Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression

Felbamate is an antiepileptic drug that is associated with minimal toxicity in preclinical species such as rat and dog but has an unacceptable incidence of serious idiosyncratic reactions in man. Idiosyncratic reactions account for over half of toxicity-related drug failures in the marketplace, and improving the preclinical detection of idiosyncratic toxicities is thus of paramount importance to the pharmaceutical industry. The formation of reactive metabolites is common among most drugs associated with idiosyncratic drug reactions and may cause deleterious effects through covalent binding and/or oxidative stress. In the present study, felbamate was compared to several other antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, and phenytoin), using covalent binding of radiolabeled drugs and hepatic gene expression responses to evaluate oxidative stress/reactive metabolite potential. Despite causing only very mild effects on covalent binding parameters, felbamate produced robust effects on a previously established oxidative stress/reactive metabolite gene expression signature. The other antiepileptic drugs and acetaminophen are known hepatotoxicants at high doses in the rat, and all increased covalent binding to liver proteins in vivo and/or to liver microsomes from human and rat. With the exception of acetaminophen, valproic acid exhibited the highest covalent binding in vivo, whereas carbamazepine exhibited the highest levels in vitro. Pronounced effects on oxidative stress/reactive metabolite-responsive gene expression were observed after carbamazepine, phenobarbital, and phenytoin administration. Valproic acid had only minor effects on the oxidative stress/reactive metabolite indicator genes. The relative ease of detection of felbamate based on gene expression results in rat liver as having potential oxidative stressor/reactive metabolites indicates that this approach may be useful in screening for potential idiosyncratic toxicity. Together, measurements of gene expression along with covalent binding should improve the safety assessment of candidate drugs.     

New antiepileptic drugs: review on drug interactions.

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.     

Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs

Therapeutic drug monitoring (TDM) is widely accepted as a method to improve the effectiveness and safety of the first generation antiepileptic drugs (AEDs) and to identify an individual's optimum concentration. Like the older AEDs, the new AEDs also have significant pharmacokinetic variability. A similar relationship between concentration and effect for the new and old AEDs in experimental seizure models suggests that it is reasonable to use TDM for the new AEDs. With the addition of generic formulations of the new AEDs, TDM can play an important role to validate bioequivalence in patients. There is a history of problems with generics of the older AEDs, primarily carbamazepine and phenytoin. The Biopharmaceutics Classification System, which correlates the solubility and permeability of a drug with oral drug absorption, predicts that there should be no significant problems with the majority of the new AEDs. Because of the controversy over the risk-benefit of generic substitution of AEDs, the use of TDM will provide a way to ensure patient safety while establishing that generics of AEDs proven to be bioequivalent in population studies are also bioequivalent in individuals. The goal of personalized medicine is to use genetic testing to target therapy and identify those individuals unlikely to respond to a drug or likely to respond adversely to the same drug. Of all the AEDs, only phenytoin undergoes significant metabolism by cytochrome P450 isozymes with significant genetic polymorphisms (CYP2C9, CYP2C19). Studies are still needed to identify genetic and biomarkers to identify patients at risk for serious idiosyncratic reactions. There have been significant advances in the understanding of the role of genetics in idiopathic as well as acquired epilepsies. Identification of experimental and clinical evidence linking functional changes associated with gene mutations to epilepsy syndromes will help provide new molecular targets for future AEDs.     

Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions

BackgroundEpilepsy is a chronic neurological disease which affects about 1% of the human population. There are 50 million patients in the world suffering from this disease and 2 million new cases per year are observed. The necessary treatment with antiepileptic drugs (AEDs) increases the risk of adverse reactions. In case of 15% of people receiving AEDs, cutaneous reactions, like maculopapular or erythematous pruritic rash, may appear within four weeks of initiating therapy with AEDs.MethodsThis study involved 300 epileptic patients in the period between September 1989 and September 2009. A cutaneous adverse reaction was defined as a diffuse rash, which had no other obvious reason than a drug effect, and resulted in contacting a physician.ResultsAmong 300 epileptic patients of Neurological Practice in Kielce (132 males and 168 females), a skin reaction to at least one AED was found in 30 patients. As much as 95% of the reactions occurred during therapies with carbamazepine, phenytoin, lamotrigine or oxcarbazepine. One of the patients developed Stevens-Johnson syndrome.ConclusionSome hypersensitivity problems of epileptic patients were obviously related to antiepileptic treatment. Among AEDs, gabapentin, topiramate, levetiracetam, vigabatrin, and phenobarbital were not associated with skin lesions, although the number o patients in the case of the latter was small.     

