Speaking of a new pharmacological class, which includes the monoclonal antibodies for Calcitonin Gene Related Peptide or its receptor (CGRP (r)) and gepants seems to be a simple thing, given the enormous expectation that has arisen around them and the enormity of data that we have seen. The numerous randomized control trials (RCTs) of the four siblings, erenumab, fremanezumab, galcanezumab, eptinezumab, show strong evidence for their differentiated use in episodic, chronic and refractory migraine, as second-line drugs for now [1, 2]. Even studies on gepants are moving, albeit with differentiated speed, in the area of prevention or acute treatment of migraine. We have on the horizon the reappearance of a pharmacological class composed of atogepant, rimegepant and ubrogepant [3] (Fig. 1). We now have recommendations from the European Headache Federation on the use of monoclonal antibodies that will act as a guide and as a beacon in the coming years to be regularly updated as new scientific evidences will be available [4]. The CGRP(r) target in migraine has solid retrospective roots, moving its first steps in the world of the trigeminovascular system of CGRP over 30 years ago, when it was demonstrated that the perivascular administration of the powerful vasoconstrictor, norepinephrine, produced the spontaneous counteract dilation response of CGRP [5, 6]. This was coined trigeminovascular reflex, aborted by lesions of the trigeminal nerve. Subsequent work revealed that CGRP was the neuronal responsible messenger [7]. The journey then had several stages, and the caravan was always enriched with new data, up to the current stage we celebrate today, a new pharmacological target dedicated to migraine and based on monoclonal antibodies directed against either CGRP or the CGRP receptor or on small molecules with antagonism activity towards the CGRP [1, 8]. Interfering with the important release of CGRP at the level of neurons and fibers of the Trigeminal Ganglion (TG), activated by the still unknown natural switch-on originating putatively in the Central Nervous System (migraine generator), CGRP (r) Mabs are the most recent drug barrier able to tackle migraine pain onset [1, 2]. Translational medicine has then transferred this basic science research data to the human science, setting-up an experimental human migraine model leading to novel vascular mechanics insights as well as neuroimaging studies through the use of functional MRI (fMRI) blood oxygenation level dependent (BOLD) revealing that CGRP acts outside the Blood-Brain-Barrier (BBB) [9]. The necessity to have these drugs now available for patients opens a new phase, stimulates new studies and generates the expectation of real-world data. In the meantime, we must consider that the clinical application of these drugs directed to the CGRP, members of the first and only pharmacological classes created de novo for migraine treatment, acting on the CGRP biomarker of disease [10], maintain their long-term efficacy reverting this way the migraine disease to a quasi-silent state [11]. With these premises, we can define this CGRP new pharmacological class as Disease-Modifying-Migraine-Drugs (DMMDs), for the benefit of the huge number of patients needing therapies that, if promptly used, can slow down or freeze or revert the natural course of migraine [12].

中文翻译：

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用疾病缓解偏头痛药物 (DMMD) 塑造靶向降钙素基因相关肽的偏头痛的未来

说到一个新的药理学类别，其中包括降钙素基因相关肽或其受体 (CGRP (r)) 和 gepants 的单克隆抗体似乎是一件简单的事情，考虑到围绕它们产生的巨大期望和大量数据我们已经看到。四个兄弟姐妹（erenumab、fremanezumab、galcanezumab、eptinezumab）的众多随机对照试验 (RCT) 显示出强有力的证据表明它们作为目前二线药物在发作性、慢性和难治性偏头痛中的差异化使用 [1, 2]。在偏头痛的预防或急性治疗领域，即使是对 gepants 的研究也在以不同的速度进行。我们即将重新出现由 atogepant、rimegepant 和 ubrogepant 组成的药理学类别 [3]（图 1）。我们现在有来自欧洲头痛联合会的关于使用单克隆抗体的建议，这些建议将作为未来几年的指南和灯塔，随着新的科学证据的出现而定期更新 [4]。偏头痛中的 CGRP(r) 靶点具有坚实的回顾性根源，在 30 多年前，它在 CGRP 三叉神经血管系统领域迈出了第一步，当时证明血管周围施用强效血管收缩剂去甲肾上腺素可产生自发性抵消作用CGRP 的扩张反应 [5, 6]。这被创造为三叉神经血管反射，因三叉神经损伤而中止。随后的工作表明，CGRP 是负责神经元的信使 [7]。然后旅程有几个阶段，大篷车总是充满新的数据，直到我们今天庆祝的当前阶段，一个新的药理学靶点专用于偏头痛，基于针对 CGRP 或 CGRP 受体的单克隆抗体，或基于对 CGRP 具有拮抗活性的小分子 [1, 8]。CGRP (r) Mab 干扰了三叉神经节 (TG) 神经元和纤维水平上 CGRP 的重要释放，由推定起源于中枢神经系统（偏头痛发生器）的仍然未知的自然开启激活。能够解决偏头痛发作的最新药物屏障 [1, 2]。转化医学然后将这些基础科学研究数据转移到人文科学中，建立一个实验性的人类偏头痛模型，通过使用功能性 MRI (fMRI) 血氧水平依赖 (BOLD) 揭示 CGRP 在血脑屏障 (BBB) 之外起作用，从而获得新的血管力学见解和神经影像学研究。 9]。现在为患者提供这些药物的必要性开启了一个新阶段，刺激了新的研究并产生了对真实世界数据的期望。与此同时，我们必须考虑到这些针对 CGRP 的药物的临床应用，这些药物属于第一个也是唯一一个从头创建用于偏头痛治疗的药理学类别，作用于疾病的 CGRP 生物标志物 [10]，保持其长期疗效以这种方式使偏头痛疾病恢复到准无声状态 [11]。有了这些场地，