丙戊酸钠与卡马西平治疗小儿癫痫的随机对照研究

目的应用临床流行病学方法评价丙戊酸钠(VPA)与卡马西平(CBZ)治疗小儿全身性强直-阵挛性发作(GTC)及部分性/继发全身性发作(P±GTC)的疗效和副作用.方法前瞻性开放的临床随机对照研究,以治疗前后癫痫发作次数的减少和用药开始到用药后第1次发作的时间作为疗效的判断标准来比较两种药物的疗效和不良反应.结果在治疗3个月后,两组患儿在癫痫发作次数的减少和用药开始到用药后第1次发作的时间上无显著性差异,VPA在减少GTC方面较CBZ更有效;共有5例患儿(6.9%)因药物的不良反应而停药,其中VPA组2例(4.6%),CBZ组3例(7%),两组均有一定的副作用.结论VPA与CBZ单药治疗小儿GTC及P±GTC均具有很好的疗效,应作为治疗的首选药物.     

Thyroid dysfunction associated with increased low-density lipoprotein cholesterol in epileptic children treated with carbamazepine monotherapy: A causal relationship?

OBJECTIVE: Lipid abnormalities and thyroid dysfunction have been reported in patients treated with antiepileptic drugs. The aim of this study was to evaluate prospectively the association between thyroid and lipid profile in children treated with carbamazepine (CBZ) monotherapy. MATERIALS AND METHODS: Thyroid function was evaluated in 18 epileptic children, previously reported with CBZ-induced changes in serum lipid profile, before and at 6, 12 and 24 months of CBZ monotherapy. RESULTS: All children had normal thyroid function before the initiation of CBZ treatment. During CBZ therapy thyroid dysfunction, with increased thyrotropin (TSH) and decreased thyroxine (T4), free thyroxine (FT4) and triiodothyronine (T3) was found, while, significant association was revealed between serum low-density lipoprotein cholesterol (LDL-C) and TSH levels at 6 (r=0.469; p=0.043) and 12 (r=0.730; p=0.001) months of treatment. CONCLUSION: Lipid abnormalities may be associated with thyroid hormone disturbance in children treated with CBZ monotherapy. Since thyroid dysfunction and hypercholesterolemia are both associated with a higher atherosclerotic risk special attention and further studies are needed in epileptic patients treated with CBZ monotherapy.     

丙戊酸钠与卡马西平对脑电活动影响的研究

目的探讨丙戊酸钠（ＶＰＡ）与卡马西平（ＣＢＺ）对脑电活动的影响。方法对单独应用ＶＰＡ或ＣＢＺ治疗,且临床上发作已被控制的患儿进行脑电图（ＥＥＧ）和脑电地形图检查。结果①ＶＰＡ治疗组可使间歇期痫样活动（ＩＥＡ）消失或减少５００％以上达６９０％,而ＣＢＺ治疗组仅为４４０％。同时ＣＢＺ治疗组临床发作虽已被控制但ＩＥＡ明显增多有４例,ＶＰＡ治疗组则未见此现象。②ＶＰＡ治疗组对脑电背景活动影响不明显,而ＣＢＺ可引起α波活动减少,θ波、δ波活动增加,治疗前后均具有显著性差异。③ＣＢＺ治疗组α１频段的相对功率及θ频段绝对功率和相对功率,其治疗前后比较经ｔ检验,Ｐ值分别＜００５,＜００５,＜００１;而在ＶＰＡ治疗组仅见θ频段相对功率在治疗前后有显著差异,Ｐ值＜００１。结论ＣＢＺ可使脑电背景活动变慢,甚至ＩＥＡ增加,而ＶＰＡ则影响不明显     

