A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy

The biochemical parameters associated with vitamin D metabolism, calcium, 25-hydroxy-vitamin D (25OHD) and alkaline phosphatase levels were assessed in 226 out-patients with epilepsy. Patients were grouped depending on the drug treatment; carbamazepine, phenytoin, phenobarbitone and sodium valproate used alone as monotherapy and a combination of these drugs as polytherapy. The most severe alterations occurred in the polytherapy group. Hypocalcaemia was more severe in the phenobarbitone monotherapy group than the carbamazepine or the phenytoin groups. No patient on sodium valproate monotherapy had subnormal levels of calcium (less than 2.1 mmol/l). 25OHD levels were similarly reduced in the carbamazepine, phenytoin and the phenobarbitone groups with no reduction in the sodium valproate group. Significant elevations in alkaline phosphatase levels were evident in all patient groups except the sodium valproate group. This study confirms biochemical evidence for anticonvulsant osteomalacia when the enzyme-inducing drugs are used, the degree of severity depending on the drug regimen.     

Pharmacotherapy of trigeminal neuralgia.

The efficacy of the anticonvulsant drug carbamazepine in the management of trigeminal neuralgia is evidenced in several controlled trials, and the numbers needed to treat to obtain one patient with at least 50% pain relief (NNT) is 1.7. Single small trials have shown that baclofen alone provides pain relief (NNT = 1.4) and that lamotrigine has an additional effect in patients with insufficient relief using carbamazepine or phenytoin (NNT = 2.1). Uncontrolled observations and clinical practice indicate that phenytoin, clonazepam, sodium valproate, gabapentin, and lidocaine will also relieve trigeminal neuralgia. In case of lacking effect of a single drug, combination of two or more drugs may be used, but with the exception of the lamotrigine-carbamazepine combination, this is not evidence-based medicine. Acute exacerbation has successfully been treated with intravenous loading with phenytoin or lidocaine, but again these procedures have not been tested in controlled trials. In conclusion, carbamazepine is the mainstay of pharmacotherapy of trigeminal neuralgia, and secondary drug choices are baclofen, lamotrigine, oxcarbazepine, phenytoin, gabapentin, and sodium valproate. Controlled trials testing the effect of some of these drugs, new drugs, and drug combinations are needed.     

A Comparative Study of the Relative Influence of Different Anticonvulsant Drugs, UV Exposure and Diet on Vitamin D and Calcium Metabolism in Out-Patients with Epilepsy

The biochemical parameters associated with vitamin D metabolism,calcium, 25-hydroxyvitamin D (25OHD) and alkaline phosphataselevels were assessed in 226 out-patients with epilepsy. Patientswere grouped depending on the drug treatment; carbamazepine,phenytoin, phenobarbitone and sodium valproate used alone asmonotherapy and a combination of these drugs as polytherapy.The most severe alterations occurred in the polytherapy group.Hypocalcaemia was more severe in the phenobarbitone monotherapygroup than the carbamazepine or the phenytoin groups. No patienton sodium valproate monotherapy had subnormal levels of calcium(<2.1 mmol/l). 25OHD) levels were similarly reduced in thecarbamazepine, phenytoin and the phenobarbitone groups withno reduction in the sodium valproate group. Significant elevationsin alkaline phosphatase levels were evident in all patient groupsexcept the sodium valproate group. This study confirms biochemicalevidence for anticonvulsant osteomalacia when the enzyme-inducingdrugs are used, the degree of severity depending on the drugregimen.     

Neurobehavioral effects of phenytoin, carbamazepine, and valproic acid: implications for use in traumatic brain injury

Due to the risk of posttraumatic epilepsy, phenytoin, carbamazepine, and valproic acid are often prescribed for patients with traumatic brain injury (TBI). In this review the literature is examined for evidence of neurobehavioral impairment due to carbamazepine, phenytoin, and valproic acid. No comparative studies have been performed in the TBI population, making if difficult to determine if one of these medications is preferable. Direct inference from studies on epilepsy patients to TBI patients is hazardous due to underlying differences in the two populations. Reported findings for epilepsy patients are subtle and not consistent across studies. All three drugs appear to exert some effect on cognitive and motor functions in epileptic patients, and these impairments worsen at increasing serum levels. The varied length of experience with each drug makes it difficult to assign relative weight to the evidence for or against each. A comparative assessment of cognitive and behavioral effects of anticonvulsants should be done in the TBI population.     

