PMID- 33995104
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210518
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 12
DP  - 2021
TI  - REL-1017 (Esmethadone) Increases Circulating BDNF Levels in Healthy Subjects of a 
      Phase 1 Clinical Study.
PG  - 671859
LID - 10.3389/fphar.2021.671859 [doi]
LID - 671859
AB  - 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.
CI  - Copyright (c) 2021 De Martin, Gabbia, Folli, Bifari, Fiorina, Ferri, Stahl, 
      Inturrisi, Pappagallo, Traversa and Manfredi.
FAU - De Martin, Sara
AU  - De Martin S
AD  - Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 
      Padova, Italy.
FAU - Gabbia, Daniela
AU  - Gabbia D
AD  - Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 
      Padova, Italy.
FAU - Folli, Franco
AU  - Folli F
AD  - Department of Health Science, University of Milan, Milan, Italy.
FAU - Bifari, Francesco
AU  - Bifari F
AD  - Department of Medical Biotechnology and Translational Medicine, University of 
      Milan, Milan, Italy.
FAU - Fiorina, Paolo
AU  - Fiorina P
AD  - Nephrology Division, Boston Children's Hospital and Harvard Medical School, 
      Boston, MA, United States.
FAU - Ferri, Nicola
AU  - Ferri N
AD  - Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 
      Padova, Italy.
FAU - Stahl, Stephen
AU  - Stahl S
AD  - Department of Psychiatry, University of California, San Diego School of Medicine, 
      La Jolla, CA, United States.
AD  - Neuroscience Education Institute, San Diego, CA, United States.
FAU - Inturrisi, Charles E
AU  - Inturrisi CE
AD  - Relmada Therapeutics, Inc., New York, NY, United States.
FAU - Pappagallo, Marco
AU  - Pappagallo M
AD  - Relmada Therapeutics, Inc., New York, NY, United States.
FAU - Traversa, Sergio
AU  - Traversa S
AD  - Relmada Therapeutics, Inc., New York, NY, United States.
FAU - Manfredi, Paolo L
AU  - Manfredi PL
AD  - Relmada Therapeutics, Inc., New York, NY, United States.
LA  - eng
PT  - Journal Article
DEP - 20210428
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC8113752
OTO - NOTNLM
OT  - BDNF
OT  - NMDAR
OT  - clinical trial
OT  - depression
OT  - esmethadone
COIS- SDM: Ongoing research projects sponsored by Relmada Therapeutics. NF: 
      Relationship with Bristol-Mayers, Daiichi-Sankyo, Pharmanutra, and Amryt Pharma. 
      SS: Consultant for Acadia, Alkermes, Allergan, AbbVie, Arbor Pharmaceuticals, 
      Axovant, Axsome, Celgene, Concert, Clearview, EMD Serono, Eisai Pharmaceuticals, 
      Ferring, Impel NeuroPharma, Intra-Cellular Therapies, Ironshore Pharmaceuticals, 
      Janssen, Karuna, Lilly, Lundbeck, Merck, Otsuka, Pfizer, Relmada, Sage 
      Therapeutics, Servier, Shire, Sunovion, Takeda, Taliaz, Teva, Tonix, Tris Pharma, 
      and Viforpharma. Board Member: GenoMind; Served on Speakers bureaus for: Acadia, 
      Lundbeck, Otsuka, Perrigo, Servier, Sunovion, Takeda, Teva, and Vertex; Research 
      and/or grand support from: Acadia, Avanir, Braeburn Pharmaceuticals, Eli Lilly, 
      Intra-Cellular Therapies, Ironshore, ISSWSH, Neurocrine, Otsuka, Shire, Sunovion, 
      and TMS NeuroHealth Centers. CI: Consultant for and owns stock in Relmada 
      Therapeutics. MP: Consultant for Relmada Therapeutics. ST: CEO of Relmada 
      Therapeutics and significant stock ownership. PM: Paid consultant of Relmada 
      Therapeutics, owns stock of Relmada and may earn Royalties from IP licensed to 
      Relmada. The remaining authors declare that the research was conducted in the 
      absence of any commercial or financial relationships that could be construed as a 
      potential conflict of interest.
EDAT- 2021/05/18 06:00
MHDA- 2021/05/18 06:01
PMCR- 2021/04/28
CRDT- 2021/05/17 06:03
PHST- 2021/02/24 00:00 [received]
PHST- 2021/04/13 00:00 [accepted]
PHST- 2021/05/17 06:03 [entrez]
PHST- 2021/05/18 06:00 [pubmed]
PHST- 2021/05/18 06:01 [medline]
PHST- 2021/04/28 00:00 [pmc-release]
AID - 671859 [pii]
AID - 10.3389/fphar.2021.671859 [doi]
PST - epublish
SO  - Front Pharmacol. 2021 Apr 28;12:671859. doi: 10.3389/fphar.2021.671859. 
      eCollection 2021.