Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care

Anticonvulsant hypersensitivity syndrome (AHS) is a delayed adverse drug reaction associated with the use of aromatic anticonvulsant drugs. It has been most commonly reported with the use of phenytoin, carbamazepine, and phenobarbital. Although its occurrence is rare, 1 in every 1000-10,000 exposures, AHS is a serious adverse event often resulting in hospitalization and even death. The clinical manifestations of AHS include a triad of symptoms consisting of dermatologic rashes, fever, and evidence of systemic organ involvement. Diagnosis is most frequently based on the recognition of this triad of symptoms and clinical judgment. The exact mechanism of AHS remains to be determined but is thought to have at least three components: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants, associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes. Arene oxides, the toxic intermediaries in the metabolism of anticonvulsant drugs, can accumulate and directly bind to macromolecules, causing cell death, as well as act as prohaptens that bind to T cells, initiating an immune response and systemic reactions. Management of AHS primarily includes discontinuation of the associated anticonvulsant drug. Systemic corticosteroids are usually required for full recovery. An important issue regarding AHS is the cross-sensitivity among aromatic anticonvulsant drugs, which has been reported to be 40-80%. This means that patients with a history of AHS should avoid further use of any aromatic anticonvulsant drug. In addition, a familial association with AHS exists, and family members of the patient with AHS should be educated that they may be at increased risk for developing AHS if they use aromatic anticonvulsant drugs. Anticonvulsant drugs that are generally considered safe are valproic acid and benzodiazepines. Other nonaromatic anticonvulsant drugs should also be acceptable. Pharmacists as health care providers can play an important role in the diagnosis, treatment, and prevention of AHS.     

Anticonvulsant hypersensitivity syndrome: an update

Introduction: Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening adverse drug reaction, primarily associated with phenytoin, phenobarbital and carbamazepine. It is characterized by a triad of fever, skin eruption and internal organ involvement (usually liver), which occur two to eight weeks after the initiation of therapy. Anticonvulsant hypersensitivity syndrome has been estimated to occur between 1 and 1000 and 1 in 10,000 exposures; however, its true incidence is unknown because of the variable presentation and inaccurate reporting. Areas covered: This paper presents the incidence, epidemiology and pathogenesis of AHS, along with recommendations for its diagnosis and management. Expert opinion: Avoidance of all aromatic anticonvulsants is recommended in patients who develop AHS with one of these agents, as there is a high degree of crossreactivity among all these agents. There are no universally recognized tests for the prediction of AHS due to aromatic anticonvulsants or lamotrigine. Yet genetic testing in a predictive sense would help guide the choice of an appropriate anticonvulsant medication. Other tests, using cellular surrogates, such as lymphocytes or platelets, have been used primarily for diagnostic testing and do not have the universal practicality afforded to genetic tests.     

Anticonvulsant hypersensitivity syndrome in children: incidence, prevention and management

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, but potentially fatal, adverse reaction that occurs in patients, including children, who are treated with anticonvulsants. During metabolism of the anticonvulsant, toxic arene-oxide compounds are produced. AHS is associated with both cutaneous and systemic symptoms and is associated with multiorgan involvement. Liver damage, in particular, seems to be associated with fatal outcomes. The pathophysiology of AHS is still uncertain but it may be linked to a genetically determined inability to detoxify reactive drug metabolites. The prompt recognition of the first clinical signs of AHS, and the rapid withdrawal of the anticonvulsant, often avoids the progression of symptoms. Pharmacological treatment is essentially based on systemic corticosteroids in association with enteral nutrition, intravenous fluid augmentation, pain relief and ocular care. Intravenous immunoglobulins may also have a possible therapeutic role in some cases. Diagnostic tests, such as patch tests or in vitro assays, for AHS could help to identify patients at risk of developing the syndrome and could represent a first step of primary prevention when applied to relatives of patients.     

Evidence for a T-lymphocyte dependent mechanism involving proinflammatory cytokines in anticonvulsant hypersensitivity syndrome: a case report

The anticonvulsant drug hypersensitivity syndrome (AHS) is a potentially fatal drug reaction associated with aromatic antiepileptic drugs, the pathogenic mechanisms of which are still unclear. We studied a 2-year-old female affected with AHS after phenobarbital treatment. In vitro experiments showed a T-lymphocyte response to the drug and an increased, dose-related, IL-6 production after drug incubation. These findings suggest that AHS may be caused by a T-lymphocyte dependent mechanism, involving pro-inflammatory cytokines.     

