Medical Beauty QA Team, Aestura Corporation, Anseong, Republic of Korea.
Vital Beautie Research Institute, AmorePacific Corporation R&D Center, Yongin, Republic of Korea.
Regul Toxicol Pharmacol. 2020 Apr;112:104613. doi: 10.1016/j.yrtph.2020.104613. Epub 2020 Feb 7.
PAC-14028 (Asivatrep: CHFNOS) cream is a novel, topical nonsteroidal, anti-inflammatory, and TRPV1 (transient receptor potential vanilloid subfamily, member 1) antagonist for the treatment of mild to moderate atopic dermatitis. Concerns about the risk of tumor development by TRPV1 blockade in the skin have been prompted, but these findings were proved to be indirect or are still controversial. This study was tested to determine whether TRPV1 selective antagonist, PAC-14028 cream is safe from the promotion of skin tumorigenesis in the two-stage carcinogenesis model. PAC-14028 cream, 0.25%, 0.5%, or 1.0% was applied once daily topically to mouse skin for up to 24 weeks in two-stage chemical carcinogenesis testing using 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). Morbidity/death, clinical signs, tumor formation, activity of EGFR/Akt/mTOR signaling, and systemic exposure to PAC-14028 were investigated. Daily dermal administration of PAC-14028, was not skin carcinogenic. There was also no evidence on the activation of EGFR/Akt/mTOR signaling pathway by the topical treatment of PAC-14028. On Day 169, 1.0% (20 mg/kg/day) of PAC-14028 in female mice resulted in a C and AUC of 12916.0 ng/mL and 78962.9 ng‧hr/mL, respectively. PAC-14028 cream was well tolerated and did not increase the risk of skin tumorigenesis in two-stage carcinogenesis study.
PAC-14028（Asivatrep：CHFNOS）乳膏是一种新型的局部非甾体抗炎药和 TRPV1（瞬时受体电位香草醛亚家族，成员 1）拮抗剂，用于治疗轻度至中度特应性皮炎。TRPV1 阻断在皮肤中引发肿瘤发展的风险引起了关注，但这些发现被证明是间接的，或者仍存在争议。本研究旨在测试 TRPV1 选择性拮抗剂 PAC-14028 乳膏在二阶段致癌模型中是否具有皮肤肿瘤促进作用。在使用 7,12-二甲基苯并[a]蒽（DMBA）和 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）的二阶段化学致癌性测试中，将 0.25%、0.5%或 1.0%的 PAC-14028 乳膏每天一次局部涂用于小鼠皮肤，持续 24 周。研究了发病率/死亡率、临床症状、肿瘤形成、EGFR/Akt/mTOR 信号通路活性以及全身暴露于 PAC-14028 的情况。PAC-14028 的每日经皮给药不会导致皮肤致癌。PAC-14028 的局部治疗也没有证据表明 EGFR/Akt/mTOR 信号通路被激活。在第 169 天，1.0%（20mg/kg/天）的 PAC-14028 在雌性小鼠中导致 C 和 AUC 分别为 12916.0ng/mL 和 78962.9ng·hr/mL。PAC-14028 乳膏耐受性良好，不会增加二阶段致癌研究中皮肤肿瘤发生的风险。
