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Multiple Dose Pharmacokinetics, Safety, and Tolerance of Velnacrine (HP 029) in Healthy Elderly Subjects: A Potential Therapeutic Agent for Alzheimer's Disease
Author(s) -
Puri Surendra K.,
Ho Irwin,
Hsu Robert,
Lassman Howard B.
Publication year - 1990
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1990.tb03576.x
Subject(s) - medicine , pharmacokinetics , dosing , cmax , placebo , urine , adverse effect , therapeutic index , pharmacodynamics , oral administration , gastroenterology , pharmacology , drug , pathology , alternative medicine
The pharmacokinetics, safety, and tolerance of 1,2,3,4‐tetrahydro‐9‐aminoacridin‐1‐ol‐ maleate (HP 029) a potential therapeutic agent for Alzheimer's disease, were assessed after multiple oral doses in a randomized double‐blind, placebo controlled, ascending dose study in 56 healthy elderly men (14 per dose group). The subjects in the first three groups received 25, 50, or 100 mg two times a day and a fourth group was administered 100 mg velnacrine tid for 28 days. All subjects received a final dose on day 29. Subjects were confined for continuous observation during the 36‐day study period. Blood and urine samples were collected for the pharmacokinetic assessment. There were no clinically important changes in the safety variables in both age groups after any dose. There was no evidence of hepatotoxicity when elderly men were given 100 mg tid for 28 days. Nine subjects reported one or two episodes of gastrointestinal (diarrhea) side effects (6 in the 100 mg bid group and 3 in the 100 mg tid dose group) during a 29‐day trial. None required treatment or were discontinued from study. These results indicate that the safety and tolerance up to 100 mg tid for 28 days in healthy elderly men are acceptable. Velnacrine was rapidly absorbed after oral administration. There were dose‐related increases in C max , AUCs, and amount of drug excreted in urine. During multiple dosing, the C max increased as a function of dose. The t max and t 1/2 were not affected by dosage nor multiple dosing. Steady state levels of velnacrine were reached between days 2 and 3 with no evidence of further accumulation of velnacrine thereafter. Approximately 11–30% of the administered dose was excreted in the urine over the course of the study. The favorable pharmacokinetic characteristics and acceptable safety and tolerance of multiple dosing oral doses of velnacrine support further testing of this compound for efficacy and safety in Alzheimer's patients.