Milbemycin A4 oxime is a semi-synthetic macrolide compound prepared by the oxidation and oximation of milbemycin A4, used for the treatment of parasitic diseases[1-2]. Milbemycin A4 oxime acts by activating glutamate-sensitive chloride channels in invertebrate neurons, leading to cell hyperpolarization and blockade of signal transmission, thereby causing paralysis and death of parasites[3-4].
In vitro, treatment of adriamycin-resistant human breast cancer cells MCF-7/adr with Milbemycin A4 oxime (0.1-5μM) in combination with adriamycin for 48 hours, Milbemycin A4 oxime significantly enhanced the cytotoxicity of adriamycin and reduced multidrug resistance in the cells[5].
In vivo, intraperitoneal administration of Milbemycin A4 oxime (0.5-2.5mg/kg/day) for 7 days in BALB/c mice with systemic Candida glabrata or Candida albicans infections, Milbemycin A4 oxime significantly reduced fungal loads in the spleen and kidneys[6].
References:
[1] Walker B, Izumikawa K, Tsai HF, et al. Milbemycin A4 oxime as a probe of azole transport in Candida glabrata. FEMS Yeast Res. 2014 Aug;14(5):755-61. doi: 10.1111/1567-1364.12164.
[2] Schares G, Hofmann B, Zahner H. Antifilarial activity of macrocyclic lactones: comparative studies with ivermectin, doramectin, milbemycin A4 oxime, and moxidectin in Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi, and B. pahangi infection of Mastomys coucha. Trop Med Parasitol. 1994 Jun;45(2):97-106.
[3] Prichard RK. Macrocyclic lactone resistance in Dirofilaria immitis: risks for prevention of heartworm disease. Int J Parasitol. 2021 Dec;51(13-14):1121-1132.
[4] Mueller RS. An update on the therapy of canine demodicosis. Compend Contin Educ Vet. 2012 Apr;34(4):E1-4.
[5] Xiang W, Gao A, Liang H, et al. Reversal of P-glycoprotein-mediated multidrug resistance in vitro by milbemycin compounds in adriamycin-resistant human breast carcinoma (MCF-7/adr) cells. Toxicol In Vitro. 2010 Sep;24(6):1474-81.
[6] Silva LV, Sanguinetti M, Vandeputte P, et al. Milbemycins: more than efflux inhibitors for fungal pathogens. Antimicrob Agents Chemother. 2013 Feb;57(2):873-86.
Milbemycin A4 oxime是一种通过氧化和肟化米尔贝霉素A4制备的半合成大环内酯类化合物，被用于治疗寄生虫相关疾病[1-2]。Milbemycin A4 oxime通过激活无脊椎动物神经元中的谷氨酸敏感性氯离子通道，导致细胞超极化并阻滞信号传递，从而使寄生虫麻痹死亡[3-4]。
在体外，Milbemycin A4 oxime（0.1-5μM）与阿霉素联合处理阿霉素耐药的人乳腺癌细胞MCF-7/adr 48小时，显著增强阿霉素的细胞毒性，并降低细胞的多要耐药性[5]。
在体内，Milbemycin A4 oxime（0.5-2.5mg/kg/day）腹腔注射治疗7天，用于处理BALB/c小鼠系统性光滑念珠菌或白色念珠菌感染。Milbemycin A4 oxime显著降低了脾脏和肾脏中的真菌负荷[6]。