PAC-14028 (Asivatrep: C21H22F5N3O3S) 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 Cmax and AUC0-τ 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.

中文翻译：

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TRPV1拮抗剂PAC-14028不会增加化学诱导的小鼠皮肤癌变过程中发生肿瘤的风险。

PAC-14028（Asivatrep：C21H22F5N3O3S）乳膏是一种新型的局部非甾体抗炎和TRPV1（瞬态受体潜在的香草类亚家族，成员1）拮抗剂，用于治疗轻度至中度特应性皮炎。已经引起人们对皮肤中TRPV1阻断引起的肿瘤发展风险的担忧，但事实证明这些发现是间接的或仍存在争议。测试该研究以确定在两阶段致癌模型中TRPV1选择性拮抗剂PAC-14028霜是否对促进皮肤肿瘤发生安全。在使用7、12-二甲基苯并[a]蒽（DMBA）和12-苯丙氨酸的两阶段化学致癌性测试中，每天两次将0.25％，0.5％或1.0％的PAC-14028乳膏局部施用于小鼠皮肤长达24周。邻十四烷酰基佛波醇13-乙酸酯（TPA）。发病/死亡，临床体征，研究了肿瘤的形成，EGFR / Akt / mTOR信号传导的活性以及与PAC-14028的全身接触。每日经皮施用PAC-14028不会引起皮肤致癌。也没有证据表明PAC-14028的局部治疗可激活EGFR / Akt / mTOR信号通路。在第169天，雌性小鼠中1.0％（20 mg / kg / day）的PAC-14028导致Cmax和AUC0-τ分别为12916.0 ng / mL和78962.9ng‧hr/ mL。在两阶段致癌研究中，PAC-14028乳膏具有良好的耐受性，并且不会增加皮肤肿瘤发生的风险。在第169天，雌性小鼠中1.0％（20 mg / kg / day）的PAC-14028导致Cmax和AUC0-τ分别为12916.0 ng / mL和78962.9ng‧hr/ mL。在两阶段致癌研究中，PAC-14028乳膏具有良好的耐受性，并且不会增加皮肤肿瘤发生的风险。在第169天，雌性小鼠中1.0％（20 mg / kg / day）的PAC-14028导致Cmax和AUC0-τ分别为12916.0 ng / mL和78962.9ng‧hr/ mL。在两阶段致癌研究中，PAC-14028乳膏具有良好的耐受性，并且不会增加皮肤肿瘤发生的风险。