碳青霉稀类抗菌药物对丙戊酸钠血药浓度的影响

目的:评价碳青烯类抗菌药物对丙戊酸钠血药浓度的影响。方法:采用回顾性分析方法,分析3例患者丙戊酸钠与碳青霉烯类抗菌药物联用治疗前后丙戊酸钠血药浓度的变化。结果:案例-A给予美罗培南与丙戊酸同时使用治疗,第6天后丙戊酸钠的血药浓度为35.6μg/mL;案例-B给予比阿培南与丙戊酸钠联用治疗后,丙戊酸钠的血药浓度从88.9μg/mL下降到13.8μg/mL,下降幅度为84.48%;案例-C给予美罗培南与丙戊酸联用治疗后,丙戊酸钠的血药浓度从78.4μg/mL下降到28.8μg/mL,下降幅度为63.26%。结论:丙戊酸钠与碳青酶烯类抗菌药物联用易使丙戊酸钠的血药浓度明显下降,达不到有效治疗浓度,应避免两者联用。     

比阿培南导致丙戊酸血药浓度异常降低的两例病例分析与文献复习

<正>丙戊酸钠(sodium valproate)是神经外科围手术期预防及治疗术后早期癫痫的首选药物,具有疗效肯定、不良反应少、剂型全的特点,其有效的血药浓度范围为50～100μg·mL~(-1)~[1]。比阿培南(biapenem)是新型1β-甲基碳青霉烯类抗生素,对革兰阴性菌(G~-)及革兰阳性菌(G~+)均具有广谱且优异的抗菌效果,并且对超广谱β-内酰胺酶     

结合病例与文献分析儿童中碳青霉烯类抗菌药物对丙戊酸钠血药浓度的影响

目的：探讨碳青霉烯类抗菌药物与丙戊酸钠的相互作用特点。方法：从1例癫痫患儿外科手术后应用美罗培南导致丙戊酸钠血药浓度降低的案例出发,查阅CNKI及PubMed等数据库,对已有的儿童患者中碳青霉烯和丙戊酸钠相互作用的文献进行回顾性分析。结果：已有文献报道中,服用丙戊酸钠的患儿使用美罗培南后,丙戊酸钠的血药浓度明显下降。结论：国内外均不推荐碳青霉烯类抗菌药物和丙戊酸钠同时使用,但实际工作中,二者同时使用的情况仍时有发生。儿科临床药师需加强药学监护,提高碳青霉烯类抗菌药物与丙戊酸钠具有相互作用的临床认知,制定应对措施,促进合理用药     

碳青霉烯类药物对丙戊酸血药浓度影响及两药联用后癫痫发作影响因素—文献Meta分析

目的：探究碳青霉烯类不同药物对丙戊酸血药浓度的影响程度及两药联用后癫痫是否发作的影响因素。方法：对PubMed、Embase、Cochrane Library、CNKI、万方、维普数据库进行文献检索,对碳青霉烯类药物使用前后丙戊酸血药浓度改变情况进行统计学分析。对患者两药联用后癫痫发作情况进行单因素分析。结果：丙戊酸与碳青霉烯类的6个药物联用,其血药浓度降幅均大于50%。合并用药对丙戊酸血药浓度降幅的影响无统计学差异（P>0.05）,患者既往是否有癫痫史和使用美罗培南患者的年龄和性别与两药联用后癫痫是否发作均无统计学差异（P>0.05）。结论：6个药物均可降低丙戊酸血药浓度,发现两药联用需监测丙戊酸血药浓度并考虑换药。本文研究具有一定局限性,所得结论仍需进一步研究。     

癫痫患者28例口服丙戊酸镁快速丙戊酸化初探

作者试用了一种新的给药法治疗癫痫患者。在常规口服丙戊酸镁的基础上加大首次剂量以使患者血药浓度于首剂之后即达到并稳定在较高的有效水平(丙戊酸化),希望以此迅速控制癫痫复发。本文的主要目的即在于寻找一种适当的首次剂量。当首次剂量约为15—20mg/kg,维持量为首量的三分之一每日口服3次时,血清丙戊酸浓度可于首剂后8小时内达75μg/ml左右。对照组则首剂用维持量,其血药浓度至少在服药32小时內低于此水平。因此,与常规服药法比较,新的给药法确能使血药浓度较早达到丙戊酸化。此外,实验还表明,首剂口服较大剂量丙戊酸镁并未加重药物的不良反应。     

