CU03-1001, 50% ethanol-extract of Moutan radices cortex and Cinnamomi ramulus (1:1) inhibited laser-induced choroidal neovascularization (CNV) in Brown Norway rats

Age-related macular degeneration (AMD) is the cause of blindness in people over 60 years of age. More than 30 million individuals worldwide suffer from visual impairment due to AMD [1]. Anti-VEGF therapies require repetitive intravitreal injections and have been successful in improving central vision about 30% [2]. long-term treatment associated with geographic atrophy, cardiovascular event and loss of the retinal neurotrophic activity [3], [4], [5]. Our goal is to develop an oral herbal drug to prevent AMD exacerbation, and reduce repetitive intravitreal injections and avert side effects of anti-VEGF therapies.

CU03-1001 was standardized with 12 compounds by HPLC. 30 compounds were identified using UPLC/Q-Orbitrap. After CNV, 60 and 90 mg/kg CU03-1001 were administrated orally BID for 15 days. CNV lesion areas and fluorescence leakage were significantly reduced. CU03-1001 constituents significantly inhibited reduction in the thickness of subretinal outer nuclear layer in N-methyl-N-nitrosourea-treated zebrafish or rats. CU03-1001 significantly decreased permeability in ARPE-19 cells, and migration and tube formation in HRMECs. Based on the GLP repeated toxicity test for 13-weeks in rats, NOAEL was determined as 1,250 mg/kg. The maximum tolerable dosage in beagle dogs after 28-day repeated oral administration was considered over 1,500 mg/kg. No evidence of GLP genotoxicity and safety pharmacology were found. Studies on CYP450 and UGT revealed CU03-1001 as a poor interactor. Finally, a combination therapy of current anti-VEGF agent and CU03-1001 might be possible to prevent against deterioration of AMD and to decrease side effects and the injection frequency of anti-VEGF therapies. [KIOM grants: K18270, KSN1911711]

• References

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