Correspondence
Tacrine in Alzheimer's Disease
N Engl J Med 1993; 328:808-810March 18, 1993
- Article
To the Editor:
In his accompanying editorial (Oct. 29 issue),1 Dr. Growdon cites the minimally positive results with tacrine in the multicenter study by Davis et al.2 to argue for the abandonment of “simple replacement” cholinomimetic therapies in favor of promising futuristic restorative approaches. Although new approaches are desperately needed, we must also be diligent in our evaluation of current methods. In our view, the most likely factor responsible for the unimpressive clinical effect of tacrine may be the deletion of the higher doses (120 and 160 mg per day) from the protocol because of their propensity to cause marked increases on liver-function tests. Until proved otherwise, the response to cholinergic replacement must be considered a dose-dependent phenomenon. Unfortunately, aminoacridines such as tacrine appear to possess poor side-effect profiles that may severely limit dosage and thus therapeutic benefits. Acetylcholinesterase inhibitors that are better tolerated and that can be given routinely at dosages close to the maximally tolerated dose are needed. Moreover, significantly positive results were also reported recently with similar dosages of tacrine (up to 80 mg per day) in 468 patients with Alzheimer's disease in a study with a parallel-group design3,4. . . .
4 ReferencesNeal R. Cutler, M.D.
John J. Sramek, Pharm.D.
California Clinical Trials, Beverly Hills, CA 902111
Growdon JH . Treatment for Alzheimer's disease? N Engl J Med 1992;327:1306-1308
Full Text | Web of Science | Medline2
Davis KL ,Thal LJ ,Gamzu ER , et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. N Engl J Med 1992;327:1253-1259
Full Text | Web of Science | Medline3
Farlow M ,Gracon SI ,Hershey LA ,Lewis KW ,Sadowsky CH ,Dolan-Ureno J . A controlled trial of tacrine in Alzheimer's disease. JAMA 1992;268:2523-2529
CrossRef | Web of Science | Medline4
Small GW . Tacrine for treating Alzheimer's disease. JAMA 1992;268:2564-2565
CrossRef | Web of Science | Medline
To the Editor:
In his editorial Dr. Growdon is unduly critical of the potential value of neurotransmitter-based strategies. He dismisses as clinically trivial the mean difference of 1.5 points on the Alzheimer's Disease Assessment Scale that the Tacrine Collaborative Study Group found between the tacrine and placebo groups, without taking into account the effects of higher doses. My group 1 has found differences of 2.7 points on the Mini-Mental State Examination, which represents the expected decline in an untreated group over a period of one year. . . .
Although it is true to say that in the long run, strategies directed at points further up the causal chain of events leading to neuronal death are likely to be longer-lasting, we should anticipate a delay of at least 10 years before any compounds based on this approach are marketed. It is also not inconceivable that any substance that, say, prevents the accumulation of beta-amyloid (A4 protein) may need to be combined with one that corrects any neurotransmitter deficits. The call to abandon neurotransmitter-based therapy is both premature and one-sided. In the short term, there is no other option, and in the longer term we may need to adopt a combined approach.
1 ReferencesRaymond Levy, M.B., Ch.B., Ph.D.
Institute of Psychiatry, London SE5 8AF, United Kingdom1
Eagger SA ,Levy R ,Sahakian BJ . Tacrine in Alzheimer's disease. Lancet 1991;337:989-992
CrossRef | Web of Science | Medline
To the Editor:
The editorial by Dr. Growdon suggests that tacrine may be a severe hepatotoxin. The following information summarizes the data on hepatotoxicity from approximately 7000 patients worldwide who have been treated with tacrine in Warner-Lambert and Parke-Davis clinical studies.
In approximately 45 percent of the patients treated with tacrine there was at least one alanine aminotransferase value above the upper limit of the normal range, and in 25 percent there was an alanine aminotransferase value more than three times the upper limit of normal. The incidence of aminotransferase elevations was slightly higher in women than in men. The mean time from the first dose of tacrine to the first elevation in alanine aminotransferase was approximately six weeks. In general, alanine aminotransferase levels have returned to the normal range in an average of four weeks after reducing the dose or interrupting treatment. In a recently reported parallel-group study of tacrine, 95 percent of the aminotransferase elevations occurred during the initial eight weeks of treatment.1 A similar finding is evident in an ongoing 30-week, parallel-group study of tacrine in which the maximal dose is 160 mg per day. Although the blinding of this study has not yet been broken, 95 percent of the withdrawals due to aminotransferase elevations occurred during the initial 12 weeks of treatment, when the maximal dose is 80 mg per day.
