氟桂利嗪对青霉素致痫大鼠苯巴比妥钠脑组织药物浓度的影响

目的研究氟桂利嗪对青霉素致痫大鼠苯巴比妥钠脑组织药物浓度的影响。方法 SD大鼠随机分成4组（n=10）,A组为空白对照组注射生理盐水,B组注射苯巴比妥钠,C组注射氟桂利嗪,D组在B组的基础上联合氟桂利嗪。空白组及各给药组干预2 h后给予青霉素致痫,致痫30 min后处死并分离脑组织制备脑组织匀浆,HPLC测定苯巴比妥钠浓度。结果与B组相比,D组脑组织苯巴比妥钠浓度显著提高（P〈0.05）。结论氟桂利嗪能提高苯巴比妥钠在致癫大鼠的脑组织药物浓度。     

苯巴比妥栓的制备及在家兔体内的药物动力学

目的：研制生物利用度较好的苯巴比妥栓剂。方法：以３种不同基质制成苯巴比妥栓剂，并比较它们在家兔体内的药物动力学。采用荧光偏振免疫分析法测定血药浓度，按二室血管外给药模型进行药物动力学参数模拟。结果：以水溶性基质脂肪酸聚氧乙烯醚（Ｓ－４０型）制成的栓剂的主要药动学参数分别为Ｋａ１．０１±０．２２ｈ－１，Ｔｍａｘ２．４２±０．１１ｈ，Ｃｍａｘ１１．１±１．３μｇ·ｍｌ－１，ＡＵＣ９２４±１１０μｇ·ｈ·ｍｌ－１，均明显优于以３６＃半合成脂肪酸酯和聚乙二醇－４０００为基质的栓剂（Ｐ＜０．０１）。结论：３种栓剂的释药性具有显著性差异，以脂肪酸聚氧乙烯醚（Ｓ－４０型）为基质的栓剂最好。     

Differential kinetics of cinromide and two of its metabolites in epileptic patients

Summary Cinromide is an experimental anticonvulsant currently in phase II testing. A single oral dose (900 mg) of cinromide was administered to 8 epileptic subjects on phenytoin therapy. Plasma samples drawn during the next 36 h were analyzed for cinromide and its amide and acid metabolites. The absorption rate of cinromide varied widely between subjects producing maximum cinromide concentrations between 0.5 and 2.5 h after the dose. The median elimination half lives of cinromide and the amide and acid metabolites were 0.73, 1.65, and 4.85 h respectively. The oral clearance of cinromide (median=135 l/h) suggests that it is subject to first pass metabolism. In all subjects the area under the curve (AUC) of acid metabolite (632 to 1777 µM/l) was greater than the AUC of amide metabolite (77 to 185 µM/l) which was greater than the AUC of cinromide (5 to 89 µM/l). Steady-state concentration ratios of metabolite to parent drug predicted from the AUC data were 3.8 for the amide and 35.8 for the acid metabolite. The amide metabolite is known to have anticonvulsant properties and, until the relative contributions of metabolites and parent drug to the efficacy of cinromide are resolved, the monitoring of metabolites as well as parent drug is imperative.     

Population pharmacokinetics of carbamazepine in Singapore epileptic patients

AIMS: To document the population pharmacokinetics of carbamazepine in patients with epilepsy living in Singapore, the majority of whom are of Chinese origin and others of minority races. METHODS: Steady-state plasma carbamazepine concentration data were gathered during routine care from various hospitals in Singapore for patients with epilepsy. Age, body weight, gender, race, formulation and concurrent medication (for other illnesses) were the fixed effects (covariates) tested simultaneously for their influence on the population mean of carbamazepine clearance, using the nonlinear mixed-effects model, in the NONMEM program. RESULTS: No age, gender, race, or formulation-related effect was found. Body weight (W), age (A) and concurrent medication with phenobarbitone (PB) emerged as the determinants of carbamazepine clearance (CL). The final regression model for carbamazepine clearance found best to describe the data was CL = 40.7 x A(0.494) x W(-1.17) x 1.44PB where CL is in l day(-1) kg(-1), A is in years, W is in kg and PB = 0 for a patient on carbamazepine only and PB = 1 for a patient on concomitant PB. The corresponding interindividual variability (CV%) in CL, described by using an exponential model, was 21.4%, and the residual error, described by using an exponential error model, was 18.2%. Predictive performance of this population covariate model was evaluated by Bayesian forecasting in a similar, but independent cohort of patients. There was no statistically significant bias between predicted and measured plasma carbamazepine concentrations. The population mean value of carbamazepine clearance obtained was similar to that previously reported for patients with a very different ethnic (Caucasians and Blacks) or geographical background (South Africa, Europe and USA). CONCLUSIONS: The derived covariate regression model reasonably predicted concentrations in the separate validation Singapore patient data set. The correlation between carbamazepine clearance and patient-specific characteristics may thus allow dosage adjustment to be made to achieve target steady-state plasma concentrations.     

