Second Alzheimer Drug Slows Deterioration

Second Alzheimer Drug Slows Deterioration

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Nov- Dec 98	Rank Last Period Sep- Oct 98
1	S.M. Hammer, et al., "A controlled trial with two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less," New Engl. J. Med., 337(11):725-33, 11 September 1997. [15 U.S. and U.K. institutions] *XV174	35	2
2	P.M. Ridker, et al., "Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men," New Engl. J. Med., 336(14):973-9, 3 April 1997. [Harvard Medical Sch., Boston, MA; Harvard Sch. Public Health, Boston; Brigham and Women’s Hosp., Boston, MA; U. Vermont, Burlington] *WR385	24	7
3	J.A. Staessen, et al., "Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension," The Lancet, 350(9080):757-64, 13 September 1997. [14 institutions worldwide] *XW282	24	4
4	S.L. Rogers, et al., "A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease," Neurology, 50(1):136-45, January 1998. [22 U.S. institutions] *YR353 23	23	†
5	J.W. Mellors, et al., "Plasma viral load and CD4⁺ lymphocytes as prognostic markers of HIV-1 infection," Ann. Int. Med., 126(12):946-54, 15 June 1997. [7 U.S. institutions] *XE549	21	10
6	L.W. Moreland, et al., "Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein," New Engl. J. Med., 337(3):141-7, 17 July 1997. [6 U.S. institutions] *Xk818	21	†
7	B. Pitt, et al., "Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)," The Lancet, 349(9054):747-52, 15 March 1997. [7 institutions worldwide] *WN124	20	8
8	R.O. Estacio, et al., "The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension," New Engl. J. Med., 338(10):645-52, 5 March 1998. [U. Colorado Health Sci. Ctr, Denver; Denver Health, CO] *YZ844	19	†
9	K. Pyöräla, et al., "Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease," Diabetes Care, 20(4):614-20, April 1997. [6 Scandinavian institutions] *WP645	18	†
10	P.D. Delmas, et al., "Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women," New Engl. J. Med., 337(23):1641-7, 4 December 1997. [Hop. Edouard Herriot, Lyons, France; Ctr. Clin. & Basic Res., Ballerup, Denmark; Lilly Res. Labs, Indianapolis, IN] *YJ871	18	†

SOURCE: ISI's Hot Papers Database. the full legend.

The London Sunday Times of January 31, 1999, carried a story on novel cognition-enhancing drugs under the title of "Viagra for the mind." The reference here was to the Neurogen/Pfizer work on NGD97-1, which is said to be directed at the GABA (gamma-aminobutyric acid) memory system. There was even talk of such drugs being given to healthy people. For the present, most clinicians are less ambitious, and the best that is hoped for from currently licensed drugs is that the mental deterioration in a patient with Alzheimer’s disease can be slowed. The main candidates of interest lately have been agents that make more choline available by inhibiting the activity of the esterases that break down this neurotransmitter. Science Watch has already covered the acridine derivative tacrine. Another agent, said to be 1,000 times more selective for acetylcholinesterase found in the brain than for the more peripherally active butyrylcholinesterase, and thus less likely to cause adverse effects, is the piperidine-based drug donepezil (E2020, Aricept). This drug has been approved for clinical use in the United States and in most of Europe and elsewhere, and the Donepezil Study Group’s trial (paper #4) provides some of the supporting evidence (this report is also listed on page 2 of this issue among the most-cited papers published in 1998). The group has completed a similar trial in North America and there is also a trial by a European group.

An Alzheimer’s disease assessment scale (ADAS-cog) is widely used to judge efficacy. Scores range from zero (best) to 70, and over a year the scale will usually fall by around 9 points, though with considerable inter-patient variation. Ten years ago a U.S. Food and Drug Administration group decided that an improvement of four or more points in the ADAS-cog would be clinically significant. In this trial (#4) patients randomized to donepezil 5 mg or 10 mg daily improved by an average of only 0.67 and 1.06, respectively. The study group argue that this FDA test is too severe—for instance, it takes no account of any decline in the placebo control group, so that improvements on donepezil over those for the placebo group were in the range of 2 to 3 points. There are other endpoints in this trial but those who find the changes reported small should note the sharp fall in scores when donepezil was stopped for six weeks once the formal 24-week trial was over.

Changes in ADAS-cog were in the range of 2.5 to 3.0 in another published trial of the same doses of donepezil (S.L. Rogers et al., Arch. Intern. Med., 158:1021-31, 1998). This drug seems not to be associated with liver toxicity, which proved a problem with the acridine class of anti-Alzheimer agents. That does not mean that it has escaped controversy. There have been disputes in the U.K. over whether an advertisement for Aricept was appropriate and about a less-than-enthusiastic review of the drug in the independent Drug and Therapeutics Bulletin.

The early controlled clinical evidence upon which this novel drug is licensed is bound to be a source of citation when the disease in question is—as Alzheimer’s disease (dementia) is—common, deeply distressing to the family, and incurable. The understandable desperation for something to offer those afflicted may explain why ADAS-cog improvements that some authorities would deem unimpressive are getting such attention. A host of other cholinesterase inhibitor drugs are now under clinical development—e.g., metrifonate, galantamine, rivastigmine, physostigmine, and eptastigmine—and if tacrine and donepezil turn out not to be wonder drugs they will have fuelled a healthy pharmaceutical interest in the possibility of at least ameliorating this serious medical condition.

Mr David W. Sharp, M.A. (Cambridge),
is a Deputy Editor of The Lancet, London, U.K.