卡马西平对癫痫患儿甲状腺激素水平影响的临床观察

目的探讨卡马西平(CBZ)对癫痫患儿甲状腺激素水平的影响.方法对27例初诊为癫痫患儿行CBZ单药治疗前、平均治疗3个月后及25例长期行CBZ单药治疗平均1年7个月后的癫痫患儿,用放射免疫法分别测定血清甲状腺素(T4)、游离T4(FT4)、三碘甲腺原氨酸(T3)、游离T3(FT3)及促甲状腺激素(TSH)的水平,并以32例健康儿童作为对照.结果CBZ平均治疗3月后T4、FT4分别为(113.1±40.6)nmol/L和(16.6±3.6)pmol/L,均明显低于治疗前的(138.2±35.6)nmol/L(P<0.01)和(20.5±4.5)pmol/L(P<0.01).长期服用CBZ平均1年7个月的患儿与健康对照组相比,T4、FT4水平同样降低,分别为(108.9±44.6)nmol/L(P<0.05)和(15.5±3.7)pmol/L(P<0.001).结论甲状腺激素水平的改变与CBZ的肝酶诱导作用有关,提示CBZ治疗期间监测患儿甲状腺功能的必要性.     

卡马西平和丙戊酸钠对癫癎患儿骨代谢的影响

目的探讨长期服用卡马西平（CBZ）或丙戊酸钠（VPA）对癫痫患儿骨代谢的影响。方法对92名单独服用CBZ或VPA2年以上的癫痫患儿及35名年龄匹配的健康儿童的骨密度进行测量,测定骨代谢特异性生化指标,血清骨钙素（OC,骨形成指标）和尿脱氧吡啶酚（DPD,骨吸收指标）,并调查每日钙摄入量。结果癫痫患儿骨密度明显低于对照组（P〈0．05）,服用抗癫痫药物（AEDs）的时间与骨密度呈负相关（rs=-0．21～-0．31,P〈0．05）。癫痫患儿中低骨密度患儿32人,占35％,明显高于对照组14％（P〈0．05）。低骨密度的癫痫患儿多体重指数较高（P〈0．05）,每日钙摄入量较少（P〈0．01）,服用AEDs的时间相对较长（P〈0．01）。癫痫患儿血清OC浓度明显低于对照组（P〈0．01）;而尿DPD浓度与对照组基本一致（P〉0．05）。结论长期服用CBZ或VPA会导致骨代谢异常,骨密度下降、骨转换降低（以骨形成减少为主）;而钙摄入量不足及体重指数偏高是加剧骨骼异常的诱发因素。     

丙戊酸钠对癫痫患儿血小板数量及功能影响研究

目的　探讨丙戊酸钠 (VPA)对癫疒间 患儿血小板数量及功能的影响。方法　对 38例服用不同剂量VPA的癫疒间患儿分别于服药前、服药 3个月和 6个月时检测其血小板数量、血小板聚集率、血栓素B2 (TXB2 )和6 酮 前列腺素 F 1α(6 Keto PGF 1α)的水平。结果　服用VPA 3个月与服药前比较 ,血小板计数明显减少 (t =2 82 4 ,P <0 0 1) ,且与VPA剂量呈负相关 ;胶原和二磷酸腺苷 (ADP)诱导的血小板聚集率显著下降 (t =2 15 3和 2 2 6 3,P均 <0 0 5 ) ,与VPA剂量呈负相关 ;TXB2 显著下降 (t =2 373,P <0 0 5 ) ,与VPA剂量不相关 ;6 Keto PGF 1α无明显变化。服药 6个月与 3个月比较 ,上述各指标差异无显著性。全身性发作组与部分性发作组比较 ,上述各指标无显著性差异。结论　VPA能影响癫疒间 患儿的血小板数量及功能 ,影响的程度与VPA剂量相关 ,与癫疒间 患儿的发作类型无关。     

