盐酸非格吡胺是一种拮抗鞘氨醇-1-磷酸受体的药物，可阻止淋巴细胞从淋巴器官进入外周循环。它已被用作人类多发性硬化症的改变疾病的药物，并且显示出比其他传统疗法更好的治疗效果。因此，本研究旨在获得非格吡胺在犬类中的临床前数据。本研究使用9只实验用比格犬并随机分为三组进行药物动力学（PK）和药理学（PD）研究。犬只口服一次低剂量（0.01 mg/kg，n=3），中剂量（0.05 mg/kg，n=3）和高剂量（0.1 mg/kg，n=3）的非格吡胺。样本被连续采集在预定时间点，并利用高效液相色谱质谱联用技术测量全血非格吡胺浓度。通过确定不同时间点白细胞的计数来评估免疫细胞对非格吡胺的反应。关于PK来说，非格吡胺在血液中的浓度呈剂量依赖性增加，但不成比例。关于PD，与基线相比，所有剂量组（低剂量，p=0.0002；中剂量，p<0.0001；高剂量，p=0.0012）中的淋巴细胞数量显著减少。在低剂量（p=0.0006）和中剂量（p=0.0006）中，嗜酸性粒细胞也显著减少，中剂量（p=0.0345）和高剂量（p=0.0016）中的中性粒细胞也显著减少。本研究为将非格吡胺用于犬类免疫介导疾病（如原发性不明脑膜脑炎）的临床应用提供了基础数据。 版权所有 © 2023 年，国际抗癌研究所（George J. Delinasios博士），保留所有权利。

Fingolimod is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes egress from lymphoid organs. It has been used as a disease-modifying drug for human multiple sclerosis and has shown better therapeutic effects than other conventional therapies. Therefore, this study was performed to obtain preclinical data of fingolimod in dogs.Nine laboratory Beagle dogs were used and randomized into three groups for pharmacokinetics (PK) and pharmacodynamics (PD). The dogs were administered once with a low-dose (0.01 mg/kg, n=3), medium-dose (0.05 mg/kg, n=3), and high-dose (0.1 mg/kg, n=3) of fingolimod, orally. Samples were collected serially at predetermined time points, and whole blood fingolimod concentrations were measured using high-performance liquid chromatography-mass spectrometry. Differential counts of leukocytes over time were determined to identify immune cells' response to fingolimod.Regarding PK, the concentration of fingolimod in the blood increased in a dose-dependent manner, but it was not proportional. Regarding PD, the number of lymphocytes significantly decreased compared to baseline in all dose groups (low-dose, p=0.0002; medium-dose, p<0.0001; high-dose, p=0.0012). Eosinophils were significantly reduced in low- (p=0.0006) and medium- (p=0.0006) doses, and neutrophils were also significantly reduced in medium-(p=0.0345) and high- (p=0.0016) doses.This study provides the basis for future clinical applications of fingolimod in dogs with immune-mediated diseases, such as meningoencephalitis of unknown etiology.Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.