Hewitt Ellen, Pitcher Thomas, Rizoska Biljana, Tunblad Karin, Henderson Ian, Sahlberg Britt-Louise, Grabowska Urszula, Classon Björn, Edenius Charlotte, Malcangio Marzia, Lindström Erik
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
J Pharmacol Exp Ther. 2016 Sep;358(3):387-96. doi: 10.1124/jpet.116.232926. Epub 2016 Jun 22.
Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions.
组织蛋白酶S抑制剂可减轻临床前神经性疼痛模型中的机械性异常性疼痛。本研究评估了在神经性疼痛小鼠模型中，将选择性组织蛋白酶S抑制剂MIV-247与加巴喷丁或普瑞巴林联合使用时的效果。通过部分坐骨神经结扎使小鼠产生神经性疼痛。MIV-247、加巴喷丁或普瑞巴林通过灌胃单独给药或联合给药。使用von Frey毛发评估机械性异常性疼痛。通过评估光束行走来评估神经行为副作用。测量各种组织中MIV-247、加巴喷丁和普瑞巴林的浓度。口服MIV-247（100-200 μmol/kg）单剂量给药或每日给药两次，连续给药5天时，剂量依赖性地减轻机械性异常性疼痛，逆转率高达约50%。在测试的任何MIV-247剂量下均未观察到行为缺陷。加巴喷丁（58-350 μmol/kg）和普瑞巴林（63-377 μmol/kg）也抑制机械性异常性疼痛，在测试的最高剂量下几乎完全逆转。MIV-247的最小有效剂量（100 μmol/kg）与普瑞巴林的最小有效剂量（75 μmol/kg）或加巴喷丁的最小有效剂量（146 μmol/kg）联合使用，可增强抗异常性疼痛疗效，且不增加副作用。MIV-247的亚有效剂量（50 μmol/kg）与普瑞巴林的亚有效剂量（38 μmol/kg）或加巴喷丁的亚有效剂量（73 μmol/kg）联合使用也具有显著疗效。MIV-247、加巴喷丁和普瑞巴林联合给药时的血浆水平与单独给药时相似。用MIV-247抑制组织蛋白酶S单独具有显著的抗异常性疼痛疗效，还可增强加巴喷丁和普瑞巴林的效果，且不增加副作用或诱导药代动力学相互作用。
