Drug‐resistant epilepsy and topiramate: Plasma concentration and frequency of epileptic seizures

Topiramate (TPM) is a second‐generation antiepileptic drug (AED), acting on drug‐resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (C_p), and frequency of epileptic seizures. A cross‐sectional analytical study was developed with patients aged 18‐60 years, for diagnosis of drug‐resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty‐seven patients were included, 83.8% of the patients presented C_p below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 μg/mL in TPMC_p, while the use of inducers predicted a reduction of 2.97 μg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 μg/mL in TPMC_p decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with C_p below the therapeutic range, the mean number of seizures per month was greater than those with C_p within the therapeutic range. The prescribed dose and the use of AED inducers influence C_p of TPM, likewise the low C_p of first‐line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures.     

A pharmacoeconomic analysis of the impact of therapeutic drug monitoring in adult patients with generalized tonic-clonic epilepsy

AIMS: To carry out a retrospective pharmacoeconomic analysis of the impact of therapeutic drug monitoring (TDM) in adult patients with generalized tonic-clonic epilepsy in an academic, non profit making organization. METHODS: Twenty-five patients who had undergone TDM were compared with 25 age, disease and duration of drug therapy matched controls who had not undergone TDM. Only direct costs were calculated. These included cost to the hospital of providing the TDM service, cost to the hospital per seizure saved, and cost to the patient per seizure saved. RESULTS: Patients undergoing TDM had much more effective seizure control (P = 0.00032, OR 4.846, 95% confidence interval 1.29,18.3), fewer adverse events, better earning and were more likely to be married than the control group. CONCLUSIONS: In patients with adult onset epilepsy, a minimum of two drug estimations per year offers significant benefit in terms of better seizure control, fewer adverse events and greater chances of remission.     

Controlled evaluation of a supplementary dose of carbamazepine on psychomotor function in epileptic patients

Summary The effect of an additional dose of 400 mg carbamazepine (CBZ) on a series of simple psychomotor tests was investigated in 8 patients with epilepsy receiving chronic CBZ monotherapy in a balanced randomised double-blind placebo controlled cross-over study. Psychomotor testing and blood sampling for total and free CBZ and CBZ 10,11 epoxide (CBZ-E) concentrations were performed at 10, 12, 14, 16 and 18 h after the extra dose which was administered at 23.00 h on the previous evening. The CBZ increment produced significant impairment of (i) choice reaction recognition time from 10–16 h after the dose (ii) total choice reaction time at 12 h (iii) card sorting at 12 h (iv) sedation scoring at 12 h. No significant effect on critical flicker fusion threshold, finger tapping or simple memory testing was noted. No patient reported increased side-effects in the placebo phase while 5 noted new symptoms likely to be attributable to the additional CBZ. Areas under the concentration-time curves from 10–18 h were higher following CBZ than placebo for total and free CBZ and CBZ-E concentrations. This study has demonstrated decrements in performance of a series of simple psychomotor tests in epileptic patients receiving a supplemental CBZ dose. Patients with epilepsy who require high CBZ concentrations for optimal control of seizures may be at risk of concurrent impairment of psychomotor function. Simple objective measures of performance may help in assessing the benefit-risk ratio.     

Thyroid hormone concentrations in epileptic patients

Summary Anticonvulsants are associated with decreased serum thyroid hormone concentrations. We have studied thyroid function in 54 epileptic patients on a variety of drugs (19 on carbamazepine, 13 on phenytoin, 10 on sodium valproate, 12 on polypharmacy). For comparison, 14 untreated epileptics and 11 healthy unmedicated volunteers were included as controls.Total thyroxine (T₄) concentrations were reduced in patients taking enzyme-inducing drugs (carbamazepine and/or phenytoin) compared with both controls and patients taking sodium valproate. Similar differences were shown with each individual drug. All nine patients whose circulating T₄ was below the lower limit of the reference range were taking enzyme inducers. Free thyroxine concentrations were also reduced in individuals treated with carbamazepine and phenytoin with five values falling beneath the reference range. Tri-iodothyronine and thyrotropin appeared unaffected by anticonvulsant administration. Thyrotropin releasing hormone stimulation revealed no true hypothyroidism.The lowering effect of anticonvulsant drugs on circulating total and free T₄ was not exhibited by the non-inducing sodium valproate. These data support the influence of enzyme induction as a likely mechanism for reduced thyroxine concentrations in treated epileptic patients.     

