Double-blind, randomized, placebo-controlled clinical trial on the efficacy and tolerability of a physostigmine patch in patients with senile dementia of the Alzheimer type

Owing to the pharmacokinetic properties of physostigmine when administered by conventional routes, longterm cholinergic treatment of Alzheimer's disea se is difficult to manage. In order to overcome the problems associated wit h the oral and intravenous application of physostigmine, and to improve pat ients' compliance, a transdermal therapeutic system was developed. The effi cacy and tolerability of this system were evaluated in a double-blind, rand omized, multicenter study comparing patches containing 30 mg and 60 mg phys ostigmine with a placebo patch. The clinical trial followed the basic princ iples of the various guidelines on the evaluation of anti-dementia drugs, a nd included patients with mild to moderate probable Alzheimer's disease. A total of 204 patients with probable Alzheimer's disease were included in th e study. Of these, 136 patients were eligible for the according-to-protocol analysis of efficacy, 167 subjects for the intention-to-treat analysis of efficacy, and 181 patients were included in the safety analysis. In contras t to the hypothesis to be tested, the efficacy of physostigmine was not sup erior to that of placebo after a treatment period of 24 weeks. On the contr ary, there was even a slight, but not statistically significant, trend towa rd a better outcome in the placebo group. Median physostigmine plasma conce ntrations of approximately 100 pg/ml were measured, showing a high degree o f interindividual variability and no linear dose relationship between the 3 0 mg and 60 mg dosages. Plasma cholinesterase activity was not significantl y affected by physostigmine. The physostigmine patch application in doses o f 30 mg and 60 mg apparently did not lead to physostigmine plasma concentra tions that were sufficient to compensate for cholinergic deficiencies in af fected brain areas and produce clinical benefits. Both the drug and the tra nsdermal system were generally well tolerated under the study conditions. M odifications of the patch system may perhaps make it possible to achieve hi gher physostigmine plasma concentrations, which seem to be required to indu ce the expected beneficial effects during long-term treatment of Alzheimer' s disease.