癫癎儿童丙戊酸钠群体药代动力学的研究

目的　建立癫疒间儿童丙戊酸钠的群体药代动力学 (populationpharmacokinetics ,PPK)模型 ,促进个体化用药。方法　检测 10 0例癫疒间 患儿丙戊酸钠的血药质量浓度 ,用USC PACK软件计算丙戊酸钠PPK参数值 ,建立PPK模型 ;据此预测 36例新癫疒间 患儿 (指未参与PPK模型建立的 )的血药质量浓度 ;将预测值与观测值做配对t检验 ;计算不同预测误差百分比的符合率及其 95 %可信区间 ,判断预测的准确程度 ,验证PPK模型。结果　PPK参数值 :消除速率常数为 (0 0 4 38± 0 0 384 ) /h ,选择吸收速率常数为 (2 5 2 2± 2 74 3) /h ,表观分布容积对体重的斜率为 (0 32 9± 0 4 96 )L/kg。预测值与观测值的配对 t检验没有统计学差异 (P =0 99) ;预测的误差百分比分别为 5 %、10 %、15 %、2 0 %、2 5 %、30 %的符合率分别为 74 %、84 %、89%、92 %、93%、95 %。结论　用USC PACK软件成功建立中国癫疒间儿童丙戊酸钠的PPK模型 ,准确预测丙戊酸钠稳态血药质量浓度 ,为获取个体药代动力学参数 ,设计个体化用药方案 ,提供了新途径。     

Use of saliva in monitoring carbamazepine medication in epileptic children

In 17 children on carbamazepine medication alone and 15 children on combined drug regimens, carbamazepine levels were determined in paired samples of serum and mixed saliva by enzyme immunoassay. Carbamazepine levels in serum and saliva were highly correlated in within-patient and between-patient series (r=0.87–0.94). Salivary levels were altered to a minor and clinically insignificant degree by stimulation of saliva flow. Mean saliva/serum ratios, calculated from drug concentrations in saliva specimens collected without and with stimulation were 0.44–0.45 and 0.41–0.43, respectively. The saliva/serum ratio was independent of the serum carbamazepine level and was not affected by concomitant drug medication. The data indicate that measuring salivary levels by enzyme immunoassay is suitable for predicting serum carbamazepine levels. Thus, measurement of carbamazepine levels in mixed saliva samples obtained by a noninvasive technique is recommended for routine monitoring of carbamazepine medication in epileptic children.Supported by Deutsche Forschungsgemeinschaft (Ba 246/11)The data comprise part of the doctoral thesis of Elke Günther, University of Kiel     

小儿癫痫及抗癫痫治疗血脂水平的监测及其临床意义

目的　探讨小儿癫痫及抗癫痫治疗血脂水平的变化。方法　对６０ 例癫痫患儿服药前、后血脂水平进行测定。结果　癫痫本身对血脂水平无影响;卡马西平可使血清总胆固醇（ＴＣ）、甘油三酯（ＴＧ）、高密度脂蛋白胆固醇（ＨＤＬ－ Ｃ） 及低密度脂蛋白胆固醇（ＬＤＬ－ Ｃ） 水平升高,且随时间延长,差异更为明显;丙戊酸钠对血脂无影响。结论　小儿癫痫治疗期间应动态监测血脂水平,如血脂有动态增高趋势应密切观察,并可适当调整饮食。     

Effect of valproate and carbamazepine on visual evoked potentials in epileptic children

The effects of carbamazepine (CBZ) and sodium valproate (SV) monotherapy on visual evoked potentials (VEP) were studied in 18 epileptic children receiving CBZ and nine epileptic children receiving SV. Pattern reversal VEP were determined before the administration of antiepileptic drugs (AED) and 1 year later during which time the patients had received AED. The VEP amplitude showed no consistent changes after 1 year of CBZ and SV therapy, but VEP P-100 latencies were significantly prolonged after 1 year of CBZ therapy. We conclude that CBZ causes a slowing down of central impulse conduction and that VEP is useful to evaluate the effects of AED within the central nervous system.     