妊娠期抗癫痫药物的安全性研究

妊娠期女性服用抗癫痫药物（antiepileptic drugs,AEDs）对妊娠结局有着重要的影响,如暴露于丙戊酸钠、苯妥英钠、卡马西平等AEDs中会导致新生儿先天性畸形的风险增加。越来越多的证据表明,宫内AEDs暴露可能与认知发展损害有关,会对新生儿造成神经发育方面的远期影响,多药联用及高剂量的AEDs会增加胎儿的致畸风险。本文就传统及新型AEDs妊娠期致畸性风险进行综述。     

The pharmacokinetics and interactions of new antiepileptic drugs: an overview

In the past decade 10 new antiepileptic drugs (AEDs)have been introduced: felbamate, gabapentin, lamotrigine, levetiracetem, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin,and zonisamide. The pharmacokinetics (PK) of these new AEDs as well as their potential for drug interactions are reviewed in this article.In general, new AEDs have better PK profiles and are less involved in drug interactions than the 4 established AEDs: phenobarbital,phenytoin, carbamazepine, and valproic acid. However, in spite of the large therapeutic arsenal of old and new AEDs, about 30% of epileptic patients are still not seizure-free, and thus, there is a substantial need to develop new AEDs.     

Skin reactions due to anti-epileptic drugs: several case-reports with long-term follow-up

In this study, the clinical findings and management of allergic skin reactions induced by the most used antiepileptic drugs, Lamotrigine (LMT) and Carbamazepine (CBZ), were evaluated. Lamotrigine is an antiepileptic drug recently released in several countries; it is effective for a variety of seizure types in adults and children, both as an add-on agent and in monotherapy, and it is generally well tolerated. Clinical and epidemiologic evidence suggest serious cutaneous reactions to antiepileptic drugs are more likely to occur during the first 8 weeks and they appear to increase when drugs are administered with other anticonvulsants, such as Valproate (VPA). We selected 10 patients who presented an idiosyncratic skin rash when treated with carbamazepine (8 patients) and lamotrigine (2 patients) administered as monotherapy, and we followed up on these patients for several years. Seven reactions were mild/severe cutaneous eruptions; one Toxic Epidermal Necrolysis, a case of Stevens-Johnson and a case of Hypersensitivity Syndrome. All severe skin drug reactions were induced by Carbamazepine. In five patients the AEDs were ceased abruptly (sometimes with the administration of a different molecule), tapered in four and continued unchanged in one. We conclude that the discontinuation of the drug with substitution with another is the most effective treatment and that corticosteroids are helpful in mild cutaneous reactions, while in severe skin reactions, such as Toxic Epidermal Necrolysis, corticosteroids are only a complementary therapy since intravenous immunoglobulins are the first choice treatment.     

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.     

Pathogenesis and clinical approaches to anticonvulsant hypersensitivity syndrome: current state of knowledge

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, but severe and potentially fatal, adverse reaction that occurs in patients who are treated with commonly used older anticonvulsant drugs (phenytoin, carbamazepine and phenobarbital) and/or with some newer agents (lamotrigine). Paediatric patients are at an increased risk for the development of AHS for the higher incidence of seizure disorder in the first decade of life. Hypersensitivity reactions range from simple maculopapular skin eruptions to a severe life-threatening disorder. AHS is typically associated with the development of skin rash, fever and internal organ dysfunctions. Recent evidence suggests that AHS is the result of a chemotoxic and immunologically-mediated injury, characterized by skin and mucosal bioactivation of antiepileptic drugs and by major histocompatibility complex-dependent clonal expansion of T cells. Early recognition of AHS and withdrawal of anticonvulsant therapy are essential for a successful outcome. In vivo and vitro tests can be helpful for the diagnosis that actually depends essentially on clinical recognition.     

口服"纯中药"患儿的抗痫西药血浓度监测

目的：用治疗药物监测(TDM)方法监测口服“纯中药”患儿的抗痫西药血浓度,及时发现和调整患儿的不合理用药。方法：凡是临床上出现药物中毒、无法解释的药理现象或者怀疑服有中药掺杂西药的癫痫患者,用HPLC法和PLIA法监测其血药浓度．并动态地现察疗效。结果：45例服用“纯中药”的癫痫患儿,血清中检测出1．5种常用抗痫西药,其中苯巴比妥最多(42例)。其次为卡马西平、丙戊酸钠、苯妥英纳和氯硝西泮,有些已达中毒浓度。这种现象给病人造成极大的诊疗困难、中毒危险、心理创伤及经济     

