J. T. Vaughan Large Animal Teaching Hospital, Auburn University, Auburn, AL, USA.
Department of Drug Discovery and Development, Auburn University, Auburn, AL, USA.
BMC Vet Res. 2020 Apr 16;16(1):115. doi: 10.1186/s12917-020-02331-5.
Keratomycosis is a relatively common, sight threatening condition in horses, where treatment is often prolonged and costly. Subconjunctival (SCo) injections offer less resistance to drug diffusion than the topical route, resulting in better penetration to the ocular anterior segment. Voriconazole, a second generation triazole antifungal, is effective against common fungal organisms causing keratomycosis. If combined with a thermogel biomaterial, voriconazole can be easily injected in the SCo space to provide sustained drug release. The purpose of this study was to evaluate the drug concentrations in the anterior segment and clinical effects after SCo injections of voriconazole-containing thermogel: poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) in healthy equine eyes.
Voriconazole aqueous humor (AH) and tear concentrations were compared between 6 horses, receiving 1% voriconazole applied topically (0.2 mL, q4h) (Vori-Top) or 1.7% voriconazole-thermogel (0.3 mL) injected SCo (Vori-Gel). For the Vori-Gel group, voriconazole concentrations were measured in AH and tears at day 2 and then weekly for 23 days, and at day 2 only for the Vori-Top group. Ocular inflammation was assessed weekly (Vori-Gel) using the modified Hackett-McDonald scoring system. Ocular tissue concentrations of voriconazole following SCo 1.7% voriconazole-thermogel (0.3 mL) injections were evaluated post euthanasia in 6 additional horses at 3 different time points. Three horses received bilateral injections at 2 h (n = 3, right eye (OD)) and 48 h (n = 3, left eye (OS)) prior to euthanasia, and 3 horses were injected unilaterally (OS), 7 days prior to euthanasia. Voriconazole-thermogel was easily injected and well tolerated in all cases, with no major adverse effects. On day 2, drug concentrations in tears were higher in the Vori-Top, but not statistically different from Vori-Gel groups. For the Vori-Gel group, voriconazole was non-quantifiable in the AH at any time point. Total voriconazole concentrations in the cornea were above 0.5 μg/g (the target minimum inhibitory concentration (MIC) for Aspergillus sp.) for up to 48 h; however, concentrations were below this MIC at 7 days post treatment.
Voriconazole-thermogel was easily and safely administered to horses, and provided 48 h of sustained release of voriconazole into the cornea. This drug delivery system warrants further clinical evaluation.
真菌性角膜炎是一种较为常见的、可致盲的马科动物疾病，治疗往往需要很长时间且费用高昂。与局部滴眼相比，结膜下注射（SCo）方式药物扩散阻力更小，药物更容易渗透至眼前节。伏立康唑是一种第二代三唑类抗真菌药物，对引起真菌性角膜炎的常见真菌病原体有效。如果与温敏型生物材料相结合，伏立康唑可轻松注射至 SCo 空间，实现药物的持续释放。本研究旨在评估结膜下注射含伏立康唑的温敏型生物材料（聚（DL-丙交酯-co-乙交酯-b-乙二醇-b-DL-丙交酯-co-乙交酯）（PLGA-PEG-PLGA））后，健康马眼内前段的药物浓度和临床效果。
6 匹马分别接受局部滴用 1%伏立康唑（0.2mL，q4h）（Vori-Top）或结膜下注射 1.7%伏立康唑温敏凝胶（0.3mL）（Vori-Gel）治疗，比较两组的伏立康唑房水（AH）和泪液浓度。Vori-Gel 组在第 2 天及第 23 天（每周）测量 AH 和泪液中的伏立康唑浓度，Vori-Top 组仅在第 2 天测量。每周（Vori-Gel）使用改良 Hackett-McDonald 评分系统评估眼表炎症。6 匹马在安乐死后 3 个不同时间点评估结膜下注射 1.7%伏立康唑温敏凝胶（0.3mL）后的眼组织中伏立康唑浓度，其中 3 匹马双侧注射，分别在安乐死前 2 小时（n=3，右眼（OD））和 48 小时（n=3，左眼（OS）），3 匹马单侧注射，在安乐死前 7 天。伏立康唑温敏凝胶在所有病例中均易于注射且耐受性良好，无重大不良反应。第 2 天，Vori-Top 组泪液中的药物浓度更高，但与 Vori-Gel 组无统计学差异。Vori-Gel 组在任何时间点的 AH 中均未检测到伏立康唑。角膜中的总伏立康唑浓度高达 48 小时，高于 0.5μg/g（曲霉菌最低抑菌浓度（MIC）的目标值）；然而，治疗后 7 天，浓度低于该 MIC 值。
伏立康唑温敏凝胶可安全、方便地用于马匹，为角膜提供长达 48 小时的伏立康唑持续释放。该药物递送系统值得进一步临床评估。