Another important issue addressed by the parallel-group study is the ability to rechallenge patients who have had elevations in aminotransferase levels. Of 382 patients exposed to tacrine in the study reported by Farlow et al.,1 83 withdrew during the double-blind phase because of aminotransferase elevations; 56 patients were subsequently rechallenged with tacrine in an open-label fashion once their alanine aminotransferase levels had returned to normal limits. Twelve of the 56 patients again had aminotransferase elevations. None of the elevations were more severe on rechallenge, and none were accompanied by clinical symptoms indicative of a hypersensitivity reaction or drug-induced hepatitis. The remaining 44 patients tolerated long-term treatment on reexposure, even though some had mild elevation initially. In fact, in 15 of the rechallenged patients the dose was titrated to the maximum allowable (120 mg per day), despite the fact that their initial elevations occurred with doses of 20 or 40 mg per day.
Furthermore, there has been no evidence that long-term administration of this drug (i.e., for more than two years) leads to detectable liver disease or dysfunction. The pathogenesis of this condition is not yet understood. However, on the basis of the extensive clinical experience with tacrine, we believe that the available data confirm that patients can be safely treated with tacrine if aminotransferase levels are appropriately monitored.
1 ReferencesStephen I. Gracon, D.V.M.
Parke-Davis Pharmaceutical Research Division Warner-Lambert Company, Ann Arbor, MI 481051
Farlow M ,Gracon SI ,Hershey LA ,Lewis KW ,Sadowsky CH ,Dolan-Ureno J . A controlled trial of tacrine in Alzheimer's disease. JAMA 1992;268:2523-2529
CrossRef | Web of Science | Medline
To the Editor:
Davis and colleagues should be lauded not only for their meticulous multicenter trial of tacrine for Alzheimer's disease in 632 patients, but also for their sensible interpretation of the data. The accompanying editorial by Growdon makes the point very well: tacrine probably improves cognitive function in a small way. Are we willing to approve a marginally efficacious drug for an eligible population of 4 million when no alternative therapy is available? The suffering of these patients and their families is great, but we do not have unlimited resources. Given the likely expense of this four-times-a-day medication, we need evidence of more than mild improvement on a variety of outcome measures, of which cognitive ability is only one.
One of the major problems in studying enhancers of cognition for the treatment of Alzheimer's disease is the appalling lack of noncognitive or behavioral outcome measures for use in clinical trials. These impairments have a major impact on the care givers of patients with Alzheimer's disease1. A patient with measurable cognitive improvement in such a trial may have persistent noncognitive deficits, such as wandering, verbal and physical outbursts, sleep disturbance, and a variety of other behavioral impairments that are partially captured but underrepresented in the Alzheimer's Disease Assessment Scale. Notably, in the Tacrine Collaborative Study Group trial, scores on the noncognitive subscale of the Alzheimer's Disease Assessment Scale changed very little in either the placebo or the tacrine group. A recent paper by Farlow and colleagues also reported no significant change in the noncognitive subscale in patients who received tacrine over a 12-week period.2
2 ReferencesMark Lachs, M.D., M.P.H.
Yale University School of Medicine, New Haven, CT 065101
Rabins PV ,Mace NL ,Lucas MJ . The impact of dementia on the family. JAMA 1982;248:333-335
CrossRef | Web of Science | Medline2
Farlow M ,Gracon SI ,Hershey LA ,Lewis KW ,Sadowsky CH ,Dolan-Ureno J . A controlled trial of tacrine in Alzheimer's disease. JAMA 1992;268:2523-2529
CrossRef | Web of Science | Medline
To the Editor:
Growdon's excellent editorial did not mention the role of aluminum in the pathogenesis of Alzheimer's disease or the potential for treatment with deferoxamine. McLachlan et al.1 studied intramuscular deferoxamine in patients with Alzheimer's disease who were treated for two years and concluded that this treatment may slow the clinical progression of the dementia. What can you tell us of this avenue of research into this important disorder?
1 ReferencesKeith Meloff, M.D., F.R.C.P.(C)
36 Burton Rd., Toronto, ON M5P 1V2, Canada1
McLachlan DRC ,Dalton AJ ,Kruck TPA , et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 1991;337:1304-1308
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drs. Cutler and Sramek and Dr. Lachs make interesting and important points. Initially, the tacrine protocol included doses of 120 and 160 mg. However, with the schedule of administration we used, elevations in liver-enzyme levels were so frequent that the 120- and 160-mg doses were discontinued. With more gradual dosing it may be possible to administer higher doses of aminoacridines than we used in our study. As we mentioned, it is possible that higher doses will be associated with a larger effect; this is one possible interpretation of the results of Eagger et al.1.
