Safety, tolerability, and pharmacokinetics of repeated oral doses of 2-hydroxybenzylamine acetate in healthy volunteers: a double-blind, randomized, placebo-controlled clinical trial

Lisa M Pitchford, Patricia M Driver, John C Fuller Jr, Wendell S Akers, Naji N Abumrad, Venkataraman Amarnath, Ginger L Milne, Sheau-Chiann Chen, Fei Ye, L Jackson Roberts 2nd, M Benjamin Shoemaker, John A Oates, John A Rathmacher, Olivier Boutaud, Lisa M Pitchford, Patricia M Driver, John C Fuller Jr, Wendell S Akers, Naji N Abumrad, Venkataraman Amarnath, Ginger L Milne, Sheau-Chiann Chen, Fei Ye, L Jackson Roberts 2nd, M Benjamin Shoemaker, John A Oates, John A Rathmacher, Olivier Boutaud

Abstract

Background: 2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer's disease.

Methods: This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated.

Results: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10-3.27 h, and an accumulation ratio of 1.38-1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing.

Conclusions: Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement.

Trial registration: Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18).

Keywords: Humans; Pharmacokinetics; Safety; Salicylamine; γ-Ketoaldehydes.

Conflict of interest statement

JCF, LMP, and JAR are employed by and NNA is co-founder and part owner of MTI BioTech Inc., which has executed an agreement for the rights to license the intellectual property for 2-hydroxybenzylamine from Vanderbilt University. WSA received payment for the clinical pharmacokinetic analysis.

Figures

Fig. 1
Fig. 1
2-Hydroxybenzylamine (2-HOBA) and primary metabolite (salicylic acid) plasma concentrations after oral administration of 2-HOBA acetate. Plasma concentrations of 2-HOBA (a) and salicylic acid (b) were measured for 8 (first dose) or 24 (last dose) hours after oral administration of 2-HOBA acetate at two dose levels
Fig. 2
Fig. 2
2-Hydroxybenzylamine (2-HOBA) metabolite does not inhibit cyclooxygenases. Urinary metabolites of a) prostaglandin E2 (PGE-M), b) thromboxane B2 (TxB2-M), and c) prostacyclin (PGI-M) were measured by LC-ESI/MS/MS before and after treatment. There were no significant changes in urinary metabolite concentration (mixed-effects model, n ≥ 5)

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