Jeffery Nick, Boudreau C Elizabeth, Konarik Megan, Mays Travis, Fajt Virginia
Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX, United States of America.
Veterinary Medical Diagnostic Laboratory, Texas A&M University, College Station, TX, United States of America.
PeerJ. 2018 Feb 26;6:e4387. doi: 10.7717/peerj.4387. eCollection 2018.
Glyburide (also known as glibenclamide) is effective in reducing the severity of tissue destruction and improving functional outcome after experimental spinal cord injury in rodents and so has promise as a therapy in humans. There are many important differences between spinal cord injury in experimental animals and in human clinical cases, making it difficult to introduce new therapies into clinical practice. Spinal cord injury is also common in pet dogs and requires new effective therapies, meaning that they can act as a translational model for the human condition while also deriving direct benefits from such research. In this study we investigated the pharmacokinetics and safety of glyburide in dogs with clinical spinal cord injury.
We recruited dogs that had incurred an acute thoracolumbar spinal cord injury within the previous 72 h. These had become acutely non-ambulatory on the pelvic limbs and were admitted to our veterinary hospitals to undergo anesthesia, cross sectional diagnostic imaging, and surgical decompression. Oral glyburide was given to each dog at a dose of 75 mcg/kg. In five dogs, we measured blood glucose concentrations for 10 h after a single oral dose. In six dogs, we measured serum glyburide and glucose concentrations for 24 h and estimated pharmacokinetic parameters to estimate a suitable dose for use in a subsequent clinical trial in similarly affected dogs.
No detrimental effects of glyburide administration were detected in any participating dog. Peak serum concentrations of glyburide were attained at a mean of 13 h after dosing, and mean apparent elimination half-life was approximately 7 h. Observed mean maximum plasma concentration was 31 ng/mL. At the glyburide dose administered there was no observable association between glyburide and glucose concentrations in blood.
Our data suggest that glyburide can be safely administered to dogs that are undergoing anesthesia, imaging and surgery for treatment of their acute spinal cord injury and can attain clinically-relevant serum concentrations without developing hazardous hypoglycemia. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25-50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury.
格列本脲（也称为优降糖）在减轻啮齿动物实验性脊髓损伤后的组织破坏严重程度及改善功能预后方面有效，因此有望用于人类治疗。实验动物的脊髓损伤与人类临床病例存在许多重要差异，这使得新疗法难以引入临床实践。脊髓损伤在宠物狗中也很常见，需要新的有效疗法，这意味着它们可作为人类疾病的转化模型，同时也能直接从这类研究中受益。在本研究中，我们调查了格列本脲在患有临床脊髓损伤的犬中的药代动力学及安全性。
我们招募了在过去72小时内发生急性胸腰段脊髓损伤的犬。这些犬的盆腔肢体急性无法行走，并被送往我们的兽医医院接受麻醉、横断面诊断成像及手术减压。每只犬口服格列本脲的剂量为75微克/千克。在5只犬中，单次口服给药后测量10小时的血糖浓度。在6只犬中，测量24小时的血清格列本脲和葡萄糖浓度，并估算药代动力学参数，以估算适用于后续类似受影响犬的临床试验的合适剂量。
在任何参与实验的犬中均未检测到格列本脲给药的有害影响。给药后格列本脲的血清峰值浓度平均在13小时达到，平均表观消除半衰期约为7小时。观察到的平均最大血浆浓度为31纳克/毫升。在所给予的格列本脲剂量下，未观察到格列本脲与血液中葡萄糖浓度之间存在关联。
我们的数据表明，格列本脲可安全地给予正在接受麻醉、成像及手术以治疗急性脊髓损伤的犬，并且能够达到临床相关的血清浓度而不会出现危险的低血糖。本研究中达到的血清格列本脲浓度表明，口服给药后，负荷剂量为150微克/千克，随后每8小时重复给予75微克/千克的剂量，将在足够短的可接受时间内使血清格列本脲浓度达到25 - 50纳克/毫升，适合用于犬脊髓损伤的临床试验。