Chronic antiepileptic drug therapy: classification by medication regimen and incidence of decreases in serum thyroxine and free thyroxine index

Results are described on the association of decreased serum total thyroxine (T4) and free thyroxine index (FTI) with antiepileptic drug therapy in a group of randomly selected chronically medicated outpatients (n = 291). For monotherapy subgroups (n = 164), the highest incidence (T4, 23.9%; FTI, 25.4%) of below normal values occurred in patients medicated with carbamazepine (CBZ), followed by phenytoin [(PHT) T4, 13.2%; FTI, 7.9%], and phenobarbital [(PB) (T4, 3.4%; FTI, 0%]. No T4 and FTI values below normal were detected in any patients (n = 30) on chronic valproic acid (VPA) monotherapy. For CBZ monotherapy (n = 67), women (n = 37) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 30). Therefore, the order of decreasing T4 and FTI effect was as follows: CBZ (women) greater than CBZ (men) greater than PHT greater than PB greater than VPA. For polytherapy subgroups (n = 127), the highest incidence (T4, 51.9%; FTI, 48.1%) was found in patients medicated with PHT and CBZ, followed by PHT and VPA (T4, 37.0%; FTI, 23.9%), and PHT and PB (T4, 17.2%; FTI, 10.3%). For PHT and CBZ poly-therapy (n = 52), women (n = 21) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 31). The magnitude of the decreasing T4 and FTI effect was greater for polytherapy subgroups (versus monotherapy subgroups) and in order as follows: PHT + CBZ (women) greater than PHT + CB (men) greater than PHT + VPA greater than PHT + PB.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carbamazepine Mucoadhesive Nanoemulgel (MNEG) as brain targeting delivery system via the olfactory mucosa

Carbamazepine (CBZ) is an antiepileptic orally administered drug, but due to its low solubility in water, its gastrointestinal absorption is slow and irregular, leading to delayed brain uptake with consequent peripheral side actions. The objective of this study was the brain targeting of CBZ via the olfactory mucosa in form of an intranasal mucoadhesive o/w nanoemulgel (MNEG). CBZ was formulated in a nanoemulgel system containing oleic acid/labrasol in a ratio of 1:5 as oil/surfactant and 0.1% xanthan gum as anionic mucoadhesive polymer. The prepared MNEG was characterized with respect to oil droplet size, mucoadhesion, in-vitro release of the drug and CBZ uptake by phosphatidylcoline liposomes as an in-vitro model for olfactory cells. The anticonvulsant action of nasal MNEG was studied on chemically and electrically induced convulsive Swiss Albino mice. The in-vitro release of CBZ from MNEG was very low, however CBZ uptake via liposomal membrane reached 65% within 1?hr. Treatment of animals with MNEG significantly prolonged the onset times for convulsion of chemically convulsive mice and protected the animals from two electric shocks. One can thus spire and hope for the emergence of a new intranasal treatment of epilepsy with consequent decrease in the peripheral side actions of CBZ.     

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.     

Pustular drug hypersensitivity syndrome due to allopurinol

Allopurinol hypersensitivity syndrome (AHS) is a severe drug reaction. It is characterized by rash, fever, and internal organ involvement. It may present in different clinical forms. We present a case of acute generalized exanthematous pustulosis occurring as a manifestation of AHS.KEY WORDS: Allopurinol, hypersensitivity syndrome, pustulosis     

Short-term effects of administration of anticonvulsant drugs on free carnitine and acylcarnitine in mouse serum and tissues.

1. The short-term evolution of concentrations of free carnitine and acylcarnitine was studied in the serum, liver, kidney, heart and skeletal muscle of mice after administration of single therapeutic doses of the anticonvulsant drugs, valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT) and phenobarbitone (PHB). 2. The effects of the drugs were immediate but transitory, control levels of free carnitine and acylcarnitine having been recovered or almost recovered in serum and in all tissues 8 h post administration (p.a.). 3. VPA was the only drug that significantly reduced free carnitine concentration in serum, which recovered control levels by 4 h p.a. 4. All the drugs studied brought about marked deficits of serum acylcarnitine, which had disappeared 2 h p.a. in the case of VPA and not until 8 h p.a. for CBZ, PHT or PHB. 5. The minimum concentrations of free carnitine and acylcarnitine in serum were invariably associated with the maximum concentration of drug in serum. 6. Free carnitine concentration was not affected by VPA in any tissue, PHT and PHB brought about significant deficits in heart and kidney, and CBZ a significant deficit in muscle. 7. Acylcarnitine concentration was significantly reduced in heart, kidney and muscle by CBZ, PHT and PHB, but in liver the effects of all drugs were very small. 8. These results are compatible with the hypothesis that the primary cause of anticonvulsant-induced alteration of carnitine metabolism is interference with renal reabsorption of carnitine.     

