生物活性

• 描述Transcription factor hypoxia inducible factor-1 (HIF-1) is a master switch under hypoxia that upregulates the expression of multiple angiogenic proteins including stromal derived factor (SDF)-1, placental growth factor (PlGF), endothelin-1, VEGF and its receptor VEGFR-1. HIF-1 consists of a HIF-1α and a HIF-1β subunit. Ciclopirox and its olamine salt are family members of hydroxypyridone, which is a prolyl hydroxylase inhibitor and can stabilize HIF-1α predominantly in fibroblasts induced capillary sprouting in endothelial cells to increase angiogenesis^[6]. Moreover, ciclopirox is a potential drug for HBV. In a vitro study, HMSCs were stimulated with ciclopirox at dose of 10 μM for 24 h to perform subsequent gene expression analysis, suggesting that decrease of HIF-1α expression on gene level, whereas VEGF expression was upregulated by ciclopirox^[7]. In another vitro assay, a kind of truncated HBV core protein, cp149, was incubated with 0.1 - 10 μM ciclopirox and an anti-HBV core antibody was added for immunoblot analysis. The result showed that IC₅₀ value of ciclopirox was 445 ± 17 nM,, which indicated that ciclopirox potently affected intracellular HBV capsid assembly. In a vivo study, endothelial cells were cultured to observe sprouts of fibroblasts and only a few longer sprouts were observed. However, when ciclopirox at dose of 0.4 mM were introduced, an increase of sprout length ensued with the formation of a basal network and formation of anastomoses, indicating that ciclopirox induced secretion of VEGF^[6]. In another study, human liver-chimeric uPA/SCID mice were injected intravenously with HBV virion (5 × 10⁷ copies per mouse), and after 6 weeks the mice were treated daily with ciclopirox at dose of 5 mg/kg daily for 5 weeks. The data indicated that ciclopirox had lowered serum HBV DNA, HBeAg and serum ALT levels significantly. Furthermore, ciclopirox also significantly reduced HBV core protein levels in the liver. These evidences proved that ciclopirox is an effective HBV capsid assembly inhibitor^[8].
• 作用机制Hydrophobic residues L19, F23, F24, P25, Y118, F122, and W102, with extensive van der Waals interactions between ciclopirox and these residues form a binding pocket^[9]. Ciclopirox Olamine is an olamine form of ciclopiro. And ciclopirox can mimic the effect of bipyridine, a well-known iron chelator and also an antifungal agent, upregulating the expression of the high-affinity iron permease gene FTR1 and the low-affinity iron permease gene FTR2, which are essential for iron metabolism^[10].

• 动物研究
  剂量	Mice: 3 µg/eye/dose, 1 µg/eye/dose[3] (dropwise to the corneal surface); 5 mg/kg - 25 mg/kg[4] (p.o.) Rat: 13 mg/kg, 38.8 mg/kg[5] (i.v.)
  给药途径	dropwise to the corneal surface, p.o., i.v.
  动物药代数据	Animal Rats[5] Dose 10.02 ± 0.04 mg/kg Administration i.v. MRT 0.446 ± 0.474 h T1/2 0.615 ± 0.404 h C0 25883 ± 13321 ng/ml Vdz 2983 ± 2319 ml/kg CL 3225 ± 342 ml/h/kg AUC0→∞ 3141 ± 349 ng·h/ml Vss 1563 ± 1853 ml/kg

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03348514	Advanced Solid Tumors	Phase 1	Recruiting	July 31, 2019	United States, Colorado ... more >> Sarah Cannon Research Institute Not yet recruiting Denver, Colorado, United States, 80218 Contact: Kari Koga    720-754-4650    kari.koga@sarahcannon.com    Principal Investigator: Gerald Falchook          United States, Florida Florida Cancer Specialists & Research Institute Recruiting Sarasota, Florida, United States, 34232 Contact: Michele LaRoc    941-377-9993    Mlaroc@flcancer.com    Principal Investigator: Manish Patel          United States, Tennessee Tennessee Oncology PLLC Recruiting Nashville, Tennessee, United States, 37203 Contact: Rachell Bellamy    615-341-7851    Rachell.Bellamy@sarahcannon.com    Principal Investigator: Howard Burris Collapse <<
  NCT02004860	Severe Seborrheic Dermatitis	Phase 3	Completed	-	France ... more >> Rouen University Hospital Rouen, France, 76031 Collapse <<
  NCT02866032	Distal Subungual Onychomycosis	Phase 3	Unknown	-	Germany ... more >> Recruiting Study sites, Germany Poland Recruiting Study sites, Poland Collapse <<

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• 参考文献

• [1] Zarember KA, Cruz AR, et al. Antifungal activities of natural and synthetic iron chelators alone and in combination with azole and polyene antibiotics against Aspergillus fumigatus. Antimicrob Agents Chemother. 2009 Jun;53(6):2654-6.

  [2] Niewerth M, Kunze D, et al. Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob Agents Chemother. 2003 Jun;47(6):1805-17.

  [3] Bernier KM, Morrison LA, et al. Antifungal drug ciclopirox olamine reduces HSV-1 replication and disease in mice. Antiviral Res. 2018 Aug;156:102-106.

  [4] Mihailidou C, Papakotoulas P, et al. Superior efficacy of the antifungal agent ciclopirox olamine over gemcitabine in pancreatic cancer models. Oncotarget. 2017 Dec 8;9(12):10360-10374.

  [5] Weir SJ, Wood R, et al. Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs. J Pharmacol Exp Ther. 2019 Aug;370(2):148-159.

  [6] Lim SH, Kim C, Aref AR, Kamm RD, Raghunath M. Complementary effects of ciclopirox olamine, a prolyl hydroxylase inhibitor and sphingosine 1-phosphate on fibroblasts and endothelial cells in driving capillary sprouting. Integr Biol (Camb). 2013 Dec;5(12):1474-84.

  [7] Kremer A, Wußmann M, Herrmann M, Raghunath M, Walles H. Ciclopirox olamine promotes the angiogenic response of endothelial cells and mesenchymal stem cells. Clin Hemorheol Microcirc. 2019;73(2):317-328.

  [8] Kang JA, Kim S, Park M, Park HJ, Kim JH, Park S, Hwang JR, Kim YC, Jun Kim Y, Cho Y, Sun Jin M, Park SG. Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly. Nat Commun. 2019 May 16;10(1):2184.

  [10] Shen T, Huang S. Repositioning the Old Fungicide Ciclopirox for New Medical Uses. Curr Pharm Des. 2016;22(28):4443-50.

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