Knudsen J F, Sokol G H, Flowers C M
New Hope Cancer Center, Hudson, FL, USA.
J Clin Pharm Ther. 2008 Oct;33(5):513-9. doi: 10.1111/j.1365-2710.2008.00943.x.
Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia.
We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia.
This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs.
We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected.
We have found hypothermia, defined as an unintentional drop in body core temperature to <35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.
托吡酯于1999年被批准用于治疗癫痫，此后又被批准用于预防偏头痛。它在结构上与大多数抗癫痫药物不同，在抑制碳酸酐酶的能力方面具有独特的药效学特性。已有托吡酯相关体温过低的上市后报告，但这一不良事件尚未得到充分描述。利用不良事件数据库进行数据挖掘，以协助识别体温过低情况。
我们试图探讨托吡酯与丙戊酸联合使用与体温过低诱导之间的可能关联。
这是一项药物警戒病例系列调查，涉及自发性体温过低，这是在单独或联合使用托吡酯和丙戊酸治疗的患者中报告的不良事件。在美国食品药品监督管理局的不良事件报告系统（AERS）数据库中搜索与托吡酯使用相关的体温过低报告。对AERS使用数据挖掘算法，以识别与抗癫痫药物相关的体温过低评分。
我们在接触托吡酯的患者中识别出22例体温过低的非重复报告。22例中有3例因患者同时过量服用多种药物而混淆，未纳入考虑。其余19例报告中的大多数提及使用了不止一种抗抗抗抗癫痫药物。在这19例报告中，7例提到了丙戊酸。19例报告中有2例仅提及托吡酯。19例患者中有11例为男性。19例患者的中位年龄为40岁（范围为3.5 - 82岁）。体温范围为29.5℃（中度体温过低）至35℃（轻度体温过低），中位体温为34℃。18例体温过低报告中有11例发生在较凉爽的月份（1例报告未指明体温过低发生的年份时间）。合并症包括6例甲状腺功能减退，其中5例是在同时接受托吡酯和丙戊酸治疗的患者中，以及5例在类似治疗患者中的高氨血症报告。抗癫痫药物的数据挖掘评分（经验贝叶斯几何均值）范围从苯巴比妥的5.845高值到加巴喷丁的2.956。使用托吡酯时报告的体温过低频率比统计学预期高4.7倍。
我们发现，对于单独耐受这两种药物的患者，体温过低（定义为体核温度意外降至<35℃）与同时给予托吡酯（一种碳酸酐酶抑制剂）和丙戊酸有关。托吡酯的数据挖掘分析显示出体温过低的信号。在数据库中，托吡酯的报告频率比考虑所有其他药物时的统计学预期高4.72倍。托吡酯可能因其降低血液HCO₃⁻和升高血液氨水平的能力而在药效学上增强丙戊酸的作用。
