Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt.
The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt.
Sci Rep. 2018 Jun 12;8(1):8959. doi: 10.1038/s41598-018-27395-0.
Drug repositioning is a revolution breakthrough of drug discovery that presents outstanding privilege with already safer agents by scanning the existing candidates as therapeutic switching or repurposing for marketed drugs. Sitagliptin, vildagliptin, saxagliptin & linagliptin showed antioxidant and neurorestorative effects in previous studies linked to DPP-4 inhibition. Literature showed that gliptins did not cross the blood brain barrier (BBB) while omarigliptin was the first gliptin that crossed it successfully in the present work. LC-MS/MS determination of once-weekly anti-diabetic DPP-4 inhibitors; omarigliptin & trelagliptin in plasma and brain tissue was employed after 2 h of oral administration to rats. The brain/plasma concentration ratio was used to deduce the penetration power through the BBB. Results showed that only omarigliptin crossed the BBB due to its low molecular weight & lipophilic properties suggesting its repositioning as antiparkinsonian agent. The results of BBB crossing will be of interest for researchers interested in Parkinson's disease. A novel intranasal formulation was developed using sodium lauryl sulphate surfactant to solubilize the lipophilic omarigliptin with penetration enhancing & antimicrobial properties. Intranasal administration showed enhanced brain/plasma ratio by 3.3 folds compared to the oral group accompanied with 2.6 folds increase in brain glucagon-like peptide-1 concentration compared to the control group.
药物重定位是药物发现的革命性突破，它通过扫描现有的候选药物作为治疗性转换或重新定位已上市药物，为已经更安全的药物提供了突出的优势。西他列汀、维格列汀、沙格列汀和利格列汀在先前的研究中显示出抗氧化和神经修复作用，这些研究与 DPP-4 抑制有关。文献表明，gliptins 不能穿过血脑屏障（BBB），而奥马格列汀是第一个成功穿过 BBB 的 gliptin。本工作采用 LC-MS/MS 法测定每周一次的抗糖尿病 DPP-4 抑制剂；奥马格列汀和替格列汀在大鼠口服给药 2 小时后的血浆和脑组织中的浓度。利用脑/血浆浓度比来推断其通过 BBB 的穿透能力。结果表明，只有奥马格列汀能够穿过 BBB，这是由于其低分子量和亲脂性特性，提示其可重新定位为抗帕金森病药物。这项 BBB 穿透的研究结果将引起对帕金森病感兴趣的研究人员的关注。本研究采用十二烷基硫酸钠表面活性剂开发了一种新型鼻内制剂，以增溶亲脂性奥马格列汀，并具有渗透增强和抗菌作用。与口服组相比，鼻内给药使脑/血浆比提高了 3.3 倍，与对照组相比，脑胰高血糖素样肽-1 浓度增加了 2.6 倍。
