探討抗癲癇藥物Lacosamide & Phenytoin在鈉離子通道的相互作用

Abstract

我們的感官知覺與肢體動作執行，皆有賴於神經的傳導，而正是電壓依賴型鈉離子通道作為傳導的重要功臣，隨著鈉離子通道打開往細胞內流入的帶正電鈉離子，會使得膜電位上升且當超過閾值時，並產生動作電位。然而當腦部產生不規律或是異常興奮地放電時，可能會形成神經性的疾病，如癲癇。而臨床上透過給予phenytoin、lamotrigine或是lacosamide等抗癲癇藥物，主因是作用於鈉離子通道上，藉由抑制鈉離子通道電流、使鈉離子通道更容易進入到不活化態或是使鈉離子通道的恢復速率變慢。這些機制都是使鈉離子通道的興奮性降低，進而達到減緩腦部的異常放電產生。而幾種傳統的抗癲癇藥物，其中如phenytoin，先前的研究已經表明其是與鈉離子通道緩慢地結合在快速不活化態上。而lacosamide作為一種近十年來較為新穎的抗癲癇藥物，其與傳統的抗癲癇藥物不一樣，lacosamide偏好作用於慢速不活化態上。因此本篇論文針對lacosamide與phenytoin利用1 s及18 s 下不同電壓(-80 mV、-60 mV及-10 mV)的不活化刺激恢復時間實驗，來分別評估大約在鈉離子通道的快速、中速以及慢速不活化態時lacosamide與phenytoin的混合作用下是否具有加成性。我們首先透過此六種情況下兩種藥物的單一使用，藉此評估其在各別不活化態時大約的kd值，並且利用藥物結合比率與recovery course推論出兩藥物是否能夠同時結合在鈉離子通道上，亦即利用單獨藥物存在下的不活化恢復曲線，與兩種藥物共同使用下的不活化曲線進行比較。從這些結果我們認為大約是當鈉離子通道可分布到快速與慢速不活化態時，lacosamide與phenytoin會分別能可能因與各自選擇性結合的通道型態之不同，進而使通道構型上之改變，使兩者共同結合時產生了”互助”現象，因此使同時投以兩種藥物時具有加成性的產生，甚至部份情況會出現協同性。然而當鈉離子通道分布在中速不活化態的比例較多時，則lacosamide與phenytoin能夠產生拮抗性。作為臨床使用上，當病態之神經放電較偏向使鈉離子通道處於快速或慢速不活化態時，同時投以lacosamide與phenytoin或許會比鈉離子通道是處於中速不活化態時，更顯得有意義。

Sensory perception and execution of body movements all depend on nerve conduction, where the voltage-dependent Na+ channel plays an important role. Upon the opening of the Na+ channel, the positively charged sodium ions flow into the cell to depolarize the membrane and an action potential may ensue when the threshold is exceeded. Epilepsy is a common neurological disease characterized by overly synchronized and excessive neural discharges. Anti-epileptic drugs such as phenytoin, lamotrigine, or lacosamide mainly act on Na+ channels, inhibiting Na+ currents by selective binging to the inactivated channel and slowing the recovery. There are at least 3 different inactivated states of the Na+ channels, and the distribution among the fast, intermediate and slow inactivated states is a function of the level and duration of membrane depolarization. The classic antiepileptic drugs, such as phenytoin, have previously been shown to bind selectively but slowly to the fast inactivated Na+ channels. Lacosamide, a new-generation anticonvulsant, is different from the classic ones and selectively binds to the slow inactive state. In this study, we applied different levels and duration of inactivated pulses (-80 mV, -60 mV, and -10 mV for 18 or 1 sec) to investigate the effect of coexisting phenytoin and lacosamide on roughly the fast, intermediate and slow inactivated state, respectively. We first applied each of the two drugs singly to acquire their apparent kd values in different conditions, and then derive the ratio of drug-bound channels and recovery courses to deduce whether the two drugs can simultaneously bind to the Na+ channel. We found that for the fast and slow inactivated Na+ channels, lacosamide and phenytoin binding are mutually beneficial, showing an additive or even a synergistic effect. This is probably because of the different binding affinity to different inactivated states. Concomitant administration of lacosamide and phenytoin may be a rational polytherapy in neurological conditions chiefly involving fast or slow inactivated than those involving intermediate inactivated Na+ channels.