癫痫儿童生活质量的研究

目的研究癫痫儿童的生活质量。方法应用美国癫痫生活质量量表，对１９２例癫痫儿童进行生活质量的评估，探讨影响因素并与正常儿童进行比较。结果癫痫儿童的生活质量明显低于正常儿童，主要表现在对发作的恐惧、长期用药的担忧、认知功能的障碍及社会交往的困难。即使发作已被控制，其生活质量并无明显改善。生活质量高低因发作类型不同而各异。结论对癫痫儿童应加强综合治疗，特别要进行心理干预，才能提高其生活质量。     

Thyroid function and volume in epileptic children using carbamazepine, oxcarbazepine and valproate

BACKGROUND: The aim of the present study was to investigate the effects of carbamazepine (CBZ), oxcarbazepine (OXC), and valproic acid (VPA) on thyroid function and volume in epileptic children. METHODS: Fifty-three epileptic children (age, 3-17 years) treated with OXC (n = 10), CBZ (n = 12), or VPA (n = 31) at least for 1 year were evaluated in terms of thyroid hormones, thyroid-stimulating hormone (TSH) levels, response to thyrotropin-releasing hormone (TRH) stimulation test, and thyroid volumes. RESULTS: The patients in the OXC and CBZ groups had similar total thyroxin (TT4) and free T4 (fT4) median levels that were significantly lower than those of the VPA group (P < 0.016). Total tri-iodothyrosin median levels were lower in the CBZ group compared to the VPA group (P < 0.016). Basal TSH levels and thyroid volumes were similar in all groups (P > 0.016). One child from the OXC group (10%), one from the CBZ group (%8.3), and six from the VPA group (19.3%) had hypothyroidic status according to the TRH stimulation test. No statistically significant correlations were found between thyroid gland volume and thyroid function variables and between anti-epileptic drug receiving time and thyroid function or thyroid volume, respectively, in any of the groups (P > 0.05). CONCLUSIONS: Thyroid function should be evaluated periodically in children using CBZ, OXC or VPA. The children taking VPA seems to be at greater risk compared to children onr CBZ or OXC therapy. Except for the basal TSH values in the VPA group, the parameters predictive for the subclinical hypothyroid status remain to be evaluated in further studies.     

托吡酯治疗后癫(癎)患儿体重和血浆甘丙肽的变化

目的探讨癫痫患儿托吡酯治疗后体重变化与血浆甘丙肽的关系。方法对服用托吡酯的61例癫痫患儿用放射免疫法测定治疗前后血浆甘丙肽浓度和观察身高、体重变化,并以16例健康儿童作为对照。结果①服托吡酯后22例（36．1％）体重下降,该组甘丙肽浓度降低有统计学意义（t=2．91,P〈0．01）。体重增加组甘丙肽变化没有统计学意义（t=1．67,P〉0．05）。对照组甘丙肽变化无统计学意义（t=1．72,P〉0．05）。②体重下降组中18例（81．8％）患儿食欲变差,与体重增加组相比,差异有统计学意义（X^2=28．50,P〈0．001）。③食欲差组甘丙肽浓度降低有统计学意义（t=4．84,P〈0．001）,而食欲好组下降无统计学意义（t=1．04,P〉0．05）。④癫痫患儿治疗后体重指数的下降[（17．48±2．22）kg／m^2比（15．24±2．38）kg／m^2]有统计学意义（t=8．628,P〈0．01）。对照组是增加的。结论服用托吡酯后部分癫痫患儿体重会有显著下降和食欲减退,同时伴有血浆中甘丙肽水平显著的下降。提示托吡酯治疗引起的体重降低和食欲减退可能与甘丙肽浓度降低有关。     

Serum lysozyme activity in children with acute leukemia

Serum lysozyme activity was measured in samples from children with acute leukemia, malignant tumours, and in normal children. All children with acute lymphatic leukemia (ALL) had significantly reduced levels of lysozyme at diagnosis, and none of the children fell within the normal range. Children with ALL in complete remission had lysozyme levels comparable to normal children, while children with ALL in relapse also had pathological low levels. Children with ALL in remission and off therapy also had normal levels of lysozyme. Children with acute myelogenous leukemia had normal lysozyme levels, while children with monomyelocytic leukemia had substantially elevated lysozyme levels before treatment. Determination of serum lysozyme activity in children with acute leukemia is of value both for diagnosis and for evaluating the effect of therapy.     

