Stepanović-Petrović Radica, Micov Ana, Tomić Maja, Pecikoza Uroš
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe, 450, POB 146, Belgrade, 11221, Serbia.
Psychopharmacology (Berl). 2017 Jun;234(11):1781-1794. doi: 10.1007/s00213-017-4583-z. Epub 2017 Mar 22.
We have reported that levetiracetam, a novel anticonvulsant with analgesic properties, synergizes with ibuprofen/aspirin/paracetamol in a model of diabetic painful neuropathy (DPN). Most guidelines recommend gabapentin, pregabalin, and duloxetine as first- or second-line agents for DPN.
We examined the effects of combination treatment of first-/second-line analgesics with levetiracetam in a model of DPN. Additionally, the levetiracetam's combinations with antioxidants, low dose of aspirin, coenzyme Q10, or α-lipoic acid were evaluated.
Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin. The antinociceptive effects of orally administered levetiracetam, gabapentin, pregabalin, duloxetine (acute treatment) and aspirin, coenzyme Q10, and α-lipoic acid (preventive 7-day treatment), as well as combinations of levetiracetam with individual drugs were examined in the tail-flick test. In combination experiments, the drugs were coadministered in fixed-dose fractions of single-drug ED; the type of interaction was determined by isobolographic analysis.
About 60-, 32-, 30-, 26-, 18-, and 6-fold reductions of doses of both drugs in levetiracetam combinations with pregabalin, gabapentin, coenzyme Q10, aspirin, duloxetine, and α-lipoic acid, respectively, were detected.
Combinations of levetiracetam with gabapentin/pregabalin/duloxetine that target different mechanisms/sites of action involved in DPN, as well as combinations of levetiracetam and low-dose aspirin/coenzyme Q10/α-lipoic acid that target underlying causes of DPN, produce marked synergistic interactions in reducing nociception in diabetic mice. This suggests that these combination treatments might be of great benefit for diabetic patients and should be explored further in clinical trials.
我们曾报道，左乙拉西坦是一种具有镇痛特性的新型抗惊厥药，在糖尿病性疼痛性神经病变（DPN）模型中，它可与布洛芬/阿司匹林/对乙酰氨基酚产生协同作用。大多数指南推荐加巴喷丁、普瑞巴林和度洛西汀作为DPN的一线或二线用药。
我们研究了一线/二线镇痛药与左乙拉西坦联合治疗在DPN模型中的效果。此外，还评估了左乙拉西坦与抗氧化剂、低剂量阿司匹林、辅酶Q10或α-硫辛酸的联合用药情况。
用单次高剂量链脲佐菌素诱导C57BL/6小鼠患糖尿病。通过甩尾试验检测口服左乙拉西坦、加巴喷丁、普瑞巴林、度洛西汀（急性治疗）以及阿司匹林、辅酶Q10和α-硫辛酸（预防性7天治疗）的镇痛效果，以及左乙拉西坦与各药物联合使用的效果。在联合实验中，将药物按单药半数有效剂量（ED）的固定剂量比例共同给药；通过等效应线图分析确定相互作用类型。
分别检测到左乙拉西坦与普瑞巴林、加巴喷丁、辅酶Q10、阿司匹林、度洛西汀和α-硫辛酸联合使用时，两种药物剂量分别约降低了60倍、32倍、30倍、26倍、18倍和6倍。
左乙拉西坦与针对DPN中不同作用机制/位点的加巴喷丁/普瑞巴林/度洛西汀联合使用，以及左乙拉西坦与针对DPN潜在病因的低剂量阿司匹林/辅酶Q10/α-硫辛酸联合使用，在减轻糖尿病小鼠的痛觉方面产生了显著的协同相互作用。这表明这些联合治疗可能对糖尿病患者大有裨益，应在临床试验中进一步探索。