Drug interactions between chemotherapeutic regimens and antiepileptics

BACKGROUND: Drug-drug interactions (DDIs) are commonly seen in daily clinical practice, particularly in the treatment of patients with cancer. Seizures are often seen in patients with brain tumors and brain metastases, in whom antiepileptic drugs (AEDs) are often indicated. The risk for DDIs between anticancer drugs and AEDs is high. OBJECTIVE: This review aimed to investigate the types of interactions that are observed between the AEDs and the most commonly prescribed chemotherapeutic regimens. The risk for DDIs is discussed with regard to tumor type. METHODS: Data on DDIs between anticancer drugs and AEDs were compiled from the British National Formulary, Drug Information Handbook, and Micromedex Healthcare Series version 5.1. Product information of the individual drugs, as well as literature on anticancer drug-AED interactions, was searched using PubMed (years: December 1970 to January 2008; search terms: anticancer, antiepileptic, chemotherapy regimen, drug interactions, and the generic names of the individual anticancer drugs and AEDs [acetazolamide, carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide]). RESULTS: Our search identified clinically important DDIs observed with single-agent and combination regimens used for the treatment of breast cancers, colorectal cancers, lung cancers, lymphomas, and renal cell carcinomas. Carbamazepine, phenytoin, phenobarbital, and primidone were found to have prominent cytochrome P450 (CYP) enzyme-induction effects, while valproic acid had an inhibitory effect. The isozymes of major relevance to anticancer drug-AED interactions included CYP3A4, CYP2C9, and CYP2C19. Induction or inhibition of these isozymes by AEDs can cause a decrease or increase in anticancer drug concentrations. Similarly, enzyme inhibition or induction by anticancer drugs can lead to toxicity or loss of seizure control. CONCLUSIONS: In this review of anticancer drug-AED DDIs, carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid were found to interact the most frequently with anticancer drugs. Based on the results of this review, clinicians should be vigilant when AEDs are prescribed concurrently with anticancer drugs. DDIs can be avoided or minimized by selecting alternative AEDs that are less likely to interact. However, if potentially interacting drug combinations must be used for treatment, serum drug concentrations should be closely monitored to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and antiepileptic coverage.     

丙戊酸钠联合氯硝西泮治疗难治性癫痫的疗效观察

目的 观察丙戊酸钠联合氯硝西泮治疗难治性癫痫的临床疗效及不良反应.方法 125例难治性癫痫患者随机分为两组,治疗组(n=65)采用丙戊酸钠联合氯硝西泮治疗,对照组(n=60)采用苯妥英钠治疗,两组疗程均为6个月,观察两组治疗总有效率及治疗期间不良反应情况.结果 治疗组总有效率(89.2%)明显高于对照组(78.3%)(P<0.05),两组治疗过程中未出现严重不良反应.结论 丙戊酸钠联合氯硝西沣治疗难治性癫痫疗效显著,不良反应少,值得临床推广应用.     

Improved sexual function in three men taking lamotrigine for epilepsy

Little information exists about the effects of newer antiepileptic drugs (AEDs) on sexual function in men with epilepsy. We report a series of three male veterans whose sexual disorders improved with lamotrigine. All three had partial seizures. One patient was taking phenobarbital and gabapentin and complained of decreased potency and anorgasmia. After lamotrigine was added for better seizure control and the dosage of gabapentin was tapered, anorgasmia improved. The second patient complained of impotence after a rash while taking phenytoin and carbamazepine. Impotence persisted with phenobarbital, valproate, and gabapentin. Eight months after gabapentin was replaced with lamotrigine, impotence improved. The third patient complained of long-standing impotence. Treatment with five AEDs had no effect on the dysfunction. Lamotrigine was added to the carbamazepine regimen; impotence improved with decrease in carbamazepine and increase in lamotrigine. The favorable effect of lamotrigine on sexual disorders in these three patients suggests this drug should be considered under appropriate circumstances for men who have sexual dysfunction while taking other antiepileptic agents.     