传统抗癫痫药物与新抗癫痫药物对癫痫患者身体成分及脂代谢的影响

目的比较新抗癫痫药物与传统抗癫痫药物对患者身体成分及脂代谢的影响。方法收集我院癫痫患者112例。患者均服用新抗癫痫药(左乙拉西坦、拉莫三嗪、加巴喷丁)或传统抗癫痫药(丙戊酸钠、卡马西平、苯妥英钠)至少6个月。单一用药治疗73例,其中,服用左乙拉西坦片14例、丙戊酸钠15例、卡马西平20例、苯妥英钠24例。其余患者采用联合用药治疗。评估患者身体成分,包括体脂量、瘦干体质量(Lean dry mass,LDM),记录总体液量(Total body water,TBW)、细胞内液(Intracellular water,ICW)、细胞外液(Extracellular water,ECW)、基础代谢率(Basal metabolic rate,BM R),检测生化指标参数。结果左乙拉西坦组患者LDM较丙戊酸钠组患者降低(P<0.05),而其他身体成分与丙戊酸钠组、卡马西平组、苯妥英钠组比较差异无统计学意义(P>0.05)。与对照组比较,丙戊酸钠治疗组LDM及细胞外液较高;其余抗癫痫药物单一用药治疗组的身体成分与对照组比较差异无统计学意义(P>0.05)。传统抗癫痫药物单一治疗及联合新型药治疗组患者的LDM高于对照组(P<0.05),血清TC、三酰甘油也高于对照组(P<0.05)。结论抗癫痫药物对身体成分及脂代谢的影响作用可能影响其对癫痫患者(特别是身体成分发生变化的患者)的治疗反应。由于样本量的限制,以上结论需进一步大样本及前瞻性研究。     

Trace elements and electrolytes homeostasis and their relation to antioxidant enzyme activity in brain hyperexcitability of epileptic patients

Epileptogenesis is a big challenge. Various experimental and human studies suggested that the homeostasis of trace elements, electrolytes, membrane lipid peroxidation, and antioxidants is crucial for brain function, and they were directly or indirectly implicated as taking part in the pathophysiology of neuronal excitability, neuronal excitotoxicity, and seizure recurrence and its resistance to treatment with antiepileptic drugs (AEDs). In addition, AEDs can also alter the homeostasis of trace elements, electrolytes, and seriously increase membrane lipid peroxidation at the expense of protective antioxidants, leading to an increase in seizure recurrence and an idiosyncratic drug effect. Differential effects were detected among different AEDs treatments in which carbamazepine (CBZ) was found to be better anticonvulsant for the control of free radical related seizures and the level of trace elements were better regulated with CBZ than with valproate (VPA) and phenytoin (PHT) therapies. It is concluded that adequate trace elements and antioxidants supply is important for brain functions and prevention of neurological diseases and further elucidation of the pathological actions of such substances in the brain should result in new therapeutic approaches. Trace elements and antioxidant might have neuroprotective biological targeted benefits when used in epileptic patients.     

Use and safety profile of antiepileptic drugs in Italy

Objective To analyse and discuss the use and the safety profile of individual antiepileptic drugs (AEDs) in Italy. Methods The AED safety data referred to the period January 1988–June 2005 and were obtained from the database of the Italian Interregional Group of Pharmacovigilance (GIF). This database collects all spontaneous reports of suspected adverse drug reactions (ADRs) from six Italian regions which are the main contributors to the Italian spontaneous reporting system. Individual AED consumption data (defined daily dose/1,000 inhabitants per day) in the GIF area and in the whole of Italy referred to the period January 2003-June 2005 and were derived from drug sales data (Institute for Medical Statistics Health). Results Phenobarbital was the most frequently used AED in the GIF area (4.26 DDD/1,000 inhabitants per day) followed by carbamazepine (1.97), valproic acid (1.33) and gabapentin (1.10). AED consumption in the whole of Italy showed a similar pattern. Gabapentin was the most frequently used AED among newer AEDs. In the GIF database 37,906 reports (up to June 2005) were present; 666 of them (1.76%) were associated with at least one AED (Anatomical Therapeutic Chemical code N03A). The AED with the highest number of reports was carbamazepine (208 reports) followed by phenobarbital (98), gabapentin (80), phenytoin (56), valproic acid (55), lamotrigine (51), oxcarbazepine (43) and vigabatrin (35). Use and toxicity profile were evaluated only for AEDs associated with at least 30 reports. Skin reactions were the most frequently reported ADRs, followed by haematological, general condition, hepatic, neurological and gastrointestinal adverse reactions. Phenobarbital, lamotrigine, carbamazepine and phenytoin had the highest percentage of skin reactions (69, 67, 60 and 54%, respectively). Many haematological reactions were reported for each AED; the highest percentage was related to valproic acid (25%). Vigabatrin was associated with the highest percentage of reactions related to hearing, vision and other senses (97%). Phenytoin and valproic acid had the highest percentage of hepatic reactions (30 and 20%), whereas gabapentin of nervous system, psychiatric, gastrointestinal and urinary reactions (26, 21, 21 and 14%, respectively) and phenobarbital of musculoskeletal reactions (13%). Conclusions In Italy antiepileptic drug therapy appears to be still dominated by traditional drugs. Our analysis showed a different safety profile related to each AED. Some of the drug-adverse reaction associations discussed are not included in the Italian drug leaflets or have not been reported before in the literature.     