Carbamazepine-phenytoin interaction: elevation of plasma phenytoin concentrations due to carbamazepine comedication

By intrapatient comparison at constant phenytoin (PHT) dose, the effect of carbamazepine (CBZ) comedication on PHT was studied in a group of 24 epileptic outpatients. In half of the patients with steady-state PHT plasma concentration, a significant increase of this concentration was noted after CBZ was added to their regimen. Twenty percent showed clinical manifestations of acute drug toxicity initially thought to be CBZ related. The mean PHT plasma concentration for the 12 patients (22.7 +/- 5.64 micrograms/ml) as well as concentration/dose ratio for PHT (4.61 +/- 1.65 micrograms/ml plasma per mg/kg/day dose) was significantly higher (p less than 0.001) with concomitant administration of CBZ than when PHT was given alone: PHT concentration, 12.54 +/- 3.93 micrograms/ml and PHT concentration/dose ratio, 2.52 +/- 0.78 micrograms/ml plasma per mg/kg/day dose. Those patients with higher PHT plasma concentrations seem to be at higher risk of PHT toxicity due to CBZ comedication.     

7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

7-Nitroindazole (7NI, a nitric oxide synthase [NOS] inhibitor) administered intraperitoneally (ip), 30 min before the test, at doses ranging between 50-200 mg/kg, raised the threshold for electroconvulsions in mice. Linear regression analysis revealed that the doses increasing the threshold by 50% (TID50) and 100% (TID100) over the control value for 7NI were 115.2 and 173.4 mg/kg, respectively. Moreover, 7NI dose-dependently potentiated the anticonvulsant effects of four conventional antiepileptic drugs (AEDs: carbamazepine - CBZ, phenobarbital - PB, phenytoin - PHT, and valproate - VPA) in the mouse maximal electroshock-induced seizure (MES) model. 7NI at 50 mg/kg enhanced only the anticonvulsant effect of PB, whereas the drug at 75 and 100 mg/kg potentiated the antiseizure effects of PB, PHT and VPA, but not those of CBZ against MES-induced seizures. Only 7NI at 150 mg/kg enhanced considerably the antielectroshock action of all studied AEDs in the MES test. Pharmacokinetic evaluation of interactions between 7NI and the investigated AEDs revealed that 7NI (150 mg/kg; ip) did not alter total brain concentrations of conventional AEDs in mice. L-arginine (L-Arg - a natural precursor of NO; administered ip, 500 mg/kg, 60 min before electroconvulsions) did not reverse the activity of 7NI (150 mg/kg), but in contrast, it significantly potentiated the anticonvulsant action of conventional AEDs combined with 7NI (150 mg/kg). Pharmacokinetic increase in total brain AED concentrations was observed for the combinations of L-Arg (500 mg/kg) with 7NI (150 mg/kg) and PHT (by 32%; p<0.01) or VPA (by 22%; p<0.05). Neither total brain CBZ nor PB concentrations were altered following the co-administration of L-Arg (500 mg/kg) with 7NI (150 mg/kg). 7NI at doses of 100-200 mg/kg significantly impaired spontaneous ambulatory activity in mice subjected to the Y-maze task. The NOS inhibitor at doses of 50 and 75 mg/kg had no significant effect on locomotor activity of animals, although the number of arm entries within the 5 min of observational time was reduced. Finally, it can be concluded that the enhancement of anticonvulsive efficacy of CBZ, PB, PHT and VPA by 7NI alone or in combination with L-Arg in the MES test, deserves more attention and further neurochemical studies are required to elucidate the exact role of NO in the brain.     

The clinical relevance of the interaction between carbamazepine and dextropropoxyphene in elderly patients in Gothenburg, Sweden

Objectives: To evaluate the clinical importance of the interaction between carbamazepine (CBZ) and dextropropoxyphene in elderly patients. Methods: All patients (n=7263) in Gothenburg, Sweden, who were part of a drug-dispensing programme, were included in the study. Eight per cent of the patients took CBZ and 18% took dextropropoxyphene, continuously. Patients who used a combination of these drugs were compared with patients who took only CBZ or dextropropoxyphene or neither of the two drugs. These four groups of patients were matched to each other with reference to gender, age and concomitant medication, which finally resulted in 21 patients in each group. A questionnaire with 30 symptoms of well-being, including symptoms typical of adverse effects of CBZ, were answered by the patients with the help of a registered nurse. Venous blood samples were drawn from the patients for the analysis of CBZ, its metabolite CBZ 10,11-epoxide (CBZ-E) and dextropropoxyphene. Results: The doses of CBZ and dextropropoxyphene were lower among patients who used the combination of the two drugs than among those who only used one of the drugs. The mean level of CBZ in serum (S-CBZ) was, however, significantly higher and the level of CBZ-E in serum (S-CBZ-E) significantly lower among the patients who used the combination of CBZ and dextropropoxyphene, thus indicating an inhibition of the metabolism of CBZ. The prevalence of symptoms indicating side effects of CBZ was significantly higher in the group of patients who used both drugs. Conclusion: This study has shown that the combination of CBZ and dextropropoxyphene is hazardous in elderly patients and should be used with caution. Received: 6 March 1997 / Accepted in revised form: 16 July 1997     

Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy

Zonisamide (CI-912) is an experimental antiepileptic drug. Since this drug is to be evaluated initially as an add-on medication, an investigation was conducted to study its kinetics in the presence of two standard antiepileptic drugs. Patients in two groups, one on maintenance phenytoin (PHT) monotherapy and the other on maintenance carbamazepine (CBZ) monotherapy, each received a single dose of four 100-mg capsules of zonisamide; and blood samples were obtained at periodic intervals. Plasma and red blood cell (RBC) concentrations of zonisamide were measured by high performance liquid chromatography. Plasma and RBC areas under the curve produced by single doses of zonisamide in patients receiving CBZ were significantly higher than those receiving PHT (p less than 0.05). Clearance values, although not statistically significantly different, were lower for the CBZ group; and consistent with this, plasma and RBC concentrations decreased more rapidly in the PHT group. The approximate values for t1/2 were 36.4 h in plasma and 54.2 h in RBC for patients treated with CBZ, and 27.1 h in plasma and 35.8 h in RBC for patients treated with PHT. The RBC/plasma ratio varied eightfold within a given curve. These findings suggest that the dosage of zonisamide in epileptic patients might need to be varied depending on the comedication.     

Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy.

We retrospectively collected plasma level assessments performed in 96 adult patients with epilepsy on stable monotherapy, including 9 patients on clobazam (CLB), 34 on carbamazepine (CBZ), 24 on phenobarbital (PB), 9 on phenytoin (PHT), and 20 on valproate (VPA); these results were compared to those obtained in 54 adult patients on stable bitherapy with the association of CLB with either CBZ (n = 17), PB (n = 17), PHT (n = 5), or VPA (n = 15). Our results show that CLB has no significant effect on the level to dose ratio (LDR) of CBZ, PB, PHT, or VPA. Conversely, CBZ, PB, and PHT significantly decrease the LDR of CLB. CBZ and PHT significantly increase the LDR of N-desmethylclobazam (NCLB), the major metabolite of CLB. A significant increase in the NCLB/CLB ratio was found in CBZ + CLB, PB + CLB, and PHT + CLB bitherapies. These findings are of clinical significance: clobazam is useful as adjunctive treatment in human epilepsy and is often chosen as the benzodiazepine adjunctive drug in chronic resistant epilepsy. Sedative side effects may occur, especially in patients treated by a CBZ + CLB or PHT + CLB bitherapy, and both CLB and NCLB plasma levels should be monitored in such patients.     

Evaluation of therapeutic drug monitoring of antiepileptic drugs

Results of the therapeutic drug monitoring (TDM) of the concentration of antiepileptic drugs (AEDs), performed at Aseer Central Hospital over a 1-year period were evaluated. Most of the requests were for phenytoin (PHT) determination followed by carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB). Serum concentrations of PB, CBZ, VPA and PHT within the presumed therapeutic range constituted 87%, 73%, 45% and 33%, respectively. Valproic acid exhibited age differences in the proportion of concentrations below the presumed therapeutic range, such that subtherapeutic concentrations increased while therapeutic concentrations decreased with age. When the requests were related to particular patients, 71% of patients were on monotherapy with PHT as the most commonly used single drug and PB the least. Patients using 2 AEDs were found to constitute 23.5% of all patients with "PHT + CBZ" and "CBZ + VPA" being the most commonly prescribed 2 drugs combination. The frequency of concentrations within the therapeutic ranges decreased when 1 or 2 more drugs were used with either PHT or VPA. In addition, combination with PHT was associated with a reduction in mean CBZ concentration, while combination with CBZ was associated with a reduction in mean VPA concentration.     

