Review of alterations in oral phenytoin bioavailability associated with formulation, antacids, and food

Since 1938, phenytoin has been widely used for the control of seizure disorders. Phenytoin is available from a variety of manufacturers in a variety of dosage forms. Certain physiochemical properties of phenytoin may lead to bioavailability changes. The physiochemical properties exert themselves not only in the presence of other drugs but also during the manufacturing process. Manufacturing processes that may influence phenytoin bioavailability include salt form, particle size, product excipient, and dosage form. Drug influences upon phenytoin bioavailability largely include antacid anions, which may form insoluble complexes. Anions present within the diet may also influence the rate and extent of phenytoin absorption. This article reviews the various influences on phenytoin bioavailability with regard to the manufacturing process, antacid, and food.     

Phenytoin: an anti-bipolar anticonvulsant?

Phenytoin, a classical anticonvulsant has been little studied in bipolar disorder. We completed a trial of phenytoin in mania and schizoaffective disorder, manic type. Thirty-nine patients entered a 5-wk double-blind controlled trial of haloperidol+phenytoin vs. haloperidol+placebo; 30 patients completed at least 3 wk; 25 completed 5 wk. Significantly more improvement was observed in those patients receiving phenytoin. Phenytoin has not previously been studied prophylactically in bipolar patients. Bipolar patients were studied who had at least one episode per year in the previous 2 yr despite ongoing prophylaxis. Patients were stable for a mean of 4 months (range 1-13) before entering the study. Phenytoin or placebo was added to their current therapy in a double-blind cross-over design for 6 months in each phase. Thirty observation periods of 6 months each were studied for 23 patients. Three patients had relapse on phenytoin and nine had relapse on placebo. There was a significant prophylactic effect of phenytoin in bipolar disorder [Cox's F test for comparing survival in two groups: F(6, 18)=3.44, p=0.02]. This study suggests prophylactic effects of add-on phenytoin in bipolar illness. However, the number of patients was small and confirmation is necessary. Lamotrigine has recently been reported to have antidepressant effects. In the past, small studies showed antidepressant effects for carbamazepine and valproate. To determine if such effects could be a class property of other voltage-activated sodium channel blockers such as phenytoin, we performed a double-blind controlled trial of phenytoin vs. fluoxetine in unipolar depression. Thirty-three depressed patients entered the study, and 28 completed at least 3 weeks and were included in data analyses. Weekly Hamilton Depression Scales for 6 wk showed no difference between fluoxetine and phenytoin. Clearly pharmaceutical company funding for clinical trials or advertising for phenytoin is minimal and this must be taken into account in evaluating literature on phenytoin vs. other drugs. The present data suggests that effects on affective disorder may be common to many anticonvulsants.     

Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro

Human peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and exposed in vitro to phenytoin or carbamazepine, two widely used antiepileptic drugs (AED). This study investigated the effects of these drugs on natural killer (NK) cell activity and antibody-dependent cell-mediated cytotoxicity (ADCC), which are both thought to protect against developing neoplasms. Also, the genotoxicity of phenytoin on human PBMC was investigated by gravity-flow alkaline elution. Concentrations of phenytoin considered therapeutic (10 and 20 micrograms/ml) and a dose considered acutely toxic (40 micrograms/ml) were used while carbamazepine levels of 8 micrograms/ml (therapeutic) and 10 and 16 micrograms/ml (acutely toxic) were tested. Phenytoin at all three concentrations significantly suppressed NK cell activity in a dose-dependent manner. Carbamazepine had no significant effect on NK cell activity at the dose levels studied. Incubation in propylene glycol, the diluent for carbamazepine, significantly decreased NK cell activity compared to saline. Phenytoin also significantly depressed interferon augmentation of NK cell cytotoxicity in a dose dependent manner. ADCC activity was significantly depressed with 20 and 40 micrograms/ml phenytoin. Alkaline elution showed a slight but significant increase in DNA single-strand breaks of PBMC exposed to 40 micrograms/ml phenytoin for 18 or 72 hr. These results show phenytoin may induce pronounced immunosuppression of NK cell and ADCC activity in patients receiving antiepileptic therapy and that this agent has a potential for genotoxic side effects. Phenytoin may also increase the potential for neoplasm development by a direct interaction with cellular DNA and/or an indirect mechanism by immunosuppression.     