Use of saliva for monitoring oxcarbazepine therapy in epileptic patients

Summary The utility of saliva sampling in monitoring oxcarbazepine therapy has been assessed in 17 epileptic outpatients treated with a mean dose 22.7 mg/kg/d for 19–411 days, i. e. at steady-state. Blood was collected before the morning dose measurement of the plasma 10-OH-carbazepine concentration and determination of the protein bound fraction. Immediately after blood sampling resting saliva and saliva produced after a masticatory stimulus were collected.Using equilibrium dialysis and an ultrafiltration technique the protein binding of 10-OH-carbazepine was found to be 40% and 45%, respectively. When the degree of protein binding was expressed as the ratio between the corresponding saliva and plasma concentrations of 10-OH-carbazepine, the concentration in resting saliva indicated that no drug was bound to plasma protein, whereas the use of stimulated saliva suggested a protein-bound fraction of 35%.The concentration in stimulated saliva reflects the free fraction of 10-OH-carbazepine, but regression analysis of paired salivary and plasma values showed that the prediction of plasma concentrations from levels in saliva is uncertain. This, together with the low degree of plasma protein binding, leads to the conclusion that it would be preferable to monitor total plasma concentrations if therapeutic drug monitoring of oxcarbazepine were to prove essential in epileptic patients.     

Effect of carbamazepine on psychomotor performance in näive subjects

Summary The effect of a single dose of carbamazepine (CBZ), 10 mg kg^–1, on a battery of simple psychomotor tests was investigated in 12 healthy subjects (6 male, 6 female) in a balanced randomised double blind placebo controlled cross-over study. Psychomotor testing and blood sampling for total and free plasma CBZ, and CBZ 10, 11 epoxide concentration were performed at 10, 12, 14, 16, 18 and 34 h after oral dosing (23.00 h the previous evening). CBZ impaired i) critical flicker fusion threshold frequency at all time points up to 18 h (p<0.005); ii) total choice reaction time at 10 h (p<0.005) and 18 h (p<0.008); iii) card sorting at 14 h (p<0.001).No significant effect on finger tapping was noted. Subjects adjudged themselves more sedated on CBZ as compared to placebo at 12, 14 and 16 h (p<0.008). Plasma total and free CBZ concentrations (mean ± SD) peaked at 10 h (8.8±0.2 mg l^–1) and 16 h (1.88±0.3 mg l^–1) after dosing respectively. CBZ 10, 11 epoxide values were all less than 10% of total CBZ concentrations and, therefore, were unlikely to contribute to the pharmacodynamic effect. Total choice reaction time was significantly more impaired in females (p<0.05) but no sex difference occurred with the other tests or CBZ concentrations at any time point. No significant correlations were found between individual total or free CBZ concentrations and corresponding test performances at each time point. This study has demonstrated impairment of psychomotor function following CBZ in healthy subjects using a series of simply performed tests. This approach can now be applied to patients with epilepsy receiving long-term treatment with CBZ and other anticonvulsants.     

The IgA immune system in epileptics on anticonvulsant therapy

Summary Disturbances in IgA have often been reported in white epileptics on anticonvulsant therapy. The clinical significance of these disorders is of interest as this aspect does not appear to have been sufficiently explored. In a previous study neither African nor Caucasian epileptics on treatment showed a deficiency of serum IgA. Since secretory IgA is the main defence factor in protecting mucosal surfaces, the object of the present study was simultaneously to determine serum and salivary IgA in suitable subjects and to monitor related clinical events. A similar elevation of salivary IgA level was found in Black and White epileptics on treatment. Clinical events were rare and were not related either to serum or secretory IgA concentrations. It is concluded that at present epileptics do not seem to require special immunological or clinical monitoring.     

氟桂利嗪抗癫痫及逆转难治性癫痫病人多药耐受基因的表达

目的 :了解氟桂利嗪对多药耐受基因 1(MDR 1)表达阴性或阳性癫痫病人的抗癫痫作用及其逆转MDR 1表达的可能性。方法 :54例病人随机分成 2组。实验组用免疫组化法测定P糖蛋白(P gp) ,加用氟桂利嗪 5～ 10mg ,po ,qn ,2wk随访 1次 ,6～ 8wk后评价临床疗效 ,发作减少 50 %者为有效。用药前P gp阳性有效者同时复查P gp。对照组加用安慰剂同步观察。结果 :P gp阳性组的2 2例病人中有效 14例 ,阴性组 12例中有效 2例 ,对照组有效 4例。P gp阳性有效的 11例完成了P gp复查 ,其中 10例病人的P gp表达下降 50 %以上。氟桂利嗪的不良反应发生率为 2 3 %。结论 :氟桂利嗪辅助治疗有效 ,其抗癫痫机制可能与逆转P gp表达有关。     

Valproic acid disposition in epileptic patients during combined antiepileptic maintenance therapy

Summary A previously developed mass spectrometric method was used to measure, in the presence of the unlabeled drug, the fate of pulse dose of tetradeuterated valproic acid given to epileptic patients. By this means the disposition of valproic acid (VPA) was studied in several epileptic patients on maintenance therapy with VPA and at least one other antiepileptic drug. For 6 patients with 6 different antiepileptic drug combinations, the mean VPA half-life was only 6.2 h, as compared to about 15 h after a single dose. The mean plasma clearance in those patients was 16.4 ml/min. The volume of distribution was 0.14 l/kg, which did not differ from values found in single dose studies. The clinical relevance of these findings is pointed out.     