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目的探讨丙戊酸治疗对癫癎患儿血浆胰岛素和瘦素水平的影响。方法测定2003-04—2004-02在山东大学齐鲁医院儿科癫癎治疗中心就诊且服用丙戊酸的32例癫癎患儿和33例对照组(儿外患儿)血浆胰岛素、瘦素水平并计算胰岛素抵抗值、体重指数,并对服用丙戊酸的癫癎患儿胰岛素抵抗值、瘦素与丙戊酸的剂量、疗程、体重指数进行相关分析。结果丙戊酸治疗组体重指数、胰岛素、胰岛素抵抗值、瘦素水平高于对照组;胰岛素抵抗值、瘦素水平与体重指数、丙戊酸疗程显著正相关,与剂量无相关性;偏相关分析示对照组胰岛素、胰岛素抵抗值与瘦素显著负相关,而丙戊酸治疗组胰岛素、胰岛素抵抗值与瘦素显著正相关。结论丙戊酸治疗可引起肥胖程度增加、胰岛素抵抗及瘦素抵抗;胰岛素抵抗、瘦素抵抗与肥胖程度增加有关,与丙戊酸疗程正相关;胰岛素抵抗与瘦素水平显著正相关。     

左乙拉西坦改善发作控制的癫痫患儿异常脑电图的疗效

目的 探讨左乙拉西坦对临床发作缓解而脑电图明显异常的癫痫患儿的脑电图的影响.方法 将就诊于我院神经专科门诊临床发作得到控制1年以上而脑电图依然明显异常的39例卡马西平单药治疗中的部分性或复杂部分性发作的癫痫患儿按来诊顺序交叉分为对照组、丙戊酸钠组及左乙拉西坦组,各13例.入组前半个月内均行脑电图检查,入组后分别予以维持原药治疗、加用丙戊酸钠口服及加用左乙拉西坦口服.观察时间6个月,6个月后复查脑电图,分析其疗效.结果 3组患儿脑电图改善率(控制+显效+有效/总例数-失访人数)分别为9.1％、23.1％和66.7％;3组患儿脑电图改善率比较差异有统计学意义(P＜0.01),丙戊酸钠组与对照组比较差异无统计学意义(P＞0.0125),左乙拉西坦组与对照组比较差异有统计学意义(P＜0.012 5).结论 添加左乙拉西坦可以有效减少癫痫患儿发作间期脑电图异常放电频率.     

Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants

Objective: To assess the effect of long-term treatment of phenobarbital, carbamazepine and sodium valproate on serum lipids and lipoproteins in epileptic children.
Methodology: One hundred and fourteen (55 male, 59 female) children and adolescents suffering from various types of epilepsy who received different antiepileptic drugs were studied. The patients were subdivided into three groups according to their therapy: (i) carbamazepine (35 patients); (ii) phenobarbital (34 patients); and (iii) sodium valproate (45 patients). One-hundred healthy sex- and age-matched children served as controls. Lipids and lipoprotein profile were evaluated before the beginning of the anticonvulsant therapy and after at least 2.5 years. In the patients receiving phenobarbital, we re-evaluated 12 children (seven male, five female) at the end of therapy.
Results: The children receiving phenobarbital showed high levels of serum total cholesterol and low-density lipoprotein (LDL) cholesterol and low levels of triglycerides, while children treated with carbamazepine had high levels of total cholesterol, triglycerides, LDL and high-density lipoprotein (HDL) cholesterol. Children treated with valproate had low triglycerides and LDL cholesterol levels with high levels of HDL cholesterol. The patients treated with phenobarbital showed a normalization of all parameters after the end of therapy.
Conclusions: Anticonvulsant drugs significantly modify serum lipids and lipoproteins in epileptic children. The changes due to phenobarbital seem to be transient.     

