对于治疗脑胶质瘤，需要新的疗法。甲苯胺咪唑在体外对犬脑胶质瘤细胞系表现出抗肿瘤效果，其平均抑制浓度（IC50）为10 ng/mL。我们的研究旨在确定甲苯胺咪唑口服剂量，使健康犬脑脊液中的浓度达到≥10 ng/mL。我们假设口服剂量高达200 mg/kg才能达到这个目标。第一阶段是一项剂量滴定研究，使用了6只混合品种犬，描述了单次口服剂量后72小时内剂量与血浆浓度的关系，剂量分别为50 mg/kg (n=2)、100 mg/kg (n=2)或200 mg/kg (n=2)。根据第一阶段结果，第二阶段有9只狗分别接受了100 mg/kg (n=4)或200 mg/kg (n=5)的口服剂量，并分别在60小时和24小时内间断采集血样和脑脊液样品。使用高效液相色谱法对血浆和脑脊液中的甲苯胺咪唑进行定量分析。中位数峰值血浆浓度（Cmax）分别达到100 mg/kg时的7±2小时，为220 ng/mL (81, 283)，达到200 mg/kg时的15±4小时，为147 ng/mL (112, 298)。相应的曲线下面积（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和200 mg/kg的血浆浓度中位数为47 (32, 52)和65 (35, 104) ng/mL。对于脑脊液，100 mg/kg和200 mg/kg的Cmax中位数分别为8 (2, 28)和21 (12, 27)，AUC分别为87 (22, 157)和345 (92, 372)。脑脊液中相对生物利用度与血浆相比为4至10%。虽然有几只动物出现了消化不良的临床症状[如呕吐 (n=2)，腹泻 (n=2)，或两者 (n=1)]，但这些事件并不严重。体外脑胶质瘤IC50浓度可以在100 mg/kg剂量下达到（n=1），然而200 mg/kg剂量可以获得更一致的浓度。Copyright © 2023 Yanke, Day, Taylor, Cruz-Espindola and Boothe.

Novel therapies are needed for treatment of gliomas. Mebendazole previously demonstrated anti-neoplastic effects on canine glioma cell lines at in vitro mean inhibitory concentrations (IC50) 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 (n = 2), 100 mg/kg (n = 2), or 200 mg/kg (n = 2). Based on phase one, phase two dogs (total of 9) received 100 mg/kg (n = 4) or 200 mg/kg (n = 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 (n = 2), diarrhea (n = 2), or both (n = 1)], these events were not considered serious. The in vitro IC50 for gliomas can be reached in CSF at 100 mg/kg (n = 1), however a 200 mg/kg dose yielded more consistent concentrations.Copyright © 2023 Yanke, Day, Taylor, Cruz-Espindola and Boothe.