抗癫痫药物左乙拉西坦对大鼠骨骼的物理及生化指标的影响
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摘要
本研究的目的是以性腺完整的动物为模型调查左乙拉西坦(LEV)是否对于骨矿物质密度、骨结构和骨代谢生化指标产生影响,探究抗癫痫药物左乙拉西坦(LEV)是否对骨骼健康存在显著风险。本研究将实验大鼠分为对照组和试验组,每组10只。对照大鼠接受标准实验室饮食(SLD),而试验组中的大鼠喂食富含LEV的实验室饮食12周,并以双能X-线吸收仪测量全身、股骨和腰椎的骨密度。在骨组织中检查骨标记的浓度,股骨和胫骨均用于生物力学测试。研究结果表明:在LEV组中,脂肪组织的绝对值和相对值显著降低,全身骨密度增高,骨碱性磷酸酶(BALP)、Ⅰ型胶原C末端肽(CTX-1)和Ⅰ型前胶原氨基端前肽(PINP)浓度显著增加。本研究初步得出结论:在性腺完整的大鼠模型中长期施用LEV对骨质不具有负面影响。骨矿物质密度(BMD)的显著增加可能表明LEV对骨质可能有正面影响。
The purpose of this study was to investigate the effects of LEV on bone mineral density, bone structure and bone metabolic biochemical parameters in animals with intact gonadal, and to find out whether the LEV, an antiepileptic drug, has a significant risk to bone health. The experimental rats were divided into control group and test group, 10 rats in each group. Control rats received the standard laboratory diet(SLD), while rats in the experimental group were fed the lab diet rich in LEV for 12 weeks. Dual-energy X-ray absorptiometry measured bone mineral density in the whole body, femur, and lumbar spine. The concentration of bone markers was examined in bone tissue; both femur and tibia were used for biomechanical testing. The results showed that, in the LEV group,the absolute and relative values of adipose tissue were significantly reduced, the whole body bone mineral density was increased, and the concentration of bone alkaline phosphatase(BALP), C-telopeptides of type I collagen(CTX-1)and Type I procollagen N-terminal propeptide(PINP) was also increased significantly. The preliminary conclusion of this study was that long-term application of LEV in a rat model with intact gonads had no negative effect on bone.A significant increase in bone mineral density(BMD) might indicate a possible positive effect of LEV on bone.
The purpose of this study was to investigate the effects of LEV on bone mineral density, bone structure and bone metabolic biochemical parameters in animals with intact gonadal, and to find out whether the LEV, an antiepileptic drug, has a significant risk to bone health. The experimental rats were divided into control group and test group, 10 rats in each group. Control rats received the standard laboratory diet(SLD), while rats in the experimental group were fed the lab diet rich in LEV for 12 weeks. Dual-energy X-ray absorptiometry measured bone mineral density in the whole body, femur, and lumbar spine. The concentration of bone markers was examined in bone tissue; both femur and tibia were used for biomechanical testing. The results showed that, in the LEV group,the absolute and relative values of adipose tissue were significantly reduced, the whole body bone mineral density was increased, and the concentration of bone alkaline phosphatase(BALP), C-telopeptides of type I collagen(CTX-1)and Type I procollagen N-terminal propeptide(PINP) was also increased significantly. The preliminary conclusion of this study was that long-term application of LEV in a rat model with intact gonads had no negative effect on bone.A significant increase in bone mineral density(BMD) might indicate a possible positive effect of LEV on bone.