Combined effects of epileptic seizure and phenobarbital induced overexpression of P-glycoprotein in brain of chemically kindled rats

Background and purpose:

The multidrug resistance of epilepsy may result from the overexpression of P-glycoprotein, but the mechanisms are unclear. We investigated whether the overexpression of P-glycoprotein in the brains of subjects with pharmacoresistant epilepsy resulted from both drug effects and seizure activity.

Experimental approach:

Kindled rats were developed by injecting a subconvulsive dose of pentylenetetrazole (33 mg·kg⁻¹·day⁻¹, i.p.) for 28 days. Groups were then treated with an oral dose of phenobarbital (45 mg·kg⁻¹·day⁻¹) for 40 days. In accord with behavioural observations, P-glycoprotein activity in brain was assessed using brain-to-plasma concentration ratios of rhodamine 123. P-glycoprotein levels in the brain regions were further evaluated using RT-PCR and Western blot analysis. The distribution of phenobarbital in the brain was assessed by measuring phenobarbital concentrations 1 h following its oral administration.

Key results:

The kindling significantly increased P-glycoprotein activity and expression. Good associations were found among P-glycoprotein activity, expression and phenobarbital concentration in the hippocampus. Short-term treatment with phenobarbital showed good anti-epileptic effect; the maximum effect occurred on day 14 when overexpression of P-glycoprotein was reversed. Continuous treatment with phenobarbital had a gradually reduced anti-epileptic effect and on day 40, phenobarbital exhibited no anti-epileptic effect; this was accompanied by both a re-enhancement of P-glycoprotein expression and decreased phenobarbital concentration in the hippocampus. P-glycoprotein function and expression were also increased in age-matched normal rats treated with phenobarbital.

Conclusions and implications:

The overexpression of P-glycoprotein in the brain of subjects with pharmacoresistant epilepsy is due to a combination of drug effects and epileptic seizures.     

Pharmacokinetics of sodium valproate in epileptic patients: Prediction of maintenance dosage by single-dose study

Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination ( phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.     

左乙拉西坦对自发性癫痫大鼠大发作和小发作的作用(英文)

目的　鉴于左乙拉西坦在各种啮齿类动物上的抗癫痫作用不同 ,未见报告其在自发性癫痫大鼠上的作用 ,故研究之。方法　在大脑海马和皮质部位安置电极 ,观察腹腔注射单剂量左乙拉西坦对自发性癫痫大鼠脑电图的影响。结果　给左乙拉西坦(40 ,80和 16 0mg·kg- 1,ip)后 135～ 16 5min ,癫痫小发作的总持续时间分别下降到给药前水平的 (87±15 ) % ,(34± 7) %和 (39± 19) %。大发作的总持续时间下降到 (81± 2 8) % ,(6 5± 11) %和 (5 2± 7) %。大发作的出现频率下降到 (71± 2 9) % ,(5 4± 12 ) %和 (32± 15 ) %。结论　左乙拉西坦具有明显的对抗自发性癫痫大鼠的大发作和小发作的作用     

Comparative kinetics of phenobarbital after administration of the acid and the propylhexedrine salt (barbexaclone)

Summary The kinetics of phenobarbital (PB) was compared after oral administration of equivalent doses of the drug as the acid or the propylhexedrine salt (barbexaclone) to 7 normal volunteers. The absorption and elimination parameters were very similar. It was concluded that propylhexedrine did not affect the serum kinetics of PB given as barbexaclone.     

Influence of phenobarbital treatment on cimetidine kinetics

Summary The pharmacokinetics of orally administered cimetidine was studied in 8 healthy subjects before and after 3 weeks of treatment with phenobarbital 100 mg daily, and in a separate study 4 subjects received cimetidine intravenously before and after the administration of phenobarbital. There was no change in the volume of distribution, but total plasma clearance was increased by a mean of 18%, mainly due to a 37% increase in nonrenal clearance. Renal clearance and half-life were not significantly altered. The area under the plasma concentration-time curve after oral administration was significantly (P0.05) reduced by a mean of 15% after phenobarbital treatment. The amount of cimetidine excreted in urine and its sulphoxide metabolite were significantly (P<0.05) reduced, on average by 34% and 26%, respectively by phenobarbital treatment. The data indicate that an apparent 20% reduction in the absorption of cimetidine was due to induction of gastrointestinal metabolism of cimetidine, with some contribution also from hepatic metabolism. Reduced absorption per se could not be totally excluded. Although the magnitude of the change was small, the finding of an 11% decrease in the time to achieve an effective plasma level of cimetidine after phenobarbital treatment may contribute to the ineffectiveness of cimetidine in certain patients.     

