Cutaneous changes like rash and hair loss, as well as other neurogenic inflammation side effects, occur frequently during anticancer treatment with the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), erlotinib. These adverse events may be so severe that they impair the patient's compliance with the treatment or even cause its discontinuation. In the current preclinical study, rats (9.2 weeks) were treated with erlotinib (10 mg/kg/day) ± aprepitant (2 mg/kg/day) for 12 weeks. Visual changes in the development of facial skin lesions/hair loss and SP-receptor expression (immunohistochemically) in facial skin tissue were assessed; also changes in plasma magnesium, 8-isoprostane, substance P (SP), neutrophil superoxide production, and cardiac function (echocardiography) were measured. Erlotinib lowered plasma magnesium 14%, elevated SP 65%, caused 3.7-fold higher basal superoxide production, 2.5-fold higher 8-isoprostane levels, 11.6% lower cardiac systolic, and 10.9% lower diastolic function. Facial dermatological changes (alopecia, skin reddening, scabbing, nose crusting) occurred by 4 weeks (± + to ++) in erlotinib-treated rats, and progressively worsened (±++ to +++) by week 12. Facial skin SP-receptor upregulation (78% higher) occurred in epidermal and hair follicle cells. All adverse effects were substantially and significantly mitigated by aprepitant, including a 62% lowering of skin SP-receptors (p < 0.05). Elevated SP levels mediated the side effects of erlotinib treatment, but aprepitant's significant prevention of the systemic and cutaneous adverse events indicates a novel potential therapy against the side effects of this anticancer treatment.

中文翻译：

---

P物质受体阻滞剂阿瑞匹坦可抑制EGFR1-TKI厄洛替尼引起的皮肤和其他神经源性炎症副作用。

在使用表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）埃洛替尼进行抗癌治疗期间，经常发生皮疹变化，如皮疹和脱发，以及其他神经源性炎症副作用。这些不良事件可能非常严重，以至于损害患者对治疗的依从性，甚至导致停药。在当前的临床前研究中，大鼠（9.2周）用厄洛替尼（10毫克/千克/天）±阿瑞匹坦（2毫克/千克/天）治疗12周。评估了面部皮肤组织中的面部皮肤病变/脱发和SP受体表达（免疫组织化学）发展的视觉变化；还测量了血浆镁，8-异前列腺素，P物质（SP），中性粒细胞超氧化物生成和心脏功能（超声心动图）的变化。厄洛替尼降低血浆镁14％，SP升高65％，导致基础超氧化物生成量增加3.7倍，使8-异前列腺素水平增加2.5倍，心脏收缩压降低11.6％，舒张压降低10.9％。厄洛替尼治疗的大鼠在4周后出现面部皮肤病学变化（脱发，皮肤变红，sc伤，鼻子结cru），在第12周时出现面部皮肤病学变化（±++到+++），面部皮肤SP逐渐恶化（±++到+++）。受体和表皮和毛囊细胞中发生了受体上调（高出78％）。阿瑞匹坦可显着缓解所有不良反应，包括皮肤SP受体降低62％（p <0.05）。SP水平升高介导了厄洛替尼治疗的副作用，但是阿瑞匹坦对全身和皮肤不良事件的显着预防表明，针对这种抗癌治疗的副作用的新的潜在疗法。