Carbamazepine-induced skin rash in children with epilepsy

The clinical and epidemiological findings in children with epilepsy who experienced skin rashes induced by carbamazepine (CBZ) were prospectively evaluated. Thirty-three (9.9%) of 335 patients who received CBZ therapy experienced a skin rash. Seven had diffuse erythema, 13 miliary exanthema, 11 maculopapular or speckled reddish rash, 3 petechiae, and 2 mucocutaneous syndrome. A skin rash was more frequent in older children (over 6 years old). The skin rashes appeared soon after initiation of the therapy, i.e., from the 8th to 60th day (mean: 14.3±9.6 days) after the start of CBZ therapy and disappeared within a few days after discontinuation of the therapy. Haematological abnormalities (30.3%), such as leucocytopenia and thrombocytopenia, and hepatic dysfunction (27.3%) sometimes appeared concomitantly with the skin rash. CBZ is an effective and safe antiepileptic drug, but careful management is necessary on initiation of the therapy.     

Serum alkaline phosphatase isoenzymes in epileptic children receiving anticonvulsant drugs

In 40 epileptic children on long-term anticonvulsant treatment, serum alkaline phosphatase (AP) isoenzymes were separated semiquantitatively using a combination of L-phenylalanine inhibition and heat inactivation. Though mean total serum AP activity was significantly increased compared to age matched controls, only 4 individual values exceeded the upper limit (mean + 2SD) of the reference sample. In epileptics the mean activity of the heat-sensitive non L-phenylalanine sensitive AP fraction (non-LPSAP) was significantly increased (P<0.01) and the mean Q-value (i.e. percentage ratio of heat-stable non-LPSAP/non-LPSAP) was significantly decreased (P<0.05), thus indicating an enhancement of the bone isoenzyme during anticonvulsant treatment. In 4 patients the isoenzyme pattern was abnormal although total serum AP activity was normal and in 3 of them the deviation indicated enhanced bone isoenzyme. The data provide evidence that in anticonvulsant treated children the bone isoenzyme, rather than hepatobiliary isoenzyme fraction, may be increased even when total serum AP activity is normal. Thus, semiquantitative separation of serum AP isoenzymes may be a helpful guide as to whether or not an epileptic child should be given vitamin D.Supported in part by Deutsche Forschungsgemeinschaft (Ba 246/11)The data form part of the thesis of H. Günther, Medical School of Lübeck     

Bioavailability of sodium valproate suppositories during repeated administration at steady state in epileptic children

Oral administration of antiepileptic drugs can temporarily be impossible under certain conditions, such as altered states of consciousness, spike-wave stupour, gastrointestinal disturbances with nausea and vomiting, prior to or during surgery or certain diagnostic procedures, and because of drug refusal in patients with mental retardation or psychiatric problems. Although rectal administration of sodium valproate (NaVPA) has been shown to be a possible alternative route, little is known about the bioavailability and local effects during repeated administration of NaVPA suppositories. These aspects were investigated in 13 epileptic children and adolescents on chronic NaVPA therapy. Eight patients were treated with the oral solution (Group A, mean age 10.6 years) and five patients with enteric coated tablets (Group B, mean age 16.4 years). In every patient five serum levels of VPA over a 24 h period were measured under steady-state conditions. Thereafter, suppositories were administered for 2–7 days and serum levels were again determined (identical dosing and sampling times). Bioavailability of NaVPA was calculated on the basis of the area under the concentration vs. time curve over 24 h. The average bioavailability for suppositories compared with the oral form was 112.4% in Group A and 99.5% in Group B. Fluctuations of serum VPA levels were very similar with suppositories and oral solution, and more pronounced than with the enteric coated tablets. Stool frequency was not increased by repeated administration of suppositories, except for a three-fold increase in one patient. There was no objective or subjective evidence of local irritation from the suppositories. In conclusion, NaVPA suppositories have the same bioavailability under steady-state conditions as oral preparations and they are well tolerated. NaVPA suppositories thus represent a useful alternative when oral administration is temporarily impossible, and no adjustment in dose is necessary.Abbreviations NaVPA sodium valproate - VAP valproate