Adjunctive use of verapamil in patients with refractory temporal lobe epilepsy: A pilot study
Introduction
For many years, the epilepsy community has addressed the burden of drug-resistant epilepsy by concentrating on the development of new antiepileptic drugs (AEDs) and epilepsy surgery. These approaches have resulted in some improvement, but the percentage of patients with refractory epilepsy is still substantial [1], [2], [3]. To date, no study has demonstrated that the new AEDs have greater potency than more established AEDs. On the other hand, only a small percentage of patients whose seizures had failed to respond to initial monotherapy achieved seizure freedom with alternative monotherapy, and a very small percentage became seizure-free on combination therapy [4]. In addition, epilepsy surgery is an invasive procedure, sometimes with significant adverse effects [5].
Two major mechanisms have been put forward in medically refractory epilepsy: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug efflux transporters such as P-glycoprotein (P-gp) and (b) reduced drug-target sensitivity in epileptogenic brain tissue [6], [7]. P-glycoprotein, the encoded product of the human multidrug resistance-1 (MDR-1; ABCB1) gene, is of particular clinical relevance in the emergence of multidrug resistance (MDR), which plays an important role in the treatment failure of tumors, infectious diseases, and epilepsy [7]. It has been shown that MDR-1 is overexpressed in brain tissue (hippocampal neurons) from rats and patients (humans) with medically refractory temporal lobe epilepsy [8], [9], [10]. It is proposed that P-gp is overexpressed at the luminal side of the brain capillary endothelial cells where it acts as an efflux pump to lower the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy resistant to treatment with AEDs [8], [9], [10], [11]. For direct proof of this theory, it should be examined whether P-gp inhibitors can be used to counteract multidrug resistance [6], [7]. Such a strategy is suggested by a report on a patient with medically refractory epilepsy in whom the P-gp inhibitor “verapamil” was added to the AED regimen. This addition greatly improved seizure control [12].
Several compounds already in clinical use, including verapamil, nifedipine, quinidine, amiodarone, nicardipine, quinine, tamoxifen, and cyclosporin A, are able to inhibit P-gp [13]. Verapamil hydrochloride is a calcium-channel blocking agent, which is usually used in the management of tachyarrhythmias, angina, hypertension, and acute myocardial infarction [14]. This drug has also been used with some success in the management of manic manifestations of bipolar disorder [15], [16]. Neurologists sometimes prescribe verapamil for prophylaxis of migraine headaches [17]. The usual initial adult dosage of oral verapamil for cardiac problems is at least 120 mg/day. Verapamil is usually well tolerated in therapeutic dosages [14].
This study was conducted to determine if adjunctive use of verapamil, as a P-glycoprotein inhibitor, in patients with refractory temporal lobe epilepsy (RTLE) is efficacious in decreasing their seizure frequency. We also tried to investigate the safety and tolerability of adjunctive use of verapamil in patients with RTLE.
Section snippets
Materials and methods
This was an non-placebo-controlled, open-label, pilot study with convenience sampling from one center (outpatient epilepsy clinic at Shiraz University of Medical Sciences). Inclusion criteria were as follows: male/female (nonpregnant female adequately protected from conception) patients, between the ages of 18 and 65 years; with diagnosis of temporal lobe epilepsy made on the basis of clinical findings; and with medically refractory seizures defined as failure of two or more AEDs at maximal
Patients
Twenty patients with confirmed refractory temporal lobe epilepsy were included in the study (six men and 14 women). The mean age of the patients was 31.7 ± 9.1 years. The mean age at seizure onset was 17.6 ± 11.4 years; the mean seizure duration was 15.16 ± 8.27 years. In three patients from group B, the dosage of verapamil was reduced from 240 mg/day to 120 mg/day because of intolerable adverse events; they were entered into group A. One patient from group A had poor drug adherence, and she was excluded
Discussion
For many years, investigators and physicians have addressed the problem of medically refractory epilepsy by investigating and developing new AEDs [24]. However, few patients whose epilepsy was resistant to older AEDs such as phenytoin, carbamazepine, and valproate have become permanently seizure-free on the new AEDs [1], and no study has demonstrated that the new AEDs have greater potency than more established AEDs [25]. Therefore, it would be desirable to either develop more effective drugs to
Conclusion
Developing new means of improving the effectiveness of existing AEDs is a desirable way of tackling the dilemma of medically refractory epilepsy. Hypothetically, P-gp inhibitors (such as verapamil) might be used to counteract the removal of AEDs from the epileptogenic tissue through excessive expression of multidrug efflux transporters such as P-glycoprotein (P-gp) [26]. Such a strategy was adopted in this study, and we observed a significant achievement in the seizure control in patients with
Conflict of interest
The authors have no conflict of interest with regards to this study.
Acknowledgment
The authors would like to thank the Center for Development of Clinical Studies of Namazi teaching Hospital for statistical assistance. The present article was extracted from the thesis written by Seyyed Mohammad Ali Razavizadegan Jahromi and was financially supported by Shiraz University of Medical Sciences grants No. 3629.
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2019, Pharmacological ResearchCitation Excerpt :Open label pilot studies were also conducted in humans, using verapamil as an ABCB1 inhibitor in adjunctive treatment. In 19 patients with drug-resistant TLE with different medication regimens, verapamil was administered in 2 doses: 13 patients received 120 mg/day and 6 received 240 mg/day [177]. They reported that 7 of the 19 patients achieved more than 50% reduction in seizure frequency, and two out of these sevenbecame seizure free.