引文
An war M.J.,Radhakrishna K.V.,and Vohora D,2014.,Phenytoin and sodium valproate but not levetiracetam induce bone alterations in female mice.,Can.J.Physiol.Pharmacol.,92(6):507-511
Artemiadis A.K.,Lambrinoudaki I.,Voskou P.,Tsivgoulis G.,Safouris A.,Bougea A.,Giannopoulos S.,Gatzonis S.,and Triantafyllou N.,2016,Preliminary evidence for gender effects of levetiracetam monotherapy duration on bone health of patients with epilepsy,Epilepsy.Behav.,(55):84-86
Beniczky S.A.,Viken J.,Jensen L.T.,and Andersen N.B.,2012,Bone mineral density in adult patients treated with various antiepileptic drugs,Seizure,21(6):471-472
Erbas O.,Oltulu F.,Ylmaz M.,Yavasoglu A.,and Task覦ran D.,2016,Neuroprotective effects of chronic administration of levetiracetam in a rat model of diabetic neuropathy,Diabetes Res.Clin.Pract.,(114):106-116
Fekete S.,Simko J.,Gradosova I.,Malakova J.,Zivna H.,Palicka V.,and Zivny P.,2013,The effect of levetiracetam on rat bone mass,structure and metabolism,Epilepsy Research,107(1-2):56-60
Gradosova I.,Zivna H.,Palicka V.,Hubena S.,Svejkovska K.,and Zivny P.,2012,Protective effect of atorvastatin on bone tissue in orchidectomised male albino Wistar rats,European Journal of Pharmacology,679(1-3):144-150
Hakami T.,O'Brien T.J.,Petty S.J.,Sakellarides M.,Christie J.,Kantor S.,Todaro M.,Gorelik A.,Seibel M.J.,Yerra R.,and Wark J.D.,2016,Monotherapy with levetiracetam versus older AEDs:a randomized comparative trial of effects on bone health,Calcified Tissue International,98(6):556-565
Hamed S.A.,Moussa E.M.M.,Youssef A.H.,Abd El Hameed M.A.,and NasrEldin E.,2014,Bone status in patients with epilepsy:relationship to markers of bone remodeling,Frontiers in Neurology,(5):142
Kim J.H.,Cho H.T.,and Kim Y.J.,2014,The role of estrogen in adipose tissue metabolism:insights into glucose homeostasis regulation,Endocrine Journal,61(11):1055-1067
Koo D.L.,Joo E.Y.,Kim D.,and Hong S.B.,2013,Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy,Epilepsy Research,104(1-2):134-139
Moon J.,Lee S.T.,Choi J.,Jung K.H.,Yang H.,Khalid A.,Kim J.M.,Park K.I.,Shin J.W.,Ban J.J.,Yi G.S.,Lee S.K.,Jeon D.,and Chu K.,2014,Unique behavioral characteristics and microRNA signatures in a drug resistant epilepsy model,PLoS One,9(1):e85617
Nissen-Meyer L.S.H.,Svalheim S.,Taubll E.,Gjerstad L.,Reinholt F.P.,and Jemtland R.,2008,How can antiepileptic drugs affect bone mass,structure and metabolism?Lessons from animal studies,Seizure,17(2):187-191
Peyrl A.,Weichert N.,Kühl J.S.,Ebell W.,and Hernáiz Driever P.,2015,Levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation,Eur.J.Paediatr.Neurol.,19(1):75-77
Phabphal K.,Geater A.,Limapichat K.,Sathirapanya P.,Setthawatcharawanich S.,and Leelawattana R.,2013,Effect of switching hepatic enzyme-inducer antiepileptic drug to levetiracetam on bone mineral density,25 hydroxyvitamin D,and parathyroid hormone in young adult patients with epilepsy,Epilepsia,54(6):e94-98
Reimers A.,2014,New antiepileptic drugs and women.,Seizure,23(8):585-591
Shen C.,Chen F.,Zhang Y.,Guo Y.,and Ding M.,2014,Association between use of antiepileptic drugs and fracture risk:Asystematic review and meta-analysis,Bone,64(7):246-253
Song J.,Li Z.,Xu Y.,Li H.,and Sheng Y.,2016,The level and influence factors of stigma in people living with epilepsy,Zhonghua Huli Zazhi(Chinese Journal of Nursing),51(1):40-44(宋杰,李真,许阳,李浩,绳宇,2016,癫痫患者羞耻感现状调查及影响因素分析,中华护理杂志,51(1):40-44)