A comparative study of the relative effects of anticonvulsant drugs and dietary folate on the red cell folate status of patients with epilepsy

In a survey of the red cell folate status of 200 patients with epilepsy, compared to 72 controls, we found that median red cell folate levels were reduced significantly in patients treated with phenytoin (p less than 0.01) or carbamazepine (p less than 0.001) alone. Patients taking more than one drug had reduced levels also (p less than 0.001), but in patients treated with sodium valproate alone there was no significant decrease in red cell folate levels compared to controls. Twenty-two per cent of patients in the group taking more than one drug had reduced levels of red cell folate compared with 17 per cent of those taking carbamazepine alone, 13 per cent of those taking phenytoin only, and 9 per cent of those taking sodium valproate only. Dietary folate intake was significantly reduced in all the patient groups compared with controls (p less than 0.001 for the carbamazepine and phenytoin groups, p less than 0.01 for the polypharmacy and sodium valproate groups); a significant correlation between red cell folate levels and dietary folate was not established. Significant negative relationships were established between carbamazepine dose (r = -0.35, p less than 0.01) or serum level (r = -0.27, p less than 0.05) and red cell folate level in patients on one drug only. The correlation between dose or serum level of phenytoin and red cell folate level was also negative but did not reach significance. Our findings show that all anticonvulsant drugs interfere with folate metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

An interaction between cytostatic and anticonvulsant drugs

A young woman with epilepsy had tonic-clonic seizures during antineoplastic therapy with adriamycin and cisplatin. During two courses of cytostatic drug administration peak and trough plasma levels of phenytoin, carbamazepine, and valproate sodium were measured. Lower plasma levels of carbamazepine and valproate sodium were observed after 2 days of antineoplastic therapy. Normal plasma levels of these drugs were found 2 to 3 days after the last cisplatin dose. Impaired absorption or accelerated elimination might explain these results. Phenytoin levels were reduced to 37% of the original values, although the drug was given intravenously. Changed Michaelis-Menten parameters suggest that cisplatin increases the metabolic rate of phenytoin. Another explanation for the decreased drug levels might be an increased volume of distribution. Calculation of this volume from peak and trough levels showed an increase of the volume of distribution during and after chemotherapy.     

Kindling as a model of drug-resistant partial epilepsy: selection of phenytoin-resistant and nonresistant rats.

Complex partial seizures comprise the major uncontrolled seizure type in adult patients with epilepsy. Any improvement of our understanding of the mechanisms through which these seizures are often refractory to antiepileptic drugs is therefore of considerable importance. By examining the effects of the anti-epileptic drug phenytoin in a large group of kindled rats, a widely used model of complex partial seizures, animals with different sensitivity to this drug were selected. Using determination of the focal seizure threshold for evaluation of phenytoin's anticonvulsant effect, most animals (about 60%) showed variable effects in response to phenytoin. However, about 20% of the animals ("phenytoin nonresponders") showed no increase in their focal seizure threshold at repeated test trials with phenytoin, and 20% ("phenytoin responders") exhibited reproducible increases in focal seizure threshold after injection of phenytoin. Phenytoin responders and nonresponders thus selected were used for subsequent experiments. The different response of focal seizures to phenytoin was not related to differences in pharmacokinetics or location of the stimulating electrode. Although phenytoin reproducibly increased the threshold for induction of afterdischarges in responders, it did not alter severity or duration of the elicited seizure response. In contrast to phenytoin, carbamazepine induced increases in focal seizure threshold in all kindled rats. Duration of seizures and afterdischarges were significantly reduced by carbamazepine in phenytoin responders, but not in nonresponders, although plasma levels of carbamazepine were the same in both groups. The difference in response of kindled rats to phenytoin was restricted to kindled seizures, because phenytoin induced the same anticonvulsant effect on the threshold for generalized tonic electroconvulsions (determined via transauricular electrodes) in both groups of kindled rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incidence of intravenous site reactions in neurotrauma patients receiving valproate or phenytoin

