替洛利生性质、用途与生产工艺
替洛利生是一种选择性组胺H3受体反向激动剂，在欧洲药品管理局(EMA)和美国食品药品监督管理局(FDA)分别获得了孤儿药认定，且被美国FDA认定为突破性治疗药物。2023年6月30日，琅钰集团宣布中国国家药品监督管理局(NMPA)正式批准盐酸替洛利生片(铧可思®)用于治疗发作性睡病(Narcolepsy)成人患者的日间过度嗜睡(EDS)或猝倒。
发作性睡病(Narcolepsy)是全球公认的罕见病，是一种罕见的睡眠/觉醒障碍疾病，通常被认为是终身性疾病，临床上以日间过度嗜睡(excessivedaytimesleepiness，EDS)、猝倒(cataplexy)、入睡前幻觉、睡眠瘫痪和夜间睡眠紊乱为主要特征，对患者的生活质量、工作或学习能力、以及身心健康往往造成严重的影响。
替洛利生（Pitolisant）由法国Bioprojet研发，是一款first-in-class选择性组胺3（H3）受体拮抗剂/反向激动剂，通过一种全新的作用机制发挥作用，即通过增强组胺能神经元活性，增加大脑中促进觉醒的神经递质组胺的合成和释放，进而提高患者的清醒度和警觉性。该药于2019年8月获FDA批准上市，是第一个也是唯一一个不受美国缉毒局管制的治疗发作性睡病药物。2020年10月，琅铧医药与Bioprojet就Pitolisant膜包衣片（4.45mg和17.8mg）达成战略合作和独家授权协议，获得中国的独家开发、注册、商业化和生产权益。2021年，Pitolisant用于发作性睡病成人患者的日间过度嗜睡或猝倒的上市申请获药监局受理。
替洛利生是全球范围内唯一获得发作性睡病适应症，并且同时被美国、欧洲和中国指南推荐的非精神管控类药物。全球上市多年来，替洛利生以出色的安全性和有效性而受到临床的广泛认可。替洛利生在中国的上市意味着结束了我国发作性睡病患者“超说明书”和“红处方”用药为主的困局，为我国患者提供安全、有效和便捷的治疗新选择。
Pitolisant 是一种有效的选择性的非咪唑类重组人组胺 H3 受体反相激动剂，Ki 为 0.16 nM。
Ki: 0.16 nM (H3 receptor)
EC50: 1.5 nM (H3 receptor)
On the stimulation of guanosine 5′-O-(3-[
35
S]thio)triphosphate binding to this receptor, Pitolisant (BF2.649) behaves as a competitive antagonist with a K
i
value of 0.16 nM and as an inverse agonist with an EC
50
value of 1.5 nM and an intrinsic activity ~50% higher than that of ciproxifan. Pitolisant displaces [
125
I]iodoproxyfan binding from mouse brain cortical membranes with an IC
50
value of 26.4±4.5 nM. Taking into account the K
d
value of the radioligand (161±9 pM), the deduced K
i
value for Pitolisant is 14±1 nM. Pitolisant displaces [
125
I]iodoproxyfan binding from membranes of rat glioma C6 cells stably expressing the human H
3
receptor with an IC
50
value of 4.2±0.2 nM. Taking into account the K
d
value of the radioligand (50±4 pM), the deduced K
i
value for Pitolisant is 2.7±0.5 nM. Pitolisant progressively reverses this response with a Hill coefficient close to unity and an IC
50
value of 330±68 nM, leading to a K
i
value of 17±4 nM. Pitolisant elicits a dose-dependent decrease of the basal-specific [
35
S]GTPγS binding to membranes with a maximal effect corresponding to 75±1% of the basal-specific binding and an EC
50
value of 1.5±0.1 nM.
The administration of Pitolisantat a single dose of 10 mg/kg 30 min before a single dose of Olanzapine (2 mg/kg b.w.) also significantly affects immobility time in the FST. Subsequent administration of the aforementioned drug sequence in mice statistically significantly increases the duration of immobility in comparison to the time determined in the control group in the FST. It decreased locomotor activity as well. In contrast, the results obtained in subchronic treatment after fifteen administrations of both drugs (Pitolisant 10 mg/kg b.w., and after 30 min Olanzapine 2 mg/kg b.w., and again after 4 h Olanzapine 2 mg/kg b.w.) show that the administration of Pitolisant followed by that of Olanzapine equalized the locomotor activity in mice; in comparison to the level of motility in the control group, to which only Pitolisant is administered. More importantly, this combination of drugs significantly reduces immobility time to the level obtained in the control group in the forced swim test in mice [one-way ANOVA; F
(3,20)
=4.226,P=0.0181]. Rats given Pitolisant (10 mg/kg) during the conditioning phase stayed 502±94 s on the paired texture, a value not statistically different from that of controls, indicating that Pitolisant did not support place preference.
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