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P1‐254: A safety, tolerability and pharmacokinetic study of dimebon in patients with Alzheimer's disease already receiving donepezil
Author(s) -
Tariot Pierre,
Sabbagh Marwan,
Flitman Stephen,
Reyes Patricio,
Taber Louise,
Seely Lynn
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.262
Subject(s) - tolerability , donepezil , placebo , medicine , adverse effect , anesthesia , pharmacology , dementia , disease , pathology , alternative medicine
family is the 5-HT6 receptor predominating in brain regions associated with cognition and behavior. The blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms. Our effective lead generation and optimization methods have resulted in a novel, potent and selective 5-HT6 receptor antagonist SUVN502 with Ki of 1.71 nM and exhibited antagonist like inhibition with EC50 of 0.103 mM. SUVN-502 is effective in animal models of cognition. In microdialysis studies, SUVN-502 enhanced brain acetylcholine and glutamate levels in rat ventral hippocampus and frontal cortex. SUVN-502 has completed all regulatory safety and toxicity studies. The objective of the present investigation is to assess the safety, tolerability and pharmacokinetics of ascending multiple oral doses of SUVN-502 in healthy subjects. Methods: A double-blind, placebo-controlled, randomized, ascending multiple-dose study was conducted with healthy male subjects. Adverse events, physical examinations, clinical chemistry examination, hematology, urinalysis and ECG were measured throughout the study. The plasma concentrations of SUVN502 and its active metabolite M1 of SUVN-502 were analyzed by non-compartmental methods. Results: SUVN-502 was generally well tolerated upto highest dose administered. No serious adverse events occurred. No clinically significant changes or study medication related abnormalities were observed with respect to ECG’s and laboratory evaluations. There were no clinically significant changes of vital sign parameters. Conclusions: SUVN-502 was safe and well tolerated at multiple doses of upto highest dose. SUVN-502 has the potential for best in the class candidate with a favorable pharmacokinetics, safety and toxicology profile. SUVN-502 completed human Phase I clinical studies (both Single Ascending Dose and Multiple Ascending Dose studies) and is ready to enter clinical proof of concept studies for cognitive dysfunction associated with Schizophrenia and Alzheimer’s diseases.