OBJECTIVE: To determine the incidence of intravenous site reactions to phenytoin and valproate in a large population of patients with neurotrauma. DESIGN: Retrospective chart review of two double-blind, randomized clinical trials evaluating the use of antiepileptic drugs to prevent posttraumatic seizures in patients with neurotrauma: phenytoin versus placebo (n = 390), and valproate versus phenytoin with placebo (n = 385). Information collected from the charts included the number, type, and location of intravenous lines and intravenous site events. SETTING: Tertiary care trauma and university teaching hospital. MAIN RESULTS: Intravenous site reactions occurred in 18% and 25% of patients receiving valproate or phenytoin, respectively, with the majority of events (70%) occurring in the first intravenous site. Patients received the neurosurgery study drug (NSSD) by either central or peripheral lines; all intravenous site reactions occurred in peripheral administration sites. When patients who received the drug by central line during the course of therapy were excluded, the estimated incidence of site reactions was 21% and 30% for valproate and phenytoin, respectively (p = 0.056). The time to the first event was shorter with phenytoin compared with valproate (2.0 +/- 1.3 vs. 3.0 +/- 1.9 d; p = 0.009). Fewer adverse events were noted with phenytoin in the phenytoin-without-valproate study than in the phenytoin-with-valproate study, with 4.3% and 8.2% of intravenous site events recorded in patients receiving placebo or phenytoin, respectively. There was no significant difference in the number of intravenous lines per patient used during NSSD drug infusion for phenytoin versus placebo or phenytoin versus valproate. CONCLUSIONS: Both intravenous phenytoin and valproate resulted in intravenous site reactions, with the loading doses responsible for the majority of the events.     

癫痫患者服用中药制剂西药成分的血药浓度检测

目的探讨某些抗癫痫"中药制剂"中是否含有抗癫痫西药成分及其含量情况,指导临床用药。方法采用荧光偏振免疫法测定58例癫痫患者所服"中药制剂"中的丙戊酸钠、苯妥英钠、苯巴比妥、卡马西平的种类及血药浓度。结果所有患者中均检测出上述1～4种常用抗癫痫西药。血药平均浓度丙戊酸钠为(12±14)μg/ml,苯妥英钠为(5±6)μg/ml,苯巴比妥为(11±9)μg/ml,卡马西平为(2.2±2.6)μg/ml。结论所谓的抗癫痫"中药制剂"中含有不同种类和剂量的常用化学药物,干扰了癫痫的正规治疗。     

Lack of pharmacokinetic interaction between valproic acid and a traditional Chinese medicine, Paeoniae Radix, in healthy volunteers

BACKGROUND AND OBJECTIVE: In addition to the standard antiepileptic drugs, traditional Chinese medicines (TCMs) are used for the treatment of epilepsy in oriental countries. The interactions between antiepileptic drugs and TCMs represent a potential problem in clinical application. Because valproic acid (VPA), one of the most widely prescribed antiepileptic drugs, may be administered concomitantly with Paeoniae Radix (PR), one of the famous TCMs, in some epileptic patients, the present study was conducted to evaluate the influences of PR on the pharmacokinetics of VPA. METHOD: The pharmacokinetics of VPA were investigated in a randomized, open-label, two-way crossover study. Six healthy volunteers received the following treatments in a crossover design: (i) 1.2 g extract powder of Paeoniae Radix once daily for 7 days and one 200 mg VPA gastro-resistant tablet on day 7 and (ii) one 200 mg VPA gastro-resistant tablet alone on day 7. Serial plasma samples were obtained on day 7. Total and free (unbound) VPA plasma concentrations were determined by fluorescence polarization immunoassay (FPIA). Safety measures included laboratory tests (haematology, serum chemistry and urinalysis) and adverse event monitoring. Statistical comparisons of pharmacokinetic parameters were performed with the Student paired t-test. RESULTS: Overall clinical safety was satisfactory. The mean maximum plasma concentration of VPA was attained at within 6 h after oral administration of VPA alone and 3-4 h after oral administration of VPA in combination with PR. The plasma level of VPA declined with a half-life of 11.71 and 11.91 h, respectively. No statistically significant difference was obtained in any of the pharmacokinetic parameters (Tmax, Cmax, AUC, t1/2, MRT, CL/F and Vd/F) of VPA between the two treatments. Also, there was no significant difference in the protein binding rates of VPA. CONCLUSION: PR did not significantly affect the absorption, distribution, metabolism and elimination of VPA in healthy volunteers.     