丙戊酸类药物592例监测结果分析

目的：对患者丙戊酸类药物浓度监测结果分析，评价治疗药物浓度监测（TDM）的意义。方法：采用毛细管气相色谱法测定丙戊酸血药浓度，统计分析592例患者TDM结果。结果：我院监测的癫痫患者丙戊酸浓度在治疗范围内的比例为37．2％，完全控制发作的比例为54．8％。结论：丙戊酸类药物口服后个体差异大，应进行血药浓度监测后制定合适的给药方案。     

碳青霉烯类抗生素致丙戊酸血药浓度降低

目的 探讨影响丙戊酸体内代谢的危险因素,促进合理用药水平,降低癫痫复发率。方法 分析2例给予丙戊酸后,血药浓度监测结果均小于1 μg/ml的患者。临床药师查阅文献,从药物相互作用、肝药酶活性及基因多态性等多方面积极分析并查找相关原因。结果 2例患者联合使用碳青霉烯类抗生素与丙戊酸,且同时服用肝药酶诱导剂苯巴比妥或利福霉素钠,促进丙戊酸代谢。基因型检测发现2例患者均携带CYP2C19突变型等位基因,丙戊酸代谢能力为中等或慢代谢。提示药物相互作用和CYP450催化活性增强是丙戊酸血药浓度降低的主要原因。结论 在碳青霉烯类抗生素和丙戊酸合用时,临床医生应密切关注丙戊酸血药浓度和癫痫发作症状。     

肿瘤脑转移患者碳青霉烯与丙戊酸钠相互作用致癫痫发作1例

目的:报告1例乳腺癌脑转移患者中碳青霉烯类药物和丙戊酸钠的相互作用。方法:对1例乳腺癌脑转移患者的患者信息、病史、化疗过程、感染治疗、抗癫痫治疗、相互作用事件分别作回顾性分析。结果:碳青霉烯类药物和丙戊酸钠的相互作用涉及很多机制,可导致丙戊酸钠血药浓度降低,使癫痫发作,应该尽量避免同时使用。如必须同用,应严密监测丙戊酸血药浓度并调整其剂量。结论:临床应用中应避免碳青霉烯类药物与丙戊酸钠的相互作用。     

丙戊酸钠的不良反应分析

丙戊酸钠(sldium valproate, VPA) 是一种广谱抗癫痫药物,近年来国内有不少文献报道其不良反应,现综述如下. 1 过敏反应 女,30岁.因癫痫发作入院治疗,经注射地西泮、苯巴比妥钠等抗癫痫药物控制症状后,改服VPA片2 d后,出现皮疹伴皮肤瘙痒,停药后症状好转,但癫痫复发,继续口服VPA片,再次出现全身瘙痒症状,全身皮肤点片状红斑疹,突出皮肤表面,压之不退色,眼睑及面部明显水肿,立即停药给予对症治疗,皮疹未再复发[1].     

Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients

OBJECTIVE: This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients. METHODS: Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model. RESULTS: The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision. CONCLUSION: The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.     

Pharmacokinetics of valproic acid in volunteers after a single dose study

The pharmacokinetics of valproic acid (VPA) was investigated in six healthy volunteers. This was done by monitoring total and free (unbound) valproic acid levels in the serum, and the amount of one of its metabolites, VPA glucuronide, in the urine as a function of time, after a single dose administration of the parent drug. VPA half-life calculated from the urine data of the metabolite was shorter than the half-life calculated from the blood data. About 15 to 20 per cent of the administered oral dose of VPA was excreted in the urine as VPA glucuronide. The average free fraction of VPA obtained in this study, by using the EMIT technique, ranged from 1.5 to 11.5 per cent with a mean value of 4.9 per cent.     

