This one is interesting for sure. It’s shown mixed results for improving cognition in healthy normal subjects, but consistent effects in regards to energy and subjective feelings, with lower doses seeming to be superior, and less likely to negatively impact sleep.
CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects.
CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.
The data presented herein support the need for further studies with CEP-26401 to assess a potential beneficial effect on cognition at doses similar to and lower than 20 μg in order to confirm or disprove the beneficial effect of CEP-26401 on cognition and to test whether effects follow a U-shaped concentration-response curve. The low dose range is well tolerated and has little or no potential to be associated with adverse effects on sleep.
In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil.
In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose.
The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 μg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 μg dose of CEP-26401, -1.65 (CI -0.572 to 1.96) for modafinil and - 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 μg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone.
Of the doses tested, the 25 μg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.
Although CEP‐26401 did not have the expected positive effect on cognition and cannot be typified as a cognitive enhancer, it may be a useful drug for certain indications that are characterized by a lack of internal drive and energy. The stimulant effects of CEP‐26401 on objective CNS tests (PSG, adaptive tracking, saccadic peak velocity) were generally dose‐dependent, whereas subjective effects were most favourable at a dose of 25 μg, but virtually disappeared after 125 μg.
the 25‐μg dose of CEP‐26401 has the optimal balance between favourable subjective and stimulatory effects, and inhibitory effects on sleep. The more strong, clear‐headed, well‐ coordinated, interested and quick‐witted feeling in combination with a more contented, attentive, proficient, happy and gregarious feeling might give benefit to patients suffering from certain types of mood disorders, such as major depression or dysthymia, negative symptoms of schizophrenia or anxiety disorders, especially social anxiety.
In conclusion, CEP‐26401 had several simulating CNS effects and induced energizing and positive feelings, with a relaxed undertone at the 5 and 25 μg doses, which disappeared at 125 μg. CEP‐26401 caused a dose‐dependent inhibition of sleep, which became symptom- atic at the highest dose.