Clinical pharmacology and therapeutic use of the new antiepileptic drugs

Although older generation antiepileptic drugs (AEDs) such as carbamazepine, phenytoin and valproic acid continue to be widely used in the treatment of epilepsy, these drugs have important shortcomings such as a highly variable and nonlinear pharmacokinetics, a narrow therapeutic index, suboptimal response rates, and a propensity to cause significant adverse effects and drug interactions. In an attempt to overcome these problems, a new generation of AEDs has been introduced in the last decade. Compared with older agents, some of these drugs offer appreciable advantages in terms of less variable kinetics and, particularly in the case of gabapentin, levetiracetam and vigabatrin, a lower interaction potential. Lamotrigine, topiramate, zonisamide and felbamate protect against partial seizures and a variety of generalized seizure types, vigabatrin is effective against partial seizures (with or without secondary generalization) and infantile spasms, while the use of oxcarbazepine, tiagabine and gabapentin is mainly restricted to patients with partial epilepsy (and, in the case of oxcarbazepine, also primarily generalized tonic-clonic seizures). Levetiracetam, the latest AED to be introduced, has been found to be effective in partial seizures, but its potentially broader efficacy spectrum remains to be determined in clinical studies. Currently, the main use of new generation AEDs is in the adjunctive therapy of patients refractory to older agents. However, due to advantages in terms of tolerability and ease of use, some of these drugs are increasingly used for first-line management in certain subgroups of patients. Due to serious toxicity risks, felbamate and vigabatrin should be prescribed only in patients refractory to other drugs. In the case of vigabatrin, however, first line use may be justified in infants with spasms.     

托吡酯联合丙戊酸钠、氯硝西泮治疗难治性癫痫临床观察

目的探讨托吡酯联合丙戊酸钠、氯硝西泮治疗难治性癫痫的疗效。方法对符合标准的157例难治性癫痫患者给予氯硝西泮、丙戊酸钠、托吡酯。观察治疗3个月、6个月、1年、2年后的疗效和不良反应。结果治疗6个月后总有效率为75.16%,随着时间的延长疗效进入平稳期;对各种发作类型都有很好的控制作用,不良反应轻微。结论托吡酯联合丙戊酸钠、氯硝西泮治疗难治性癫痫疗效确切,安全性高。     

Interaction of antiepileptic drugs with human P-glycoprotein in vitro

About one-third of epilepsy patients are resistant to treatment with antiepileptic drugs (AEDs). This refractoriness is not fully understood, but is thought to be attributed to overexpression of multidrug transporters at the blood-brain barrier, particularly P-glycoprotein (Pgp). In certain cases pharmacoresistance can be overcome by add-on therapy, raising the question of whether the coadministered drugs act as inhibitors of Pgp. Indeed, several AEDs are substrates and to some extent also inducers of Pgp. To date nothing is known about possible Pgp inhibitory activities of AEDs. Therefore, we investigated whether AEDs commonly used in mono or add-on therapy inhibit Pgp using a calcein acetoxymethylester uptake assay with L-MDR1 cells and primary porcine brain capillary endothelial cells, as well as confocal laser-scanning microscopy with L-MDR1 cells and bodipy-verapamil as Pgp substrate. In the calcein assay only carbamazepine inhibited Pgp, which was confirmed in confocal laser-scanning microscopy. In this assay, also phenytoin, lamotrigine, and valproate revealed Pgp inhibitory potency. Because Pgp inhibition by AEDs appeared at significantly higher concentrations than that of well known inhibitors and because the effective concentrations exceeded therapeutic AED plasma concentrations, Pgp inhibition appears not to be of clinical relevance, at least in antiepileptic monotherapy. However, it is possible that this inhibition may contribute to the effectiveness of certain add-on therapies.     