High incidence of a concentration-dependent skin reaction in children treated with phenytoin.

A particularly high incidence of rash was seen in children with epilepsy treated with phenytoin. Ten children with untreated epilepsy were therefore included in a prospective study and given either 3 (group 1) or 6 (group 2) mg of phenytoin/kg body weight/day for five days followed by 6 mg/kg body weight/day for both groups. Four of the five children in group 2 compared with only one of the five in group 1 developed a rash seven to 12 days after the start of treatment. Patients with rashes had significantly higher plasma phenytoin concentrations. Whenever the phenytoin concentration was higher than 14 micromol/l on day 5 a rash occurred. These findings indicate that the generalised skin reaction is caused by a high body burden of phenytoin, which results from either a high load of the drug or a low clearance rate.     

The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin

Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects.     

Drug-induced skin, nail and hair disorders.

Drug eruptions are among the most common adverse drug reactions, affecting approximately 3% of hospitalised patients. Although the rate of severe cutaneous adverse reactions to medications is low, these reactions can affect anyone who takes medication, and can result in death or disability. Two general patterns can be distinguished, depending on the type of onset of these cutaneous adverse drug reactions: acute or chronic. Acute-onset events are usually rather specific cutaneous 'syndromes' that constitute emergencies and should therefore be promptly recognised and treated, while chronic-onset events often present as dermatological diseases. The challenge is therefore to recognise the drug aetiology in front of a 'classical' dermatosis such as acne, lichen or pemphigus. Therefore, clinicians should carefully evaluate the signs or symptoms of all adverse reactions thought to be drug related, and discontinue the offending agent when feasible. Erythematous drug eruptions are the most frequent and less severe acute immune drug-induced rashes, and are sometimes difficult to differentiate from viral eruptions. On the other hand, acute urticaria and angioedema are sometimes life-threatening eruptions for which a drug aetiology must be investigated. Photosensitivity, vasculitis and skin necrosis belong to the acute onset reactions, which are not always drug-induced, in contrast to fixed drug eruptions. The early recognition of acute generalised exanthematous pustulosis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis are of high importance because of the specific mechanisms involved and the different prognosis of each of these diseases. Chronic onset drug-induced disorders include pigmentary changes, drug-induced autoimmune bullous diseases, lupus, pseudo lymphoma and acneiform eruptions; these are discussed, along with specific data on drug-induced hair and nail disorders. As the disorders are numerous, the mechanisms and the drugs involved in the development of these various reactions are multiple. The list of drugs discussed in relation to the different disorders are as accurate as possible at the time of preparation of this review, but will need updating as new drugs emerge onto the market. We emphasize the clinical recognition, pathophysiology and treatment of skin, hair and nail adverse drug reactions, and the role of each doctor involved in the management of these patients in the notification of the adverse drug reaction to health authorities, using the minimal requirement for notification proposed.     

EMPACT syndrome

Phenytoin is commonly used an antiepileptic medication for seizure prophylaxis in patients with brain metastases. In these oncology patients group, phenytoin-induced severe adverse reactions may occur. Antiepileptic, particularly phenytoin-induced severe skin reactions including Stevens-Johnson syndrome (SJS) and bullous form of erythema multiforme have been reported in the patients treated with cranial irradiation due to brain metastasis. The acronym EMPACT (Erythema Multiforme associated with Phenytoin And Cranial radiation Therapy) was recently described as a clinical entity. Herein, we report a 36-year-old female with breast carcinoma, who developed EMPACT syndrome after treating with cranial radiation therapy for brain metastasis and phenytoin for seizure prophylaxis.     

