Kappa opioid agonists in the treatment of itch: just scratching the surface?
Kappa opioid agonists in the treatment of itch: just scratching the surface?
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DOI：
10.1097/itx.0000000000000072
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发表时间：
2023-10
期刊：
影响因子：
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通讯作者：
Tyler C. Beck;Elena M. Wilson;Erik Wilkes;Lara Wine Lee;Russell A Norris;Manuel Valdebran
中科院分区：
文献类型：
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作者：
Tyler C. Beck;Elena M. Wilson;Erik Wilkes;Lara Wine Lee;Russell A Norris;Manuel Valdebran
慢性瘙痒症是一种使人衰弱的疾病，影响着 23-4400 万美国人。最近，κ阿片受体激动剂（KOA）已成为一类新型强效止痒剂。 2021年，美国食品和药物管理局批准difelikefalin（Korsuva）用于治疗接受血液透析的成人与慢性肾脏病相关的中度至重度瘙痒。 Difelikefalin 是一种有效的外周限制性 KOA，可静脉注射。尽管很有前景，但迪非利克法林目前仅可作为静脉注射组合物使用，限制了使用范围。在最近的2期临床试验中，difelikefalin的口服制剂未达到主要终点标准；然而，更多的临床研究正在进行中。 KOA 在治疗瘙痒方面的前景令人鼓舞。口服活性途径偏向的 KOA，例如三唑 1.1，可能作为具有更广泛应用的可行替代品。缓释组合物，例如 TP-2021 ProNeura 皮下植入物，可以避免与基于肽的 KOA 相关的药代动力学问题。最后，双重作用的κ阿片受体激动剂/μ阿片受体拮抗剂具有口服生物利用度，并且可用于治疗各种形式的慢性瘙痒。在这篇综述中，我们总结了KOAs在临床和临床前试验中的结果，并讨论了药物开发的未来方向。
Chronic pruritus is a debilitating condition affecting 23–44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.