TACRINE - 1ST DRUG APPROVED FOR ALZHEIMERS-DISEASE

OBJECTIVE: To review the pharmacology, biopharmaceutics/pharmacokineti cs, clinical efficacy, adverse effects, and therapeutic considerations regarding the use of tacrine in patients with Alzheimer's disease. DA TA SOURCES: Data from the scientific and professional literature were analyzed, interpreted, and summarized. Citations were obtained by perf orming a MEDLINE search using the following indexing terms: tacrine, t etrahydroaminoacridine, and Alzheimer's drug therapy. Data also were o btained from a summary of the New Drug Application (Summary Basis of A pproval of Cognex) and from the approved product labeling. STUDY SELEC TION: Studies in Alzheimer's disease have been plagued by methodologic inconsistencies and deficiencies. Only efficacy studies subsequent to the Food and Drug Administration's (FDA) issuance of recommendations for studies in Alzheimer's disease (1991) were used. Therefore, only d ouble-blind, placebo-controlled, parallel design studies of at least t hree-month's duration using the Alzheimer's Disease Assessment Scale-C ognitive Subscale and the Clinical Interview-Based Impression of Chang e as efficacy parameters were included. DATA EXTRACTION: Trials were a ssessed according to the criteria listed above. Results were evaluated on the basis of both completed patients and last observation carried forward models. DATA SELECTION: Tacrine is a cholinesterase inhibitor that increases the availability of acetylcholine in muscarinic neurons . It has a mean bioavailability after oral administration of about 17 percent and an elimination half-life of approximately three hours. Alt hough drug interactions are poorly studied, tacrine is metabolized by isoenzyme P450IA2 and may interact with other drugs metabolized by thi s isoenzyme. Tacrine has been shown to have efficacy in mildly to mode rately impaired Alzheimer's patients on both psychometric testing and a clinician's structured interview. Although efficacious, its effects are not dramatic, and it does not affect the ultimate course of the di sease. Adverse effects are frequent, and significantly elevated hepati c transaminase concentrations may occur in approximately 25 percent of patients. CONCLUSIONS: Tacrine is die first drug approved by die FDA for treatment of Alzheimer's disease. Although it may improve psychome tric test scores in mild to moderately impaired patients, it is not a panacea and does not affect the course of the disease. Patients must b e monitored closely for elevated transaminase, cholinergic adverse eff ects, and interactions with drugs metabolized through P-450IA2.