New tacrine hopes for Alzheimer patients in US

BMJ 1994; 308 doi: (Published 16 April 1994) Cite this as: BMJ 1994;308:999
  1. F B Charatan

    A 30 week study reported in the 6 April issue of JAMA of 663 patients at 33 outpatient centres throughout the US has opened a new chapter in the evaluation of tacrine (tetrahydroaminoacridine; Cognex). The study was led by the manufacturer of the drug, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company. Last September the Food and Drug Administration (FDA) approved the use of tacrine, a long acting anticholinesterase, in Alzheimer's disease.

    The study was to determine the effects of high dose (up to 160 mg/day) tacrine in patients with a probable diagnosis of Alzheimer's disease with the presence of symptoms for at least one year. Because the drug was found to be ineffective in severe Alzheimer's disease, the patients in the study were categorised as mild to moderate cases. The study recorded significant improvements on several outcome measures. For example, at week 30, 42% of patients receiving 160 mg/day of tacrine were rated improved compared with 18% of patients given placebo.

    An editorial in the same issue of JAMA stated: “Overall, tacrine improved patients' cognitive function by an amount equivalent to the deterioration that occurs over 6 months of the disease.” The journal reports that the two main side effects were hepatotoxicity and dose related cholinergic effects such as nausea, vomiting, anorexia, dyspepsia, and diarrhoea.

    Dr Stephen Gracon, one of the investigators, said that tacrine's benefits are strongly related to dosage. The effects of treatment with 80 mg/day could be shown, but improvement was greater when patients tolerated 160 mg/day. Dr Gracon thought that six months was the minimum period of treatment required. Asked about the BMJ's editorial (7 April, p 868) entitled “Tetrahydroaminoacridine and Alzheimer's disease: for the few, but we don't know which few,” he said, “Not so few, based on the higher dosage.”

    The rise in alanine aminotransferase activity, said Dr Gracon, is reversible and not dose related. Many patients can resume tacrine treatment after temporary cessation, maintain treatment, and move to higher dosage.

    Liver biopsies have shown that the pathological changes are acute cellular changes. Patients receiving treatment for as long as two years have not shown permanent liver damage. The dose related cholinergic effects of tacrine are manageable by dividing doses and giving the drug with food. Dr Gracon said, “In reality many more will be able to take tacrine with proper treatment.”

    Dr Barry Reisberg, professor of psychiatry and clinical director of the Ageing and Dementia Research Centre at New York University School of Medicine, said that the work with tacrine needs to be placed in context. Doctors have been using drugs to treat the behavioural symptoms of Alzheimer's disease. The advent of tacrine has given doctors a new drug for the treatment of cognitive as well as behavioural symptoms. The effects seem to be modest and temporary. Dr Reisberg said, “We still do not have a medication effective in treating the underlying disease process of Alzheimer's disease over the long term. However, tacrine increases our armamentarium in treating with neurochemical disturbances in Alzheimer's disease.”

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