptide. Additionally, short-term ibuprofen treatment of transgenic mice expressing mutant APP reduces concentrations of A␤42 in the brain (Nature 2001; 414: 212–16). “We think that the NSAIDs may be inducing a subtle change in the activity of ␥-secretase, the enzyme

Restenosis often occurs without symptoms than women”, noted Ruygrok, which ore than half of patients whose he suggested was perhaps because heart arteries re-narrow after women have arteries with smaller angioplasty may have no symptoms diameters (Circulation 2001; 104: of possible renewed disease, accord2289–94). ing to US researchers this week. Previous studies have indicated These patients may therefore have a that there are clearly sex differences risk of future coronary events, such in treatment of patients with coroas myocardial infarctions, but would nary heart disease. have no symptoms. Patients with less“55% of restenosis Rights were not granted severe blockage [the re-narrowing and those whose of arteries after to include this image in arteries had a they are unelectronic media. Please wider reference clogged] in the refer to the printed diameter were also populations we journal. more likely to have studied was sympsilent restenosis. tomless, therefore “Although our these patients research will probremain well, but Silent but deadly ably not cause any with a potentially changes in clinical practice, it may significant coronary problem”, says lead to raised clinical suspicion in investigator Peter Ruygrok, (Green patients in whom the clinical Lane Hospital, Auckland, New diagnosis in not clearcut”, says Zealand). “Yet, they believe they Ruygrok. have had a successful treatment for According to Neal Kleiman their obstructive artery narrowing.” (Baylor College of Medicine, In a study of 2690 patients Houston, TX, USA) “these data treated for obstructed heart arteries, seem to imply that in patients with the investigators identified factors, compelling anatomy and risk factors, including sex, age, and smoking hisincreased vigilance with either tory that influenced whether patients aggressive non-invasive testing or were more or less likely to develop surveillance angiograms may be symptomless heart disease needed”. within 6 months after initial angioplasty. “Of importance, men were more likely to have silent restenosis Sally Hargreaves Science Photo Library

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responsible for A␤42 production”, says Koo. “This is interesting work”, says Patrick McGeer (University of British Columbia, Vancouver, Canada), “but how well do in-vitro data—in which individual cells are put under enormous pressure by high levels of APP and very high doses of NSAIDs—reflect what goes on in the living brain? There is plenty of epidemiological data available that should now be reanalysed to tease out what different NSAIDs do to reduce the risk of Alzheimer’s disease.” In addition, the US National Institutes of Health (NIH) are sponsoring a large trial of naproxen, a NSAID that had no effect in Koo’s assays. The NIH trial ends in January, so clinical data might soon be available to support or refute Koo’s results. Jane Bradbury

News in brief UK guidelines on chemotherapy The UK government has published guidelines on safe administration of intrathecal chemotherapy drugs. Since 1985, 13 patients have died or been paralysed due to accidental intrathecal administration of vincristine, rather than intravenous delivery. The guidelines state that intrathecal chemotherapy should only be prescribed by a consultant or specialist registrar, and hospitals will be required to set up a register of staff who are trained and authorised to prescribe intrathecal chemotherapy. Doctors must also follow a set procedure laid out on a specially designed chart (www.doh.gov.uk). New phase for landmark study The Framingham Heart Study is entering a new phase by recruiting a third generation of participants. The investigators plan to recruit about 3500 grandchildren of the study’s original participants. Key goals of the third-generation study are to identify genes that contribute to good health and to development of cardiovascular, lung, and blood diseases, and the development of new imaging tests to detect very early stages of atherosclerosis in otherwise healthy individuals.

THE LANCET • Vol 358 • November 10, 2001

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