PMID- 37724688
OWN - NLM
STAT- MEDLINE
DCOM- 20231229
LR  - 20240305
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 90
IP  - 1
DP  - 2024 Jan
TI  - Administration of oxathridine, a first-in-class histamine-3 receptor partial 
      agonist in healthy male volunteers: Central nervous system depression and 
      pseudo-hallucinations.
PG  - 321-335
LID - 10.1111/bcp.15910 [doi]
AB  - AIMS: To characterise the safety, tolerability, pharmacokinetics (PK) and 
      pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class 
      histamine-3 receptor partialagonist, in healthy male volunteers. METHODS: A 
      randomised, double-blind, placebo-controlled study including the NeuroCart, 
      consisting of a battery of drug sensitive neurophysiological tests, was 
      performed. Oxathridine was administered orally as an aqueous solution. After 
      dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], 
      saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to 
      Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], 
      pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task 
      [SART]) were performed at set times. RESULTS: Forty volunteers completed the 
      study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and 
      unanticipated adverse events (AEs) of (orthostatic) hypotension and 
      pseudo-hallucinations were reported. Statistically significant effects ([CI]; 
      p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28, -1.60]; p = 
      0.0048), ([-8.10, -1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 
      93.1]; p = 0.0205) and SPV ([-59.0, -15.9]; p = 0.0011), ([-43.9, -1.09]; p = 
      0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS 
      Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal 
      ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). 
      CONCLUSION: NeuroCart tests indicated central nervous system (CNS) depressant 
      effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this 
      led to the decision to stop further development of oxathridine, these 
      observations suggest that the H3R system could be an interesting new target for 
      the development of novel antipsychotics.
CI  - (c) 2023 British Pharmacological Society.
FAU - Dijkstra, Francis M
AU  - Dijkstra FM
AUID- ORCID: 0000-0001-5804-0708
AD  - Centre for Human Drug Research, Leiden, the Netherlands.
AD  - Leiden University Medical Center, Leiden, ZA, the Netherlands.
FAU - Zuiker, Rob G J A
AU  - Zuiker RGJA
AUID- ORCID: 0000-0001-5604-0157
AD  - Centre for Human Drug Research, Leiden, the Netherlands.
AD  - Leiden University Medical Center, Leiden, ZA, the Netherlands.
FAU - Heuberger, Jules A A C
AU  - Heuberger JAAC
AUID- ORCID: 0000-0001-7202-5088
AD  - Centre for Human Drug Research, Leiden, the Netherlands.
FAU - Kanhai, Kawita M S
AU  - Kanhai KMS
AUID- ORCID: 0000-0002-4503-6467
AD  - Centre for Human Drug Research, Leiden, the Netherlands.
AD  - Leiden University Medical Center, Leiden, ZA, the Netherlands.
FAU - De Kam, Marieke
AU  - De Kam M
AD  - Centre for Human Drug Research, Leiden, the Netherlands.
FAU - Duvauchelle, Thierry
AU  - Duvauchelle T
AUID- ORCID: 0000-0002-4762-588X
AD  - Bioprojet Pharma, Paris, France.
FAU - Lecomte, Jeanne-Marie
AU  - Lecomte JM
AD  - Bioprojet Pharma, Paris, France.
FAU - Labeeuw, Olivier
AU  - Labeeuw O
AD  - Bioprojet Biotech, Saint Gregoire, France.
FAU - Landais, Laurent
AU  - Landais L
AD  - Bioprojet Biotech, Saint Gregoire, France.
FAU - Ligneau, Xavier
AU  - Ligneau X
AD  - Bioprojet Biotech, Saint Gregoire, France.
FAU - Robert, Philippe
AU  - Robert P
AD  - Bioprojet Biotech, Saint Gregoire, France.
FAU - Capet, Marc
AU  - Capet M
AD  - Bioprojet Biotech, Saint Gregoire, France.
FAU - Schwartz, Jean-Charles
AU  - Schwartz JC
AD  - Bioprojet Pharma, Paris, France.
FAU - van Gerven, Joop M A
AU  - van Gerven JMA
AD  - Centre for Human Drug Research, Leiden, the Netherlands.
AD  - Leiden University Medical Center, Leiden, ZA, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20231011
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 820484N8I3 (Histamine)
SB  - IM
MH  - Humans
MH  - Male
MH  - *Histamine
MH  - *Depression
MH  - Electroencephalography
MH  - Central Nervous System
MH  - Hallucinations
MH  - Double-Blind Method
MH  - Healthy Volunteers
MH  - Dose-Response Relationship, Drug
OTO - NOTNLM
OT  - first-in-man
OT  - histamine-3 partial agonist
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - tolerability
OT  - translatability
EDAT- 2023/09/19 17:42
MHDA- 2023/12/29 06:43
CRDT- 2023/09/19 07:13
PHST- 2023/09/07 00:00 [revised]
PHST- 2023/06/16 00:00 [received]
PHST- 2023/09/08 00:00 [accepted]
PHST- 2023/12/29 06:43 [medline]
PHST- 2023/09/19 17:42 [pubmed]
PHST- 2023/09/19 07:13 [entrez]
AID - 10.1111/bcp.15910 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2024 Jan;90(1):321-335. doi: 10.1111/bcp.15910. Epub 2023 
      Oct 11.