多药耐药基因1C3435T多态性在癫痫患者中的分布及其与癫痫耐药的关系

目的研究多药耐药基因1（MDR1）C3435T多态性在癫痫患者中的分布特点,并探讨其与癫痫患者对抗癫痫药物反应的关系。方法收集的230例癫痫患者中,其中对抗癫痫药物不敏感的患者（耐药组）108例和敏感的患者（敏感组）122例,选择90例正常人作对照;再按癫痫类型和病因选取耐药组和敏感组。用多聚合酶链反应扩增后继以限制性内切酶片断长度分析法（PCR-RFLP方法）分别测定各组患者MDR1基因C3435T位点的基因型频率和等位基因频率。然后对耐药组、敏感组和对照组的基因型频率和等位基因频率进行比较。结果 （1）总耐药组和总敏感组病例中的基因型比较和等位基因频率比较,差异均无统计学意义（P〉0.05）。（2）不同癫痫类型中,耐药组和敏感组基因型频率和等位基因频率比较均无统计学意义（P〉0.05）。（3）在不同病因的癫痫患者中,耐药组和敏感组病例比较,结果基因型频率和等位基因频率的差异均无统计学意义（P〉0.05）。结论无论在考虑癫痫分型和病因还是不考虑分型和病因,MDR1C3435T位点多态性与癫痫患者对抗癫痫药物的耐药性均没有关系。     

Pharmacokinetic drug interactions in children taking oxcarbazepine

OBJECTIVE: Our objective was to evaluate the drug-drug interactions of oxcarbazepine with coadministered antiepileptic drugs in children. METHODS: In a clinical trial, pediatric patients receiving an oxcarbazepine dose titrated to 30 to 46 mg. kg(-1). d(-1) given twice daily had 1 to 4 blood samples collected per patient for population pharmacokinetic analysis of oxcarbazepine's major bioactive 10-monohydroxy metabolite. With the use of NONMEM, 7 concomitant antiepileptic drugs and 12 additional covariates were examined for their effects on the pharmacokinetics of 10-monohydroxy metabolite. In addition, for each concomitant antiepileptic drug, the ratio of its mean concentration with coadministration of oxcarbazepine to that without coadministration at baseline was calculated to evaluate the effect of oxcarbazepine on the coadministered antiepileptic drugs. RESULTS: The population pharmacokinetic data for 10-monohydroxy metabolite consisted of a total of 376 observations from 109 patients, aged 3 to 17 years. Body surface area and 3 antiepileptic drugs (carbamazepine, phenobarbital, and phenytoin) were significant predictors of the apparent clearance of 10-monohydroxy metabolite, whereas height was a significant predictor of apparent volume. Weight-normalized clearance of 10-monohydroxy metabolite was higher in young children than in older children and adults. Carbamazepine, phenobarbital, or phenytoin administered with oxcarbazepine increased the apparent clearance of 10-monohydroxy metabolite by 31% to 35%, whereas carbamazepine levels decreased by 15% and phenobarbital levels increased by 14%. CONCLUSIONS: Oxcarbazepine has a low propensity to inhibit or induce oxidative enzymes. Young children could be given higher milligrams-per-kilogram oxcarbazepine doses than older children and adults to achieve the same mean steady-state concentration of 10-monohydroxy metabolite. The adjustment is based simply on body size.