Pharmacokinetics of furosemide in anephric patients and in normal subjects

Summary The pharmacokinetics of furosemide 40 mg i.v. were compared in 7 anephric patients and in 7 normal subjects. The average serum clearance was 66 ml/min in the patients and 219 ml/min in the normal subjects, and the corresponding weight corrected clearances were 1.33 ml/min · kg and 2.96 ml/min · kg. Binding to serum proteins was significantly decreased in the anephric subjects, in whom a significant negative correlation was found between the percentage binding and the volume of distribution V_Dss. In the patients, but not in the normal subjects, there was a significant positive correlation between and serum clearance. Both in normal and anephric individuals 4-chlor-5-sulphamoylanthranilic-acid (CSA) was found, but there was no evidence of special accumulation either of CSA or anthranilic acid in the anephric patients. In the patients the initial increase in serum concentration of sodium and protein followed by a more conspicuous decrease were more pronounced, but none of the changes were statistically significant.     

自发性癫痫大鼠海马Ⅰ型与Ⅲ型钠通道α亚基表达上调

目的通过对照实验探讨自发性癫痫大鼠(SER)与野生型正常大鼠(WTC)海马Ⅰ型和Ⅲ型电压门控性钠通道α亚基mRNA与蛋白的表达情况。方法发现SER癫痫大发作后即刻提取海马组织总RNA,应用逆转录-聚合酶链反应(RT-PCR)表达α1与α3亚基mRNA;应用免疫荧光与免疫组化定位与表达α1亚基蛋白与α3亚基ⅢN蛋白。结果SER海马Ⅰ型与Ⅲ型钠通道α亚基mRNA表达高于WTC(P<0·01);SER海马Ⅰ型钠通道α亚基蛋白表达高于WTC(P<0·01);α3亚基ⅢN型蛋白在SER成鼠有表达,而WTC成鼠无表达。结论SER脑内海马Ⅰ型与Ⅲ型电压门控性钠通道α亚基表达上调,可能是神经元高兴奋性的原因或癫痫发作的继发表现。     

比较RP-HPLC法与荧光偏振免疫法测定苯巴比妥、卡马西平、苯妥英钠在癫痫患者的血药浓度

目的 建立同时测定人血清苯巴比妥、卡马西平、苯妥英钠(抗癫痫药)浓度的RP-HPLC法,并与荧光偏振免疫法测定方法比较.方法 以乙酸乙酯-二氯甲烷(4:1)为提取溶剂、氯硝西泮为内标,固定相为Diamonsil C18柱(250mm×4.6 mm,5 μm),流动相为乙腈-水(35:65),紫外检测波长285 nm,流量1.0 mL·min-1;收集患者服药后稳态谷浓度样本,分别用2种方法测定,考察2种方法的相关性.结果 3种药物均具有良好的线性范围,日内、日间RSD均小于8%;苯妥英钠、苯巴比妥2种方法的测定值无统计学差异(P>0.05);而卡马西平2种测定方法比较有统计学差异(P<0.01),卡马西平RP-HPLC法测定值较低.结论 RP-HPLC法适用于治疗药物浓度监测.     

Effect of food on the bioavailability of triclabendazole in patients with fascioliasis

Aims Preliminary results indicate higher absorption of triclabendazole (TCBZ) administered postprandially. Therefore, the influence of food on the pharmacokinetics of TCBZ and its active sulphoxide (TCBZ-SO) and sulphone (TCBZ-SO2) metabolites was investigated.
Methods Two single doses (10  mg  kg⁻¹ ) of TCBZ were administered to 20 patients with fascioliasis. Ten patients were first given the drug after a high energy breakfast and then, 48  h later, after an overnight fast. The other 10 patients first received the drug in fasting state and then, 48  h later, after breakfast. A low energy breakfast was served 2  h after drug administration for fasting state.
Results Compared with the fasting state, an increased AUC and C _max after food intake (significant, P <0.0001) was shown from the values of TCBZ, TCBZ-SO and TCBZ-SO2. The mean AUC for TCBZ (fasting: 1.55, fed: 5.72  μmol  l⁻¹ h), TCBZ-SO (fasting: 177, fed: 386  μmol  l⁻¹ h) and TCBZ-SO2 (fasting: 13.9, fed: 30.5  μmol  l⁻¹ h) indicated a large availability increase with food and the strong systemic predominance of the active sulphoxide metabolite over the unchanged drug. (All patients were cured at the end of the trial except one who required a second course of two postprandial doses of triclabendazole (10  mg  kg⁻¹ each). Tolerability to the treatment among the patients was good.
Conclusions The administration of triclabendazole with food is recommended for improved systemic availability in patients with fascioliasis or paragonimiasis.     