Disposition of valproic acid in patients with liver disease

Summary The disposition of valproic acid (di-n-propylacetate; VA) has been studied after a single oral dose of a solution of 450 mg in 7 patients with alcoholic cirrhosis and in 4 patients recovering from acute hepatitis. The diagnosis was based on biochemical function tests and histological findings. The pharmacokinetic parameters were compared with those reported for healthy volunteers. VA in therapeutic concentration (80 µg/ml) in plasma was less bound to plasma proteins in patients with alcoholic cirrhosis (70.7±11.3%) and in patients recovering from acute hepatitis (78.1±14.1%) than in controls (88.7±5.2%). The reduced binding affected the blood/plasma concentration ratio and the apparent distribution volume Vd₍₎; the latter was increased from the normal value of 0.14±0.05 l/kg to 0.22±0.09 (p<0.05) in alcoholic cirrhotics, and to 0.20±0.07 (p=0.056) in patients recovering from acute hepatitis. The half-life of elimination T_{1/2 ()} (controls=12.2±3.7 h) was significantly (p<0.05) prolonged in cirrhotics (18.9±5.1 h) and in patients recovering from acute hepatitis (17.0±3.7 h). The plasma of total drug was not impaired, which can best be explained by the lower plasma protein binding, which might have increased the of this drug which shows restricted clearance. In addition, the plasma of free drug was significantly (p<0.02) reduced in alcoholic cirrhotics. During a two day urine collection no measurable amount of unchanged VA was recovered. There was considerable excretion of VA-conjugates, which could be hydrolyzed either by HCl or by -glucuronidase/arylsulphatase (4–23% of the dose). These percentages were in the same range as in normals (26.7±16.1%). The study indicates that elimination of VA is slightly impaired in patients with dysfunction of the liver.Supported by the Robert Bosch Foundation, Stuttgart, Federal Republic of Germany     

Computational study of the competitive binding of valproic acid glucuronide and carbapenem antibiotics to acylpeptide hydrolase

The efficacy of the antiepileptic drug VPA is decreased by co-administered carbapenems (CBPMs). The mechanism of CBPM selective inhibition of acylpeptide hydrolase (APEH) hydrolysis of VPA-glucuronide (VPA-G) to VPA is unclear due to the lack of APEH structural information. Here we performed homology modeling of the three-dimensional structure of APEH and subsequent docking simulations with a modeled structure to understand this mechanism. Docking simulations indicated that four groups of binding structures were involved in the binding of VPA-G, panipenem, and meropenem to APEH, but only one or two binding structures were involved in the binding of meropenem with an open β-lactam ring structure and other antibiotics involving ampicillin. One of the four VPA-G binding structures was close enough to the APEH catalytic triad to facilitate VPA-G hydrolysis. This binding structure was also the most stable binding structure for panipenem, suggesting potential inhibition of VPA-G hydrolysis by panipenem. Fragment molecular orbital calculations of interaction energies of amino acid residues of APEH with VPA-G, panipenem, and meropenem indicated that the binding structure for panipenem closest to the catalytic triad is stabilized upon APEH interaction. These data suggest that APEH binding characteristics with CBPMs may help explain the selective inhibition of APEH by CBPMs.     

Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid

The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4-butanediol divaiproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4-butanediol.     

丙戊酸群体药代动力学研究进展

丙戊酸是广谱抗癫疒间药,临床应用广泛。该药体内代谢个体差异大,治疗窗窄,需要个体化治疗。丙戊酸体内代谢受多种因素影响,大量研究报道了丙戊酸群体药代动力学参数及其在个体化治疗中的应用。本文分别从人口学因素、遗传因素及合并用药等方面,对丙戊酸群体药代动力学研究及应用进行综述,为临床制定合理、安全的给药方案提供参考。     

高效液相色谱-柱前衍生化法测定丙戊酸血浓度

目的　 建立高效液相色谱法测定血清中丙戊酸浓度。 方法 　血清用正己烷提取 ,经α 溴苯乙酮衍生后浓缩进样。 结果 　丙戊酸的线性范围为 1 76～ 176 0 μg/ml,平均回收率大于 97% ,日内及日间RSD小于5 %。 结论 　本法快速、简便、准确 ,可应用于临床丙戊酸血药浓度测定     

衍生化-HPLC法测定人血清中丙戊酸浓度

目的建立HPLC法测定丙戊酸血清浓度。方法以环己基丙酸为内标,血清样品经乙醚提取后,经2,4′-二溴苯乙酮衍生化并用HPLC法进行测定。Shim-pack CLC-C18为色谱柱（150mm×4.6mm,5μm）;流动相：甲醇-乙醇-水（70：8：22）;流速：1.1mL/min;柱温：35℃;紫外检测波长：248nm;结果血清中丙戊酸在5.0～150.5μg/mL浓度范围内呈良好线性关系（r=0.9996）,回收率为98.2%～101.3%,日内与日间RSD≤5.2%。结论本法简便、准确、专属性强,适用于临床常规监测需要。