妊娠期癫痫患者左乙拉西坦药动学行为变化

目的：系统研究左乙拉西坦（levetiracetam,LEV）在妊娠期癫痫患者体内药动学行为变化,并探究基于LEV血药浓度监测,调整妊娠期癫痫患者的给药方案。方法：回顾性收集2017年1月至2021年7月于中国医科大学附属盛京医院就诊并进行LEV血药浓度监测的妊娠期癫痫患者的临床病历资料,计算孕前至产后LEV的表观清除率（CL）,分析妊娠期癫痫患者LEV的给药方案,并探究妊娠期合并用药对LEV体内药动学行为的影响。结果：对17例单用LEV治疗的妊娠期癫痫患者138次血药浓度监测数据的回顾性分析表明,妊娠期LEV的CL显著增加,与孕前基线相比,在妊娠早期、中期及晚期分别增加了86.39%（P<0.01）、148.30%（P<0.01）和134.69%（P<0.01）,分娩后迅速下降,于产后6周左右恢复至孕前水平。不同妊娠时期LEV给药剂量存在差异,妊娠中、晚期给药剂量较孕前分别增加了44.93%（P<0.01）和96.07%（P<0.01）。妊娠期合用具酶诱导作用的抗癫痫药能够诱导LEV代谢,使LEV的CL增加。结论：妊娠期癫痫患者LEV体内药动学行为变化显著,其CL于妊娠中期达到峰值,分娩后迅速降低。与具酶诱导作用的抗癫痫药合用会增加LEV的CL。定期监测LEV血药浓度可为妊娠期癫痫患者的药物治疗管理提供指导。     

Therapeutic drug monitoring of mycophenolate in adult solid organ transplant patients: an update

Introduction: Mycophenolate (MPA) therapeutic drug monitoring (TDM) in adult solid organ transplant recipients was summarized extensively in consensus reports published between 2009 and 2011. Thus, this review provides an update on the science of MPA TDM over the past 5 years.

Areas covered: PubMed and Google Scholar (January 2010-January 2016) were searched; relevant articles from bibliographies of identified articles were extracted for further review. New evidence on TDM-guided dosing in MPA efficacy and toxicity and best approaches for estimating MPA area-under-the-curve for TDM were retrieved.

Expert opinion: Since 2011, little advancement in consensus on MPA TDM has been established for any type of solid organ transplant. Lack of systematic studies validating or further defining MPA’s target range suggests that routine TDM is still unwarranted.

Accurate, precise, and user-friendly limited sampling strategies (LSSs) are available in specific patient populations taking mycophenolate mofetil but not enteric-coated mycophenolate sodium. In absence of outcome data, routine use of LSSs in MPA TDM still cannot be recommended.

Further research should attempt to define factors that modulate MPA’s pharmacokinetics to elucidate their impact on utility of TDM. Future studies should also validate LSSs in larger patient populations and demonstrate benefits of LSSs in improving patient outcomes.     

Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients

Summary In four refractory epileptic patients, peak plasma levels of sodium valproate occurred within 1.5 to 3 h after a single oral dose of valproate and the decline in plasma levels followed a monoexponential course with a t_1/2 of 11.4 ± 0.1 h. The mean value for apparent volume of distribution was 0.176 ± 0.013 l/kg and for total plasma clearance 0.0106 ± 0.0009 l/h/kg. Steady state plasma levels were predicted using the method of superposition utilizing pharmacokinetic parameters determined following a single dose of valproate and were 78–123% of the predicted values for two patients receiving valproate alone, and 37–64% of the predicted values for the two patients receiving carbamazepine in addition to valproate. In a further group of 20 patients the mean daily doses of valproate for 8 patients receiving valproate alone (25.4 ± 4.9 mg/kg) was significantly less than those for the 12 patients receiving concomitant anticonvulsant therapy (41.6 ± 12.3 mg/kg) (p<0.005). In addition, the steady state predose plasma levels of valproate were significantly higher in the valproate alone patients (90.3 ± 8.7 µg/ml) compared to the patients receiving additional anticonvulsants (75.3 ± 13.8 µg/ml) (p<0.01). The higher dose requirements of valproate and lower predose and steady state plasma levels for those patients on multiple anticonvulsants indicate an interaction between valproate and other anticonvulsants.     

