Efficacy of THN102 (a combination of modafinil and flecainide) on vigilance and cognition during 40‐hour total sleep deprivation in healthy subjects: Glial connexins as a therapeutic target

Abstract

Aims THN102 is a novel combination of modafinil and low‐dose flecainide, targeting glial connexin activity to modulate modafinil effects. We investigated THN102 efficacy compared to modafinil and to placebo on vigilance and cognitive function during 40‐hour total sleep deprivation (TSD). Methods Twenty healthy men participated in a double‐blind, randomized, incomplete‐block 3‐period cross‐over trial with 5 treatments (n = 12 per group): placebo (PBO), modafinil 100 mg (MOD100), THN102 100/1, 100/3, 100/9 (modafinil 100 mg and flecainide 1, 3 or 9 mg). Each period included a baseline day and a TSD day with treatments administered 3 times (01:00, 09:00 and 19:00). Reaction time in psychomotor vigilance test, subjective somnolence and vital signs were assessed before and during treatment. Working memory (2‐Back) and executive processes (Go/noGo for vigilance and inhibition, Wisconsin card sorting task for mental flexibility, and Tower of London test for planning) were evaluated at 16:30. Results At 5 hours postdose−1 (after 23 hours TSD, primary endpoint), THN102 100/1 resulted in statistically higher psychomotor vigilance test speed vs MOD100 (3.97 ± 0.09 vs 3.74 ± 0.14, P < .05). No increase in effect was observed with higher flecainide doses in combinations. Most THN102 doses vs MOD100 also improved the number of correct responses in 2‐Back and Go errors in Go/noGo (P < .05 for all doses), and perseverative responses in Wisconsin card sorting task (for 100/1 and 100/9). No impact on cardiac conduction was noted with THN102, and safety was similar to MOD100. Conclusions THN102 seems more efficient than modafinil on vigilance, working memory and executive functions, opening new perspectives in management of hypersomnolence disorders.

Efficacy of THN201, a Combination of Donepezil and Mefloquine, to Reverse Neurocognitive Deficits in Alzheimer’s Disease

“…Astroglial Cxs play a central role in physiological functions and notably in neuronal modulations (Han et al, 2014;Dallerac and Rouach, 2016;Clasadonte et al, 2017). Previous studies proposed that astroglial networks may contribute to strengthen neuronal signaling in CNS disorders (Duchêne et al, 2016;Jeanson et al, 2016;Charvériat et al, 2017;Vodovar et al, 2018;Sauvet et al, 2019). Interestingly, expression of both Cx43 and Cx30 was found to be upregulated in AD mice models (Mei et al, 2010) and brains from AD patients (Nagy et al, 1996), supporting the idea that Cxs may also play a role in neuronal FIGURE 3 | Effects of mefloquine (MEF) on donepezil-induced acetylcholine outflow (A) or donepezil (DPZ)-induced inhibition of acetylcholinesterase (AChE) activity (B).…”

Modeling and Targeting Neuroglial Interactions with Human Pluripotent Stem Cell Models

“…Modeling neuroglial interactions at physiological and pathological levels is hence of paramount importance from both fundamental and translational perspectives in drug discovery [14,18,[27][28][29][30]. This field largely benefited from the work of two Nobel Prize laureates, Pr.…”

Pharmaco-fUS for Characterizing Drugs for Alzheimer’s Disease – The Case of THN201, a Drug Combination of Donepezil Plus Mefloquine

“…Those proteins are upregulated in AD mice models ( Mei et al, 2010 ) and brains from AD patients ( Nagy et al, 1996 ). Meanwhile, previous non-clinical and clinical studies demonstrated that the modulation of astroglial connexins may enhance efficacy of drugs in neurological disorders ( Duchêne et al, 2016 ; Jeanson et al, 2016 ; Vodovar et al, 2018 ; Sauvet et al, 2019 ). Importantly, we recently demonstrated that mefloquine, a connexin modulator, both used in vitro ( Picoli et al, 2012 , 2019 ) and in vivo ( Jeanson et al, 2016 ; Droguerre et al, 2019 ), significantly potentiated the efficacy of one of the gold standard treatments in AD, donepezil ( Adlimoghaddam et al, 2018 ), both in scopolamine and amyloid-beta (Aβ) rodent models ( Droguerre et al, 2020 ).…”