Jacobson Laura H, Chen Sui, Mir Sanjida, Hoyer Daniel
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.
Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Curr Top Behav Neurosci. 2017;33:105-136. doi: 10.1007/7854_2016_47.
The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX and OX receptors (OXRs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OXR antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OXR antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OXR is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OXR antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OXR antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.
食欲素系统的发现是过去三到四十年睡眠领域的一项重大进展。两种食欲素肽及其两种受体在觉醒和睡眠/觉醒周期中起主要作用。食欲素系统的缺陷会导致人类和犬类发作性睡病伴猝倒，并且在啮齿动物中可以通过实验重现。至少六种食欲素受体拮抗剂已进入失眠症的II期或III期临床试验，其中五种是同时作用于OX1和OX2受体（OXRs）的双重食欲素受体拮抗剂（DORAs）。所有经过临床测试的DORAs都能诱导并维持睡眠：最近在美国和日本获批用于治疗失眠症的苏沃雷生，代表了一种与目前标准药物作用方式完全不同的催眠原理。然而，很明显，在临床上，所有DORAs主要通过增加快速眼动（REM）睡眠来促进睡眠，而对慢波（SWS）睡眠几乎没有影响。目前，对于单纯促进REM睡眠是否会对失眠患者产生负面影响尚无共识。然而，DORAs已被证明会导致睡眠起始快速眼动（SOREM），这显然是一种不良影响，特别是对于发作性睡病患者，以及在脆弱人群（如老年患者）中，与REM相关的肌张力丧失可能会增加跌倒风险。因此，关于实现REM睡眠和非快速眼动（NREM）睡眠平衡增加的理想食欲素药物仍存在争议。在此，我们回顾了相关证据，即对于失眠症的治疗，OXR拮抗剂至少应与DORA相当，甚至可能更优。OXR拮抗剂可能会产生比DORA更平衡的睡眠。啮齿动物睡眠实验表明，OXR是食欲素受体拮抗剂在睡眠调节中的主要靶点。此外，从理论上讲，OXR拮抗剂的发作性睡病/猝倒风险应该更低。在临床上，情况仍不明确，因为OXR拮抗剂尚处于早期阶段：MK-1064已完成I期试验，MIN202目前正处于临床II/III期试验。然而，失眠症患者的数据尚未公布。宣传材料表明MIN-202确实能诱导出平衡的睡眠，而据报道，在志愿者中MK-1064的作用与DORAs类似。
