A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-d-aspartate receptor blockade in healthy veterans

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-d-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.Subject terms: Biomarkers, Neurophysiology, Neuroscience     

Knowledge and Attitudes of Saudi Dental Undergraduates on Oral Cancer

Oral cancer awareness among future dental practitioners may have an impact on the early detection and prevention of oral cancer. A cross-sectional survey was undertaken to assess the current knowledge of future Saudi dentists on oral cancer and their opinions on oral cancer prevention. A pretested questionnaire was sent to 550 undergraduate dental students in the fourth, fifth, and sixth year of the Al-Farabi College for Dentistry and Nursing, Riyadh, Saudi Arabia. Questions relating to knowledge of oral cancer, risk factors, and opinions on oral cancer prevention and practices were posed. Four hundred seventy-nine students returned the questionnaire (87.1 %). Eighty-one percent of respondents correctly answered questions relating to oral cancer awareness. Eighty-seven percent of respondents felt confident in performing a systematic oral examination to detect changes consistent with oral malignancy. Interestingly, 57 % of respondents had seen the use of oral cancer diagnostics aids. Thirty-seven percent of respondents felt inadequately trained to provide tobacco and alcohol cessation advice. There is a need to reinforce the undergraduate dental curriculum with regards to oral cancer education; particularly in its prevention and early detection. Incorporating the use of oral cancer diagnostic aids should be made mandatory.