EMPACT syndrome

Phenytoin is commonly used an antiepileptic medication for seizure prophylaxis in patients with brain metastases. In these oncology patients group, phenytoin-induced severe adverse reactions may occur. Antiepileptic, particularly phenytoin-induced severe skin reactions including Stevens-Johnson syndrome (SJS) and bullous form of erythema multiforme have been reported in the patients treated with cranial irradiation due to brain metastasis. The acronym EMPACT (Erythema Multiforme associated with Phenytoin And Cranial radiation Therapy) was recently described as a clinical entity. Herein, we report a 36-year-old female with breast carcinoma, who developed EMPACT syndrome after treating with cranial radiation therapy for brain metastasis and phenytoin for seizure prophylaxis.     

Imatinib mesylate and dermatology part 2: a review of the cutaneous side effects of imatinib mesylate

Cutaneous reactions to imatinib are common and occur in 9.5% to 69% of patients depending on the series reported. Maculopapular eruptions, erythematous eruptions, edema, and periorbital edema are the most common adverse events observed. Imatinib can also induce severe skin eruptions and generalized skin eruptions. Toxic epidermal necrolysis and Stevens Johnson syndrome has been linked to the use of imatinib. Imatinib has caused acute generalized exanthematous pustulosis. Purpuric vasculitis and mycosis fungoides-like reactions has occurred after imatinib use. Rarer side effects include: hypopigmentation, lichenoid reactions, pityriasiform eruptions, pityriasis rosea, psoriasis, reactivation or induction of porphyria cutanea tarda, neutrophilic eccrine hidradenitis, Sweet's syndrome, erythema nodosum, EBV-positive cutaneous B-cell lymphoproliferative disease, possible induction of squamous cell, hyaline cell syringomas, follicular mucinosis, pseudolymphoma-type drug eruptions, and malpighian epitheliomas. Most cutaneous eruptions caused by imatinib do not necessitate discontinuance of imatinib and are usually self limited, despite continued treatment. Administration of oral or topical corticosteroids can ameliorate some of imatinib's cutaneous side effects.     

Pharmacokinetic drug interactions with phenytoin (Part I)

Phenytoin, which is used primarily as an anticonvulsant agent, has a relatively low therapeutic index, and monitoring of plasma phenytoin concentration is often used to help guide therapy. It has properties which predispose it to an involvement in pharmacokinetic interactions, a large number of which have been reported. These properties include: low aqueous solubility and slow rate of gastrointestinal absorption; a relatively high degree of plasma protein binding; a clearance that is non-linear due to saturable oxidative biotransformation; and the ability to induce hepatic microsomal enzymes. Because of its narrow therapeutic range, drug interactions leading to alterations in plasma phenytoin concentration may be clinically important. Such interactions have often been reported initially as either cases of phenytoin intoxication or of decreased effectiveness. Drugs may modify the pharmacokinetics of phenytoin by altering its absorption, plasma protein binding, or hepatic biotransformation; alterations in the absorption and/or biotransformation may lead to changes in both the unbound plasma phenytoin concentration and, as a result, the clinical effect. Preparations which may decrease the gastrointestinal absorption of phenytoin include nutritional formulae and charcoal. There are many reports of drugs which may increase (e.g. folic acid, dexamethasone and rifampicin) or decrease (e.g. valproic acid, sulthiame, isoniazid, cimetidine, phenylbutazone, chloramphenicol and some sulphonamides) the metabolism of phenytoin. It is important to bear in mind that, as a result of its non-linear clearance, changes in phenytoin absorption and/or biotransformation will lead to more than proportionate changes in plasma drug concentration. Drugs which may displace phenytoin from plasma albumin include valproic acid, salicylic acid, phenylbutazone and some sulphonamides. Although an alteration in the unbound fraction of phenytoin in plasma would not, in itself, be expected to alter the unbound plasma phenytoin concentration, the interpretation of total plasma concentrations for therapeutic drug monitoring may be confounded. Some drugs appear to alter phenytoin pharmacokinetics via dual mechanisms (e.g. valproic acid and phenylbutazone), while for other compounds the mechanism of interaction has not been fully elucidated. Phenytoin has been reported to alter the pharmacokinetics of a large number of drugs. The majority of these interactions arise because phenytoin is a potent inducer of cytochrome P450 microsomal enzymes, and therefore may increase the clearance of drugs which are extensively metabolised; drugs affected include carbamazepine, theophylline, methadone, prednisolone, dexamethasone, metyrapone and several cardiac antiarrhythmic agents. With all of these, the resultant decrease in plasma concentrations may be clinically important.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential kinetics of phenytoin in elderly patients.