Pharmacokinetic interactions of topiramate

Topiramate is a new antiepileptic drug (AED) that has been approved worldwide (in more than 80 countries) for the treatment of various kinds of epilepsy. It is currently being evaluated for its effect in various neurological and psychiatric disorders. The pharmacokinetics of topiramate are characterised by linear pharmacokinetics over the dose range 100-800 mg, low oral clearance (22-36 mL/min), which, in monotherapy, is predominantly through renal excretion (renal clearance 10-20 mL/min), and a long half-life (19-25 hours), which is reduced when coadministered with inducing AEDs such as phenytoin, phenobarbital and carbamazepine. The absolute bioavailability, or oral availability, of topiramate is 81-95% and is not affected by food. Although topiramate is not extensively metabolised when administered in monotherapy (fraction metabolised approximately 20%), its metabolism is induced during polytherapy with carbamazepine and phenytoin, and, consequently, its fraction metabolised increases. During concomitant treatment with topiramate and carbamazepine or phenytoin, the (oral) clearance of topiramate increases 2-fold and its half-life becomes shorter by approximately 50%, which may require topiramate dosage adjustment when phenytoin or carbamazepine therapy is added or discontinued. From a pharmacokinetic standpoint, topiramate is a unique example of a drug that, because of its major renal elimination component, is not subject to drug interaction due to enzyme inhibition, but nevertheless is susceptible to clinically relevant drug interactions due to induction of its metabolism. Unlike old AEDs such as phenytoin and carbamazepine, topiramate is a mild inducer and, currently, the only interaction observed as a result of induction by topiramate is that with ethinylestradiol. Topiramate only increases the oral clearance of ethinylestradiol in an oral contraceptive at high dosages (>200 mg/day). Because of this dose-dependency, possible interactions between topiramate and oral contraceptives should be assessed according to the topiramate dosage utilised. This paper provides a critical review of the pharmacokinetic interactions of topiramate with old and new AEDs, an oral contraceptive, and the CNS-active drugs lithium, haloperidol, amitriptyline, risperidone, sumatriptan, propranolol and dihydroergotamine. At a daily dosage of 200 mg, topiramate exhibited no or little (with lithium, propranolol and the amitriptyline metabolite nortriptyline) pharmacokinetic interactions with these drugs. The results of many of these drug interaction studies with topiramate have not been published before, and are presented and discussed for the first time in this article.     

Current issues in the treatment of epilepsy

General principles of antiepileptic drug (AED) therapy are reviewed, current issues involving the use and monitoring of AEDs are examined, promising investigational agents are briefly reviewed, and situations that require potentially difficult decisions about long-term care are discussed. The initial treatment should be monotherapy with a first-line AED for the particular seizure disorder. The usual approach is to maximize seizure control and minimize the adverse effects of AED therapy. Current issues involving the pharmacokinetics, use, and monitoring of the conventional AEDs phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, ethosuximide, benzodiazepines, and acetazolamide are discussed. AED therapy may have adverse effects on behavior and cognition. The risk of teratogenicity with well-monitored AED therapy is probably low, and severe hepatotoxicity is uncommon. Because carbamazepine, phenobarbital, phenytoin, and primidone all have enzyme induction properties, a number of clinically important interactions are possible. Issues related to discontinuing AED therapy, serum concentration monitoring, and generic interchange of AED products are addressed. Whether AEDs should be used to prevent recurrent febrile seizures, alcohol withdrawal seizures, or seizures in patients with head trauma or stroke must be considered. The treatment of seizure disorders is a complex process involving identification of the seizure disorder, selection and monitoring of an appropriate AED(s), and consideration of adverse effects and drug interactions. Whether therapy should be discontinued after a prolonged seizure-free period, compliance issues, and whether to treat certain conditions prophylactically also must be considered.     

