Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy.
Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy.
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DOI：
10.3389/fvets.2016.00107
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发表时间：
2016
影响因子：
3.2
通讯作者：
Patterson EE
中科院分区：
文献类型：
--
作者：
Vuu I;Coles LD;Maglalang P;Leppik IE;Worrell G;Crepeau D;Mishra U;Cloyd JC;Patterson EE
开发人类癫痫持续状态治疗的障碍包括实验动物模型的不足。相比之下，自然发生的犬癫痫与人类的情况相似，可以作为一个平台，将研究从啮齿动物转化为人类。本研究的目的是描述癫痫犬静脉注射托吡酯（TPM）的药代动力学特征，并评价其对颅内脑电图（iEEG）特征的影响。本研究使用了5只自然发生癫痫的犬。3例接受至少一种抗癫痫药物作为维持治疗，包括苯巴比妥（PB）。四个（ID 1 - 4）用于10 mg/kg IV TPM + PO TPM研究，三个（ID 3 - 5）用于20 mg/kg IV TPM研究。在两种剂量下，在5分钟内输注IV TPM。观察动物的呕吐、腹泻、共济失调和嗜睡。在计划的给药前和给药后时间采集血样。采用经验证的高效液相色谱-质谱法测定血浆浓度。使用研究中所有犬的血浆浓度进行非房室和群体房室建模（Phoenix WinNonLin和NLME）。在一只狗中获得iEEG。使用Kruskal-Wallis检验评估给药前和给药后15分钟的平均iEEG能量水平之间的差异。未观察到不良事件。TPM浓度-时间曲线最佳拟合为二室模型。PB联合给药的清除率增加5.6倍，消除半衰期缩短约4倍。iEEG数据显示TPM在给药的15分钟内在所有16个电极上在> 4Hz的频率下产生显著的能量增加。模拟表明，接受酶诱导剂的犬需要25 mg/kg，而接受非诱导药物的犬需要20 mg/kg，以在给药后30 min达到目标浓度（20 - 30 μ g/mL）。这项研究表明，IV TPM起效相对较快，负荷剂量似乎是安全的，PB的存在需要更高的剂量才能达到目标浓度。因此，它是一个很好的候选人，用于进一步评价治疗犬和人的癫痫发作紧急情况。
Barriers to developing treatments for human status epilepticus include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features. Five dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB). Four (ID 1–4) were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3–5) were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 min at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME) using plasma concentrations from all dogs in the study. iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 min pre- and post-dose was assessed using a Kruskal–Wallis test. No adverse events were noted. TPM concentration–time profiles were best fit by a two compartment model. PB co-administration was associated with a 5.6-fold greater clearance and a ~4-fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 min of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20–30 μg/mL) at 30 min post-dose. This study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of PB necessitates a higher dose to attain targeted concentrations. Consequently, it is a good candidate for further evaluation for treatment of seizure emergencies in dogs and people.
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影响因子：
2.2
作者：
Davis, Kathryn A.;Sturges, Beverly K.;Vite, Charles H.;Ruedebusch, Vanessa;Worrell, Gregory;Gardner, Andrew B.;Leyde, Kent;Sheffield, W. Douglas;Litt, Brian
通讯作者：
Litt, Brian
影响因子：
5.6
作者：
Patterson, Edward E.;Leppik, Ilo E.;Cloyd, James C.
通讯作者：
Cloyd, James C.
影响因子：
1.4
作者：
Akyildiz, Basak Nur;Kumandas, Sefer
通讯作者：
Kumandas, Sefer
影响因子：
2.9
作者：
Yang, Y;Shuaib, A;Siddiqui, MM
通讯作者：
Siddiqui, MM
影响因子：
2.6
作者：
Bensalem, MK;Fakhoury, TA
通讯作者：
Fakhoury, TA