Yanke Amy B, Day Kendall E, Taylor Amanda R, Cruz-Espindola Crisanta, Boothe Dawn M
Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, United States.
BluePearl Pet Hospital North Dallas, Lewisville, TX, United States.
Front Vet Sci. 2023 Aug 28;10:1231769. doi: 10.3389/fvets.2023.1231769. eCollection 2023.
Novel therapies are needed for treatment of gliomas. Mebendazole previously demonstrated anti-neoplastic effects on canine glioma cell lines at mean inhibitory concentrations (IC) of 10 ng/mL. Our study aimed to titrate the oral dose of mebendazole necessary to achieve concentrations ≥10 ng/mL in cerebrospinal fluid (CSF) of healthy dogs. We hypothesized that an oral dose up to 200 mg/kg would be necessary. Phase one was a dose titration study using a total of 6 mixed breed dogs that described dose vs. plasma concentrations for 72 h after single oral dosing of either 50 mg/kg ( = 2), 100 mg/kg ( = 2), or 200 mg/kg ( = 2). Based on phase one, phase two dogs (total of 9) received 100 mg/kg ( = 4) or 200 mg/kg ( = 5) orally and blood samples were collected intermittently for 60 h with CSF samples collected intermittently for 24 h. Mebendazole was quantitated in plasma and CSF using high performance liquid chromatography. Median peak plasma concentrations (Cmax) were reached at 7 ± 2 h (100 mg/kg) of 220 ng/mL (81, 283) and at 15 ± 4 h (200 mg/kg) of 147 ng/ml (112, 298). The respective area under the curve (AUC: ng/ml/h) reported as a median was 2,119 (1,876, 3,288) vs. 3,115 (1,559, 4,972). Median plasma concentrations (ng/ml) for 100 vs. 200 mg/kg were 47 (32, 52) vs. 65 (35, 104), respectively. For CSF, the median value for Cmax (at 100 mg/kg vs. 200 mg/kg) was 8 (2, 28) vs. 21 (12, 27) and AUC was 87 (22, 157) vs. 345 (92, 372), respectively. Relative bioavailability in CSF vs. plasma was 4 to 10%. Although several animals demonstrated clinical signs indicative of gastrointestinal upset [i.e., vomiting ( = 2), diarrhea ( = 2), or both ( = 1)], these events were not considered serious. The IC for gliomas can be reached in CSF at 100 mg/kg ( = 1), however a 200 mg/kg dose yielded more consistent concentrations.
胶质瘤的治疗需要新的疗法。甲苯咪唑先前已证明对犬胶质瘤细胞系具有抗肿瘤作用，其平均抑制浓度（IC）为10 ng/mL。我们的研究旨在确定健康犬脑脊液（CSF）中达到≥10 ng/mL浓度所需的甲苯咪唑口服剂量。我们假设需要高达200 mg/kg的口服剂量。第一阶段是剂量滴定研究，共使用6只混种犬，描述单次口服50 mg/kg（n = 2）、100 mg/kg（n = 2）或200 mg/kg（n = 2）后72小时的剂量与血浆浓度关系。基于第一阶段，第二阶段的犬（共9只）口服100 mg/kg（n = 4）或200 mg/kg（n = 5），间歇性采集血样60小时，间歇性采集脑脊液样本24小时。使用高效液相色谱法对血浆和脑脊液中的甲苯咪唑进行定量。血浆中峰值浓度中位数（Cmax）在100 mg/kg组7±2小时达到220 ng/mL（81, 283），在200 mg/kg组15±4小时达到147 ng/ml（112, 298）。曲线下面积（AUC：ng/ml/h）中位数分别为2,119（1,876, 3,288）和3,115（1,559, 4,972）。100 mg/kg与200 mg/kg组的血浆浓度中位数（ng/ml）分别为47（32, 52）和65（35, 104）。对于脑脊液，Cmax中位数（100 mg/kg与200 mg/kg）为8（2, 28）和21（12, 27），AUC分别为87（22, 157）和345（92, 372）。脑脊液相对于血浆的相对生物利用度为4%至10%。尽管几只动物出现了胃肠道不适的临床症状[即呕吐（n = 2）、腹泻（n = 2）或两者皆有（n = 1）]，但这些事件不被认为严重。100 mg/kg（n = 1）时脑脊液中可达到胶质瘤的IC，但200 mg/kg剂量产生的浓度更稳定。