Pharmacologic management of epilepsy in the elderly

OBJECTIVE: To review the epidemiology and pharmacologic management of epilepsy in elderly patients. DATA SOURCES: Controlled trials, case studies, and review articles identified via MEDLINE using the search terms epilepsy, seizures, elderly, phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Recently published standard textbooks on epilepsy were also consulted. DATA SYNTHESIS: Epilepsy is a common neurologic disorder in the elderly. Cerebrovascular and neurodegenerative diseases are the most common causes of new-onset seizures in these patients. Alterations in protein binding, distribution, elimination, and increased sensitivity to the pharmacodynamic effects of antiepileptic drugs (AEDs) are relatively frequent, and these factors should be assessed at the initiation, and during adjustment, of treatment. Drug-drug interactions are also an important issue in elderly patients, because multiple drug use is common and AEDs are susceptible to many interactions. In addition to understanding age-related changes in the pharmacokinetics and pharmacodynamics of AEDs, clinicians should know the common seizure types in the elderly and the spectrum of AED activity for these seizure types. AEDs with activity against both partial-onset and generalized seizures include felbamate, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide. Other AEDs discussed in this review (carbamazepine, gabapentin, phenobarbital, phenytoin, primidone, and tiagabine) are most useful for partial-onset seizures. CONCLUSION: The provision of safe and effective drug therapy to elderly patients requires an understanding of the unique age-related changes' in the pharmacokinetics and pharmacodynamics of AEDs as well as an appreciation of common seizure types and the drugs that are effective for the specific types seen in the elderly.     

3种抗癫痫药的血药浓度监测及个体化用药体会

目的 :为临床抗癫痫药的合理应用提供参考。方法 :采用荧光偏振免疫法对88例服用苯妥英钠、63例服用苯巴比妥和63例服用卡马西平的患者进行血药浓度监测242次 ,并提供个体化给药方案。结果 :癫痫患者对这3种抗癫痫药的敏感性个体差异很大。结论 :癫痫患者的个体化用药必须以血药浓度数据为依据 ,还需综合考虑其他方面的因素     

Various pharmacogenetic aspects of antiepileptic drug therapy: a review

Pharmacogenetics concerns the influence of an individual's genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Much of the pharmacogenetic data in the field of epilepsy deals with the pharmacokinetics of antiepileptic drugs (AEDs). In particular, two polymorphisms of cytochrome P450 2C9 are known to slow down the metabolism of phenytoin to a degree that increases the risk of the neurotoxic adverse effects of this drug among carriers of these polymorphisms. A significant number of patients with epilepsy do not respond to AEDs and such pharmacoresistance is a major, largely unsolved, problem that is likely to be multifactorial in nature. In this regard, genetic factors may influence transmembrane drug transporter proteins, thereby modifying the intracerebral penetration of AEDs. Monogenic idiopathic epilepsies are rare and frequently associated with ion channel mutations; however, to date, a consistent relationship between changes in channel properties and clinical phenotype has not been established nor has any association between genotype and response to specific treatment options. Polymorphisms of drug targets may represent another genetic facet in epilepsy: a recent study demonstrated for the first time a polymorphism of a drug target (the alpha-subunit of a voltage-gated sodium channel) associated in clinical practice with differing response to two classic AEDs. Adverse drug reactions and teratogenicity of AEDs remain a major concern. Whole-genome single nucleotide polymorphism profiling might in the future help to determine genetic predisposing factors for adverse drug reactions. Recently, in Han Chinese treated with carbamazepine and presenting with Stevens-Johnson syndrome, a strong association was found with HLA B*1502. If genetically targeted drug development becomes more affordable/cost efficient in the near future, the development of new drugs for relatively rare diseases could become economically viable for the pharmaceutical industry. The synergy of lower trial costs and efficacy-based prescribing may reduce the cost of medical treatment for a particular disease. This hypothetical advantage of the practical use of pharmacogenetics is, however, counterbalanced by several possible dangers, including illicit data mining and the development of a human 'genetic underclass' with the risk of exclusion from, for example employment or health insurance, because of an 'unfavourable' genetic profile.     

244例抗癫痫药血药浓度监测结果分析

目的：通过对抗癫痫药物血药浓度监测结果分析，为临床提高本类药物的治疗水平作参考。方法：采用荧光偏振免疫法对26例服用苯妥英钠、74例服用卡马西平、144例服用丙戊酸钠的患者血药浓度监测结果及临床疗效分析、评价。结果：本类药物治疗指数小，安全度较低，其作用的个体差异大。结论：癫痫患者应重视血药浓度监测，并结合其他因素调整用药方案。以达到安全、有效、合理应用本类药物。     

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.