The elderly have a relatively high risk of developing adverse drug reactions. Phenytoin continues to be a preferred drug for treating generalised tonic-clonic seizures in the elderly and simple partial seizures that generalise. Phenytoin is eliminated almost entirely by hepatic oxidation. The principle enzymes responsible are cytochrome P450 (CYP)2C9 and CYP2C19. CYP2C9 is saturated by therapeutic doses of phenytoin, and at steady state both enzymes are probably operant in most people. The nonlinear pharmacokinetics of phenytoin make it a difficult drug for which to establish safe and effective administration regimens. An important area of inquiry is whether the differential disposition kinetics of phenytoin in the elderly render its administration an even more difficult challenge. Moreover, since the elderly are generally subject to more polypharmacy than younger adults, are they, as a result, subject to either more frequent or more severe drug interactions with phenytoin than younger adults? In order to examine these issues we were interested in learning the extent to which old age might affect the plasma protein binding of phenytoin, its hepatic metabolism and, ultimately, its pharmacokinetic profile. With regard to the latter we looked carefully at the methods that have been used to characterise the disposition kinetics of phenytoin in general, and in the elderly, in particular. There are many conflicting findings with regard to the effect of age on the disposition kinetics of phenytoin. However, the strategies used for estimating kinetic parameters for phenytoin [viz the maximum rate of metabolism/elimination (Vmax) and the Michaelis-Menton constant (Km)] exhibit deficiencies that could account for some of the disparate findings. Certainly, more careful prospective studies focusing on the effects of age on phenytoin disposition kinetics are warranted. However, in light of the information currently available, no special attention need be paid to the initiation of phenytoin administration in elderly patients who are taking multiple anticonvulsants. On the other hand, for the elderly receiving phenytoin monotherapy, the initiation of phenytoin administration should occur at lower doses than would be customary for younger adults, and phenytoin blood concentrations should be appropriately monitored in order to evaluate individual Vmax and Km values for informed dosage adjustments.     

Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam.

Twelve healthy male volunteers received phenytoin 0.5 and 1 g, lamotrigine (a new anticonvulsant) 120 and 240 mg, diazepam 10 mg and placebo orally in a double-blind, cross-over, randomized trial. Maximum drug concentrations at 4 h, measured in plasma were 11.5 +/- 2.2 micrograms ml-1 for phenytoin and 2.7 +/- 0.4 micrograms ml-1 for lamotrigine. These levels were in the therapeutic range for phenytoin and the putative therapeutic range for lamotrigine. Side effects after diazepam (mainly sedation) and phenytoin (mainly unsteadiness) differed markedly from lamotrigine which produced no important side effects. Subjective effects as measured by visual analogue scales were caused by phenytoin and diazepam but not by lamotrigine. Diazepam impaired eye movements, adaptive tracking and body sway. Phenytoin impaired adaptive tracking, increased body sway and impaired smooth pursuit eye movement. Lamotrigine produced only a possible slight increase in body sway. There were significant correlations between performance and saliva levels of phenytoin and diazepam. It was concluded that the tests used were suitable for monitoring CNS effects of anticonvulsants and that lamotrigine possibly could have a more favourable CNS side effect profile than phenytoin.     