Effects of N-(morpholinomethyl)- p-isopropoxyphenylsuccinimide on the protective action of different classical antiepileptic drugs against maximal electroshock-induced tonic seizures in mice

BackgroundThe aim of this study was to determine the effects of N-(morpholinomethyl)-p-isopropoxy-phenylsuccinimide (MMIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) against maximal electroshock (MES)-induced seizures in mice.MethodsTonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Total brain concentrations of AEDs were measured to determine the characteristics of interaction between MMIPPS and classical AEDs in the mouse MES model.ResultsMMIPPS administered intraperitoneally (ip) at 100 mg/kg significantly elevated the threshold for electroconvulsions in mice (p < 0.01). MMIPPS at doses of 25 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, MMIPPS (50 mg/kg) significantly enhanced the anticonvulsant activity of PB and VPA(p < 0.05), but not that of CBZ or PHT, in the MES test in mice. Pharmacokinetic studies revealed that MMIPPS (50 mg/kg) did not alter total brain concentrations of PB, but significantly elevated total brain concentrations of VPA in mice (p < 0.05).ConclusionsThe enhanced anticonvulsant action of PB byMMIPPS in themouseMESmodel and lack of any pharmacokinetic interaction between drugs make the combination of MMIPPS with PB of pivotal importance for further experimental and clinical studies. Pharmacokinetic increase in total brain VPAconcentration seems to be responsible for the enhanced anticonvulsant action of VPAby MMIPPS in the mouse MES model. The combinations of MMIPPS with CBZ and PHT are neutral from a preclinical viewpoint.     

Effect of stiripentol on carbamazepine plasma concentration and metabolism in epileptic children

Objective: To study the relationship between the plasma concentration of stiripentol (STP), a new antiepileptic drug, and its inhibitory effect on the formation of carbamazepine epoxide (CBZE) in epileptic children treated with carbamazepine (CBZ) either alone or in combination with another antiepileptic drug. Methods: Minimum plasma concentration of antiepileptic drugs was measured before initiation of STP therapy (day 0) and on days 28 (STP 60 mg⋅kg⁻¹⋅day⁻¹) and 84 (STP 90 mg⋅kg⁻¹⋅day⁻¹) by HPLC. Results: The CBZE/CBZ plasma concentration ratio decreased exponentially with increasing minimum plasma STP concentration (r = 0.80). The asymptote of the curve allowed the calculation of the minimum plasma STP concentration required to obtain the maximum inhibitory effect, i.e. 6.7 mg⋅l⁻¹. Conclusion: The inhibitory effect of STP on CBZ metabolism expressed as the CBZE/CBZ plasma concentration ratio is dependent on STP plasma concentration, with a maximum effect at an average of 7 mg⋅l⁻¹. The present data suggest that in order to evaluate the anticonvulsant efficacy of STP as add-on therapy, the minimum plasma STP concentration should be maintained above 7 mg⋅l⁻¹ and the dosage of CBZ should simultaneously be decreased in steps by more than 50% to minimize the change in CBZ plasma concentration. Received: 27 September 1995 / Accepted in revised form: 5 January 1996     

丙戊酸钠与苯妥英钠或卡马西平相互作用的血浓度观察

本文报告丙戊酸钠和苯妥英钠或卡马西平合用治疗各型癫痫９０例，丙戊酸钠使苯妥英钠和卡马西平血浓度下降；苯妥英钠和卡马西平是强有力的肝酶诱导剂，使丙戊酸钠血浓度降低，作者认为，抗癫痫药之间的相互作用错综复杂，临床上最好选择单一用药，昼避免联合用药。     

Nevirapine-induced rash with eosinophilia and systemic symptoms (DRESS)

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse reaction commonly occurring with antiepileptic agents. It was earlier referred to by various names such as dilantin hypersensitivity syndrome and anticonvulsant hypersensitivity syndrome. It is characterized by the triad of fever, skin eruption, and systemic involvement. DRESS syndrome has also been reported with a number of other drugs including allopurinol, minocycline, terbinafine, sulfonamides, azathioprine, dapsone, and antiretroviral agents such as abacavir and nevirapine. We describe a rare case of nevirapine-induced hypersensitivity syndrome that was successfully treated with oral steroids.KEY WORDS: Drug reaction with eosinophilia and systemic symptoms syndrome, drug rash, hypersensitivity, nevirapine     

癫痫患者2种治疗药物浓度的监测及其临床意义

目的：监测治疗癫痫患者血清中苯妥英（ＰＨＴ）和卡马西平（ＣＢＺ）的浓度。方法：建立高效液相色谱法,测定住院和门诊７８例癫痫患者血药浓度。结果：其中服用苯妥英２３例,卡马西平５５例,低于治疗有效浓度分别有１４例和１９例,各占６０．８７％和３４．５５％,中毒浓度１例。结论：癫痫患者的治疗与苯妥英和卡马西平的用药水平有关,治疗剂量不能仅凭经验用药,有条件则应进行血药浓度监测,实行个体化给药。