Department of Pharmaceutical Technology, Faculty of Pharmacy, Altinbas University, Istanbul,Turkey.
Department of Basic Medicine Sciences, Faculty of Medicine, Dokuz Eylul University, Izmir,Turkey.
Curr Drug Deliv. 2021;18(10):1515-1525. doi: 10.2174/1567201818666210322144631.
Olmesartan Medoxomil (OM) is an angiotensin receptor blocker and has the adverse effect of celiac like enteropathy which was accepted by the FDA in 2013. This disease is characterized by severe diarrhea, weight loss and enteropathy. Although there are many case reports associated with olmesartan-related enteropathy in humans, it has not been described in a long-term animal model study so far.
We developed a self-microemulsifying drug delivery system (OM-SMEDDS) in our previous study to reduce this side effect of the drug and to enhance bioavailability.
In this study, an artificial hypertension model was established with a dose of 185 μmol /kg L-NAME (N ω-nitro-L-arginine methyl ester) twice in a day intraperitoneally in Wistar albino rats. To determine and compare side effects, the OM-Suspension and OM-SMEDDS were administered at 1.3 mg/kg therapeutic dose during one-month period to the rats.
Tension of rats was recorded by measuring from their tails with non invasive blood pressure system. We observed celiac like enteropathy findings like villous atrophy and intraepithelial lymphocytosis and clinical changes like weight loss and severe diarrhea after the treatment with OM-Suspension during one-month experiment. It was also observed that the antihypertensive efficacy of the OM-SMEDDS formulation was higher than the suspension during the experiment, which did not cause enteropathy, diarrhea and weight loss by reducing intestinal exposure.
Hereby, we evaluated the side effects of two different pharmaceutical forms by designing a sustainable and reproducible celiac rat model that can be induced with olmesartan medoxomil.
奥美沙坦酯（OM）是一种血管紧张素受体阻滞剂，具有类似乳糜泻的肠病的不良反应，这一不良反应于 2013 年被 FDA 认可。这种疾病的特征是严重腹泻、体重减轻和肠病。尽管有许多与奥美沙坦相关的肠病相关的病例报告，但迄今为止，在长期的动物模型研究中尚未对其进行描述。
我们在之前的研究中开发了一种自微乳给药系统（OM-SMEDDS），以减少药物的这种副作用并提高生物利用度。
在这项研究中，我们通过每天两次腹膜内注射 185μmol/kg 的 L-NAME（N ω-硝基-L-精氨酸甲酯）在 Wistar 白化大鼠中建立了人工高血压模型。为了确定和比较副作用，我们在一个月的时间内以 1.3mg/kg 的治疗剂量向大鼠给予 OM 混悬剂和 OM-SMEDDS。
通过使用非侵入性血压系统从大鼠尾巴上测量，记录大鼠的张力。我们观察到在一个月的实验中，用 OM 混悬剂治疗后出现了类似乳糜泻的肠病的发现，如绒毛萎缩和上皮内淋巴细胞增多，以及临床变化，如体重减轻和严重腹泻。我们还观察到，在实验过程中，OM-SMEDDS 制剂的降压效果高于混悬剂，通过减少肠道暴露，它不会引起肠病、腹泻和体重减轻。
通过设计一种可持续且可重复的乳糜泻大鼠模型，我们评估了两种不同药物制剂的副作用，该模型可由奥美沙坦酯诱导。