苯巴比妥对小鼠的敏感性及药物代谢动力学的昼夜差异

苯巴比妥对ICR小白鼠的急性毒性及药效均呈明显的昼夜节律性差异,夜间用药的毒性高于白昼用药,死亡峰值时在21:29,反之,白昼用药催眠作用起效快,维持时间久,血药浓度高,半衰期短,在较低的血药浓度下仍能维持有效的催眠作用,结果表明苯巴比妥的毒性及药效的昼夜节律性差异并非完全取决于其药物动力学的昼夜差异,而可能是主要依赖于动物的敏感性的昼夜差异。     

差示分光光度法测定血清苯巴比妥浓度

目的：改进差分分光光度法测定血清苯巴比妥浓度。方法：以二氯甲烷在酸性条件下二次提取,用苯巴比妥在不同ＰＨ值的介质中吸收度之差值,按差示分光光度法测定血清中苯巴比妥浓度。结果：５－２０μｇ．ｍｌ＾－１与２５－１００μｇ．ｍｌ＾－１的苯巴比妥标准溶液之间稳定性差异显著性。     

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。     

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.     

Kinetics of atrial natriuretic peptide in young and elderly subjects

Summary To study the influence of age on the kinetics of atrial natriuretic peptide (ANP) in man, human (99–126) ANP 2.0 g·min^–1 was infused IV for 60 min in 8 healthy young (18 to 25 y) and 9 healthy elderly (71 to 84 y) subjects.Both baseline ANP values and the levels at the end of infusion were higher in the elderly subjects. The mean residence time of ANP in the two age groups was not significantly different, whereas total body clearance (CL) was markedly diminished in the elderly as compared to the young subjects (mean±SD 3.1±1.0 l·min^–1 and 6.2±4.1 l·min^–1, respectively). The apparent volume of distribution at steady state was lower in the elderly than in the young, but the difference was not significant (mean±SD 44±19 and 103±111, respectively. The decrease in CL largely explained the higher ANP levels found in the elderly subjects. The MRT and the plasma half-life of the terminal phase did not differ between the two groups.In the elderly but not in the young subjects the calculated endogenous creatinine clearance was closely correlated with the CL (r=0.90, P<0.001), thereby emphasizing the importance of the kidney in the metabolic clearance of ANP in the elderly.     

Serum low-density lipoprotein and high-density lipoprotein cholesterol,and liver size in subjects on drugs inducing hepatic microsomal enzymes

Summary Serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentration and the ratio between them, major risk factors of coronary heart disease, and liver size were investigated in 18 subjects who were on enzyme-inducing anti-convulsants, phenytoin alone or in combination with phenobarbital and/or carbamazepine. The subjects with a high liver cytochrome P-450, indicating hepatic microsomal enzyme induction, who showed an increase in liver size, had an elevated high-density lipoprotein concentration and high-density lipoprotein cholesterol/total cholesterol ratio, and a reduced low/high-density lipoprotein cholesterol ratio. The high-density lipoprotein cholesterol concentration and its ratio to total cholesterol were directly and related to the ratio between low and high-density lipoprotein cholesterol were inversely related to the extent of liver enlargement. The serum cholesterol distribution profile associated with an increase in liver size was typical of subjects with a low risk of coronary heart disease. The results suggest that enzyme-inducers, such as phenytoin and phenobarbital, induce structural and functional changes in hepatocellular membranes associated with liver enlargement and cholesterol distribution characteristic of low susceptibility to atherosclerotic vascular disease.     

头孢氨苄分散片人体药动学及相对生物利用度

目的研究健康人体内头孢氨苄分散片药动学及相对生物利用度。方法12名健康志愿受试者自身交叉口服头孢氨苄分散片和头孢氨苄片500mg后,采用高效液相色谱法测定血清中头孢氨苄浓度。结果头孢氨苄分散片和片剂的体内过程均符合一房室模型,AUC分别为(1328.0±303.9)和(1304.4±266.7)μg·ml