ECG features of sodium channel blockade in rodent phenytoin toxicity and effect of hypertonic saline

Phenytoin remains a commonly used anticonvulsant agent with sodium channel blocking effects. Much of the cardiotoxicity of phenytoin has been attributed to the propylene glycol vehicle, however there is reason to postulate a contribution from sodium channel blockade. The purpose of this paper is to establish whether, in a rodent model, ECG effects of phenytoin toxicity are consistent with sodium channel blockade and whether these effects and mortality can be lessened by pretreatment with hypertonic saline. Forty rats were given the described LD 50 for phenytoin. Animals were pretreated with either hypertonic saline or gelofusine. The ECG was periodically sampled and mortality assessed. The QRS duration increased with phenytoin administration (p<0.001), without any effect from hypertonic saline on this prolongation. The increase in RR Interval (p<0.001) was diminished by hypertonic saline (p<0.01). Mortality was not different between groups. Phenytoin toxicity has ECG effects consistent with its mechanism as a sodium channel blocker. Pretreatment with hypertonic saline protected against bradycardia, but not mortality nor QRS duration prolongation. Further study is warranted to establish whether hypertonic saline has a role in treating phenytoin's toxic cardiac effects.     

Effects of phenytoin on memory, cognition and brain structure in post-traumatic stress disorder: a pilot study

Phenytoin (Dilantin) is an anticonvulsant used in the treatment of epilepsy. It is believed to act by modulation of glutamatergic transmission. Because the neurobiology of post-traumatic stress disorder (PTSD) has been hypothesized to involve alterations in glutamatergic transmission with subsequention neurotoxicity, we assessed the effects of phenytoin on cognition and brain structure in PTSD patients. Phenytoin was administered in an open label fashion for 3 months to nine adult patients with PTSD related to a variety of traumas, including early abuse, combat and car accidents. Subjects underwent magnetic resonance imaging for measurement of whole brain and hippocampal volume, and neuropsychological testing of memory and cognition, before and after treatment. Phenytoin treatment resulted in a significant 6% increase in right brain volume (p < 0.05). Increased hippocampal volume was correlated with reductions in symptom severity as measured by the Clinician Administered PTSD Scale and improvements in executive function as measured by the Trails test. However, treatment associated improvements in memory and cognition did not achieve statistical significance. These findings suggest that phenytoin treatment may be associated with changes in brain structure in patients with PTSD.     

Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies

Erythema multiforme major (EMM; Stevens-Johnson syndrome) is a cutaneous disorder associated with a wide variety of factors including ingestion of drugs such as phenytoin and exposure to intracranial radiation therapy. Based on observations of a 47-year-old black man with brain metastases who developed EMM after combined phenytoin and radiation therapy, we conducted a MEDLINE literature search for articles on similar cases from 1966 to the present. Twenty cases were identified that support the hypothesis that EMM is associated with combined phenytoin and radiation therapy. The reaction, or its severity, has no relationship to the phenytoin or radiation therapy dosage, or to the histologic type of brain tumor. Also, EMM has no apparent age or gender predisposition in association with phenytoin-radiation therapy. Thus this is a clinical phenomenon that occurs with unusual frequency in patients with brain tumor who undergo radiation therapy while taking phenytoin. Phenytoin and other anticonvulsants such as phenobarbital and carbamazepine induce cytochrome P450 3A and produce oxidative reactive intermediates that may be implicated in hypersensitivity reactions such as EMM. Both carbamazepine and barbiturates have shown cross-sensitivity with phenytoin; furthermore, a case of EMM in a patient receiving carbamazepine and whole brain radiation therapy has been reported. As carbamazepine, valproate, and barbiturates have been associated with EMM, gabapentin may be considered as alternative anticonvulsant therapy when appropriate.     