Dr. Lachs argues that, if approved, a drug that is only marginally efficacious in Alzheimer's disease is likely to involve so much expense that its widespread distribution cannot be justified. Indeed, the differences in Alzheimer's Disease Assessment Scale scores in our study were not apparent to clinicians, as reflected in the Clinical Global Impression of Change, although a subsequent study has reported a significant drug-induced change in that measure2. Focusing on differences in the mean change between patients treated with tacrine and those given placebo can leave unanswered the question of whether there is a subgroup of patients with more dramatic, clinically meaningful responses. Whether such a group exists could not be addressed adequately by our study. However, the devastation associated with this disease makes it important to determine whether there are subgroups of responsive patients. In such a circumstance a focus on mean differences between all patients receiving the drug and all receiving placebo obviously cannot be used as the basis for evaluating cost effectiveness.
2 ReferencesKenneth L. Davis, M.D.
Mount Sinai Medical Center, New York, NY 10029Leon J. Thal, M.D.
Veterans Affairs Medical Center, San Diego, CA 921611
Eagger SA ,Levy R ,Sahakian BJ . Tacrine in Alzheimer's disease. Lancet 1991;337:989-992
CrossRef | Web of Science | Medline2
Farlow M ,Gracon SI ,Hershey LA ,Lewis KW ,Sadowsky CH ,Dolan-Ureno J . A controlled trial of tacrine in Alzheimer`s disease. JAMA 1992;268:2523-2529
CrossRef | Web of Science | Medline
Author/Editor Response
We must move beyond the cholinergic hypothesis of memory dysfunction as the mainspring for generating ideas about treatment strategies for Alzheimer's disease. In contrast to Drs. Cutler and Sramek, I believe that time, effort, and money will be better spent in developing treatments that attack fundamental problems of neuronal degeneration than in designing a “better” acetylcholinesterase inhibitor. To learn that tacrine has been given to 7000 patients and has produced hepatotoxicity so often with so little clinical benefit reinforces my opinion that other treatments for Alzheimer's disease must be sought. I hope that Parke-Davis, having exhaustively tested tacrine, will now apply its resources to the development of drugs that will represent new approaches to the treatment of Alzheimer's disease1,2.
In response to Dr. Meloff, the importance of metals in the pathogenesis of neurodegeneration is still speculative3. Whether aluminum acts as a neurotoxin in Alzheimer's disease, or simply accumulates in dying neurons, has not been fully resolved. Along the same lines, accumulation of iron associated with increased lipid peroxidation and impaired mitochondrial function have been implicated in neuronal death in Parkinson's disease4; similar oxidative stresses have been proposed as mechanisms of cell death in Alzheimer's disease. If future research implicates these or other metals in the pathogenesis of Alzheimer's disease, treatments directed toward lowering their concentrations in brain will become important goals.
Dr. Levy raises the question of what constitutes a substantial drug effect in clinical trials among patients with Alzheimer's disease. I agree with Dr. Lachs' point that cognitive scores should be supplemented by noncognitive outcome measures. Patients with Alzheimer's disease, their family members, and physicians alike would welcome convincing data that tacrine (or any other treatment) stabilized Alzheimer's disease or even delayed its progression. In order to claim that a treatment has delayed the progression of illness by one year, however, it is necessary to conduct a parallel-design study comparing that drug with placebo for at least one year. The course of Alzheimer's disease is sufficiently variable that it is not possible to extrapolate the course of decline from the initial (early) slope of change. I agree with Dr. Levy's second point that neurotransmitter-based therapy may yet prove useful as an adjunct to treatments directed toward the fundamental lesions of Alzheimer's disease. For example, my colleagues and I recently showed that stimulation of human embryonic kidney cells in culture with the muscarinic agonist carbachol increased the release of nonamyloidogenic fragments from the transmembrane amyloid precursor protein5. If a similar effect occurred in the intact human brain, cholinomimetic agents might be expected to decrease the production and deposition of beta-amyloid in Alzheimer's disease.
5 ReferencesJohn H. Growdon, M.D.
Massachusetts General Hospital, Boston, MA 021141
Growdon JH . Treatment for Alzheimer's disease? N Engl J Med 1992;327:1306-1308
Full Text | Web of Science | Medline2
Growdon JH. Biologic therapies for Alzheimer's disease. In: Whitehouse PJ, ed. Dementia. Contemporary neurology series. Vol. 40. Philadelphia: F.A. Davis, 1993:375-99.
3
Lovell MA ,Ehmann WD ,Markesbery WR . Laser microprobe analysis of brain aluminum in Alzheimer's disease. Ann Neurol 1993;33:36-42
CrossRef | Web of Science | Medline4
Olanow CW . An introduction to the free radical hypothesis in Parkinson's disease. Ann Neurol 1992;32:Suppl:S2-S9
CrossRef | Web of Science | Medline5
Nitsch RM ,Slack BE ,Wurtman RJ ,Growdon JH . Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 1992;258:304-307
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Eric Granholm, Shaunna Morris, Douglas Galasko, Clifford Shults, Erin Rogers, Boris Vukov. (2003) Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer's and Parkinson's disease. International Journal of Psychophysiology 47:2, 95-115
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