Bioprojet-Biotech, Saint-Grégoire, France.
Pharmacol Res Perspect. 2021 Oct;9(5):e00855. doi: 10.1002/prp2.855.
Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.
目前有几种治疗选择可用于治疗患有嗜睡症或阻塞性睡眠呼吸暂停的患者的日间过度嗜睡（EDS）。然而，在作用机制、疗效或安全性方面，尚无各种促醒药物之间的比较。本研究的目的是比较安非他命、莫达非尼、索利那新和 pitolisant 在其已知的主要药理学靶点，组胺 H3 受体（H3R）、多巴胺、去甲肾上腺素和 5-羟色胺转运体，以及与神经化学、运动、行为敏化和食物摄入相关的各种体内临床前模型中的作用。结果证实，安非他命、莫达非尼和索利那新的主要药理学作用是增加中枢多巴胺神经传递，部分是通过抑制其转运体。此外，索利那新增加了伏隔核中外周多巴胺的水平，并降低了纹状体中的 3,4-二羟基苯乙酸（DOPAC）/DA 比值，这与莫达非尼和安非他命报道的情况相同。所有这些化合物都产生了过度运动、行为敏化和食欲减退，这是精神兴奋剂和具有滥用潜力的化合物的共同特征。相比之下，作为一种促觉醒的选择性和强效 H3R 拮抗剂/反向激动剂的 pitolisant，对纹状体多巴胺、运动或食物摄入没有影响。此外，pitolisant 本身没有行为敏化作用，可减弱莫达非尼或索利那新诱导的过度运动。因此，与安非他命和其他精神兴奋剂（如莫达非尼或索利那新）相比，pitolisant 具有不同的生化、神经化学和行为特征。总之，与精神兴奋剂相比，pitolisant 是一种差异化的治疗选择，用于治疗 EDS，因为该药物在体内临床前模型中没有表现出任何安非他命样特性。