Electrophysiological interactions between quinidine-lidocaine and quinidine-phenytoin in guinea-pig papillary muscle

The interactions between quinidine and lidocaine or phenytoin at the sodium channel level have been studied in the present work. The maximum upstroke velocity (Vmax) of the guinea-pig papillary muscle action potential has been used as a measure of the sodium current. Lidocaine interfered with the use-dependent blocking effects on Vmax of quinidine, by decreasing the fraction of sodium channels blocked by quinidine during the conditioning action potential, in an apparently competitive way. These results strongly suggest that quinidine and lidocaine bind to a common receptor site. Alternatively, it has been suggested that lidocaine and quinidine bind to different but related receptor sites, since lidocaine may induce allosteric changes in quinidine's receptor. Phenytoin increased the use-dependent blocking effects on Vmax of quinidine by slowing the time course of the slow component of reactivation of Vmax induced by quinidine. Phenytoin did not change the fraction of sodium channels blocked by quinidine during the conditioning action potential. These results suggest that phenytoin binds to a different receptor site than quinidine.     

苯妥英钠治疗海洛因依赖者稽延性戒断症状临床研究

目的:了解苯妥英钠是否能缓解稽延性戒断症状及患者心理渴求。方法:采用稽延症状自评量表,SAS焦虑自评量表,不良反应监测表,苯妥英钠血药浓度监测等手段,对我所在院病人进行临床观察和实验研究。结果:苯妥英钠组对海洛因依赖者后期稽延性戒断症状的控制与洛非西丁组无明显的差异(P>0.05),对焦虑渴求的控制两组间也无明显差异(P>0.05)。且在整个用药过程中,苯妥英钠的血药浓度在安全有效的范围内。结论:苯妥英钠对治疗阿片类依赖者后期稽延症状,有改善焦虑及心理渴求的作用。     

Skin eruption with gabapentin in a patient with repeated AED-induced Stevens-Johnson's syndrome

Skin eruptions have been reported with the use of all antiepileptic drugs and there is a significant risk of cross-reactivity between these agents in causing serious eruptions such as Stevens-Johnson's syndrome. Gabepentin is usually considered a safe agent for patients with a previous history of drug allergies and there have been no cases of skin eruption reported to the gabapentin post marketing surveillance. We report a patient who had severe Stevens-Johnson's syndrome induced by phenytoin and later by carbamazepine. Subsequent use of gabapentin also resulted in a skin eruption which was limited to the lower extremities but without systemic or mucosal involvement. This case suggests that patients with a strong history of drug-induced idiosyncratic reactions may experience such reactions to gabapentin as well.     

大鼠出生前接触苯妥英和(或)褪黑素对学习记忆的影响

目的　探讨褪黑素对苯妥英诱发的仔代学习记忆功能发育异常的影响。方法　Wistar孕大鼠于妊娠d 11～ 14ig苯妥英 10 0 ,2 0 0mg·kg- 1·d- 1或合并ig褪黑素 4 0mg·kg- 1(每日 3次 ) ,观察F1代仔鼠的味觉回避反射、穿梭反射和Morris水迷宫空间识别能力。结果　出生前染毒仔鼠成年后味觉回避反射、主动回避反射及空间识别等学习和记忆能力下降。褪黑素和苯妥英合并用药组仔鼠上述 3种学习和记忆能力均有不同程度的改善。结论　褪黑素对苯妥英诱发的大鼠仔代学习记忆功能发育异常具有拮抗作用 ,该效应可能与其拮抗胚胎脑组织中氧化应激反应有关。     

Effects of phenytoin and carbamazepine on calcium transport in Caco-2 cells.

Adverse effects of anti-seizure/anti-epileptic medications on bone density have been observed and reported since the early 1960s. Phenytoin and carbamazepine are two commonly prescribed anti-epileptic drugs most frequently associated with osteomalacia including fractures, bone demineralization, and reduced bone formation. The mechanism by which anti-epileptic drugs induce bone loss is not fully explained. We hypothesized that anti-epileptic drugs may impair dietary calcium absorption in the intestine. Using Caco-2 cells, a model transport system for study of the function of the intestinal epithelium, we determined the effects of several anti-epileptic drugs on intestinal epithelial calcium transport. In our system, phenytoin and carbamazepine dose-dependently inhibit active calcium transport from the apical to basolateral side of Caco-2 cells under physiologic calcium conditions. Vitamin D ameliorates the anti-epileptic drug-induced decrease in calcium permeability.