Svalheim S.,Rste L.S.,Nakken K.O.,and Taub覬ll E.,2011,Bone health in adults with epilepsy,Acta Neurologica Scandinavica Supplementum,124(191):89-95
Artemiadis A.K.,Lambrinoudaki I.,Voskou P.,Tsivgoulis G.,Safouris A.,Bougea A.,Giannopoulos S.,Gatzonis S.,and Triantafyllou N.,2016,Preliminary evidence for gender effects of levetiracetam monotherapy duration on bone health of patients with epilepsy,Epilepsy.Behav.,(55):84-86
Beniczky S.A.,Viken J.,Jensen L.T.,and Andersen N.B.,2012,Bone mineral density in adult patients treated with various antiepileptic drugs,Seizure,21(6):471-472
Erbas O.,Oltulu F.,Ylmaz M.,Yavasoglu A.,and Task覦ran D.,2016,Neuroprotective effects of chronic administration of levetiracetam in a rat model of diabetic neuropathy,Diabetes Res.Clin.Pract.,(114):106-116
Fekete S.,Simko J.,Gradosova I.,Malakova J.,Zivna H.,Palicka V.,and Zivny P.,2013,The effect of levetiracetam on rat bone mass,structure and metabolism,Epilepsy Research,107(1-2):56-60
Gradosova I.,Zivna H.,Palicka V.,Hubena S.,Svejkovska K.,and Zivny P.,2012,Protective effect of atorvastatin on bone tissue in orchidectomised male albino Wistar rats,European Journal of Pharmacology,679(1-3):144-150
Hakami T.,O'Brien T.J.,Petty S.J.,Sakellarides M.,Christie J.,Kantor S.,Todaro M.,Gorelik A.,Seibel M.J.,Yerra R.,and Wark J.D.,2016,Monotherapy with levetiracetam versus older AEDs:a randomized comparative trial of effects on bone health,Calcified Tissue International,98(6):556-565
Hamed S.A.,Moussa E.M.M.,Youssef A.H.,Abd El Hameed M.A.,and NasrEldin E.,2014,Bone status in patients with epilepsy:relationship to markers of bone remodeling,Frontiers in Neurology,(5):142
Kim J.H.,Cho H.T.,and Kim Y.J.,2014,The role of estrogen in adipose tissue metabolism:insights into glucose homeostasis regulation,Endocrine Journal,61(11):1055-1067
Koo D.L.,Joo E.Y.,Kim D.,and Hong S.B.,2013,Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy,Epilepsy Research,104(1-2):134-139
Moon J.,Lee S.T.,Choi J.,Jung K.H.,Yang H.,Khalid A.,Kim J.M.,Park K.I.,Shin J.W.,Ban J.J.,Yi G.S.,Lee S.K.,Jeon D.,and Chu K.,2014,Unique behavioral characteristics and microRNA signatures in a drug resistant epilepsy model,PLoS One,9(1):e85617
Nissen-Meyer L.S.H.,Svalheim S.,Taubll E.,Gjerstad L.,Reinholt F.P.,and Jemtland R.,2008,How can antiepileptic drugs affect bone mass,structure and metabolism?Lessons from animal studies,Seizure,17(2):187-191
Peyrl A.,Weichert N.,Kühl J.S.,Ebell W.,and Hernáiz Driever P.,2015,Levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation,Eur.J.Paediatr.Neurol.,19(1):75-77
Phabphal K.,Geater A.,Limapichat K.,Sathirapanya P.,Setthawatcharawanich S.,and Leelawattana R.,2013,Effect of switching hepatic enzyme-inducer antiepileptic drug to levetiracetam on bone mineral density,25 hydroxyvitamin D,and parathyroid hormone in young adult patients with epilepsy,Epilepsia,54(6):e94-98
Reimers A.,2014,New antiepileptic drugs and women.,Seizure,23(8):585-591
Shen C.,Chen F.,Zhang Y.,Guo Y.,and Ding M.,2014,Association between use of antiepileptic drugs and fracture risk:Asystematic review and meta-analysis,Bone,64(7):246-253
Song J.,Li Z.,Xu Y.,Li H.,and Sheng Y.,2016,The level and influence factors of stigma in people living with epilepsy,Zhonghua Huli Zazhi(Chinese Journal of Nursing),51(1):40-44(宋杰,李真,许阳,李浩,绳宇,2016,癫痫患者羞耻感现状调查及影响因素分析,中华护理杂志,51(1):40-44)
Svalheim S.,Rste L.S.,Nakken K.O.,and Taub覬ll E.,2011,Bone health in adults with epilepsy,Acta Neurologica Scandinavica Supplementum,124(191):89-95