REL-1017 (Esmethadone) Increases Circulating BDNF Levels in Healthy Subjects of a Phase 1 Clinical Study

Frontiers in Pharmacology

Franco Folli¹  Francesco Bifari²  Nicola Ferri³  Sara De Martin³  Daniela Gabbia³  Paolo Fiorina⁵  Stephen Stahl⁶  Charles E. Inturrisi⁷  Paolo L. Manfredi⁷  Marco Pappagallo⁷  Sergio Traversa⁷ 

[1] Department of Health Science, University of Milan, Milan, Italy;Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy;Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy;Department of Psychiatry, University of California, San Diego School of Medicine, La Jolla, CA, United States;Nephrology Division, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States;Neuroscience Education Institute, San Diego, CA, United States;Relmada Therapeutics, Inc., New York, NY, United States;

关键词: esmethadone;    BDNF;    depression;    clinical trial;    NMDAR;   

DOI  :  10.3389/fphar.2021.671859

来源: DOAJ

【 摘 要 】

Brain-derived neurotrophic factor (BDNF), a neurotrophin widely expressed in the central nervous system, exhibits important effects on neural plasticity. BDNF has been implicated in the mechanism of action of ketamine, a N-methyl-d-aspartic acid receptor (NMDAR) antagonist with rapid anti-depressant effects in humans. REL-1017 (esmethadone), the d-optical isomer of the racemic mixture d-l-methadone, is devoid of clinically relevant opioid activity at doses expected to exert therapeutic NMDAR antagonistic activity in humans. The present study was conducted to ascertain the effects of oral administration of 25 mg of REL-1017 for 10 days on plasma BDNF in healthy subjects confined to an inpatient unit for a phase 1 clinical trial. We observed an increase in post-treatment BDNF plasma levels compared to pre-treatment levels. Post-treatment, Day 10 BDNF plasma levels ranged from 2 to 17 times pre-treatment levels in the 25 mg REL-1017 treatment group, whereas in the placebo group, BDNF plasma levels remained unchanged (p = 0.028). Diastolic blood pressure decreased significantly in subjects treated with REL-1017, while no effect could be observed in the placebo group. In conclusion, the administration of 25 mg REL-1017 significantly increased BDNF plasma levels and significantly decreased diastolic blood pressure in healthy subjects confined to an inpatient unit for a phase 1 clinical trial.

【 授权许可】

Unknown