成人万古霉素血药浓度监测的探讨

万古霉素(糖肽类抗生素)是治疗耐甲氧西林金黄色葡萄球菌(MRSA)感染的主要药物之一。进行血药浓度监测,能降低毒性和提高疗效。AUC/MIC是预测万古霉素疗效的重要参数,监测谷浓度是最为准确和实用的方法;但并非所有患者都必须进行监测。应继续开展相关研究,促进万古霉素临床使用安全、有效。     

Psychomotor performance of psychiatric inpatients under therapy: assessment by paper and pencil tests

Fifty psychiatric inpatients included in the study were diagnosed as having substance related disorder, schozophrenia, bipolar disorder, depressive disorder or anxiety disorder based on DSM-IV and ICD-10. All the patients were on multiple drug therapy for a minimum of 7 days in the hospital. The psychomotor performance score assessed with the help of the six letter cancellation test and the digit letter substitution test was compared with a matched group of 50 normal volunteers. The significantly low scores for patients may be considered indicative of the fact that prolonged therapy would be required to attain normal psychomotor status. Thus, simple paper and pencil tests may provide valuable information in assessment of psychomotor and cognitive functions of psychiatric patients during recovery.     

丙戊酸钠血药浓度监测对治疗儿童癫痫的临床意义

目的:分析评价治疗药物监测(TDM)对丙戊酸钠(VPA)治疗儿童癫痫的临床意义。方法:采用高效液相色谱法检测丙戊酸钠血药浓度,统计分析血药浓度与临床疗效、剂量、合用药物等因素的相关性。统计学处理采用SPSS 11.5软件。结果:在2 002例次儿童癫痫患者的丙戊酸钠血药浓度监测结果中,血药浓度在50～100μg.mL-1范围内1 185例(59.19%),<50μg.mL-1 538例(26.87%),>100μg.mL-1 279例(13.94%);丙戊酸钠血药浓度与临床疗效、不良反应及年龄密切相关,其他抗癫痫药可能降低丙戊酸钠血药浓度而影响疗效。结论:丙戊酸血药浓度个体差异大,且受药物间相互作用等多种因素影响,临床为实现个体化用药,应常规监测血药浓度。     

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001‐2015, 1308 pre‐dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%‐7% of cases in bi‐ or triple therapy. About 61% of plasma levels were found within the TR during 2001‐2005, compared to 75% and 74% during 2006‐2010 and 2011‐2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3‐fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001‐2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.     

Antioxidant agents and physiological responses in adult epileptic patients treated with lamotrigine

BackgroundThe aim of our research was to evaluate some biochemical changes in blood during lamotrigine (LTG) monotherapy of adult patients with epilepsy, and to check possible associations between typical selenium status parameters and the frequency of seizures.MethodsThe study was performed by examining aspartate aminotransferase (AspAT), alanine aminotransferase (AlaAT), creatinine, ferric reducing ability of plasma (FRAP), serum uric acid (UA), uric-acid-independent FRAP (UAiFRAP), plasma glutathione peroxidase (GPX3), selenoprotein P (SelP), plasma superoxide dismutase (pSOD), 8-hydroxy-2’-deoxyguanosine (8-OHdG) in serum and urine, serum selenium (sSe) and zinc (sZn), in 22 adult patients with epilepsy and 22 healthy controls. Additionally, the levels of LTG were determined in patients.ResultspSOD activity was higher in the study group (5.32 ± 1.24 U/ml) compared with the controls (4.05 ± 0.92 U/ml, p = 0.008). No other statistical difference between patients and controls was found.ConclusionLack of difference in parameters other than SOD, particularly no difference in 8-OHdG concentrations between the patients treated with LTG compared to the control subjects suggests that these patients are at no particular risk of oxidative DNAdamage. In patients who are well or moderately well clinically controlled, selenium status parameters (sSe, GPX3, SelP) are not directly connected with the frequency of seizures.     

Retrospective analysis of drug treatment in epileptic patients

An epidemiological analysis was performed of the adult, out-patient epilepsy clinic population of a university hospital during the period from 1 January 1981 through 30 June 1985. The number of patients that could be traced amounted to 590. An at random sample of 207 were retrospectively analysed. Gender distribution was male:female = 1.46. The mean age was 37.4 years. The diagnoses were classified according to the classification of the International League Against Epilepsy (ILAE). A preponderance of partial seizures was present, reflecting the selection in a university out-patient clinic of more difficult to treat forms of epilepsy. Antiepileptic drugs used in the treatment varied; monotherapy was obtained in 46% of the cases and carbamazepine was the most frequently prescribed drug (49%). Changes in seizure severity and factors associated with epilepsy are described. A discrepancy was found between the suspected drug levels, based upon the physician's judgement, and the plasma level measured in those patients in whom drug levels were monitored; factors interfering with clinical judgement are discussed.     

Brain concentrations of phenytoin,phenobarbitone and primidone in epileptic patients

Summary Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10–14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.