丙戊酸钠联用碳青霉烯类药物血药浓度变化特点探讨

目的：探讨丙戊酸钠联用碳青霉烯类药物后引起丙戊酸钠血药浓度变化特点,为临床合理用药提供参考。方法：采用化学发光免疫分析法检测丙戊酸钠联用碳青霉烯类药物前、期间以及停用碳青霉烯类药物后的血药浓度,总结变化特点,并研究给药剂量调整与血药浓度变化情况。结果：丙戊酸钠联用碳青霉烯类药物后,美罗培南使其血药浓度下降（83.2±7.8）%,亚胺培南使其血药浓度下降（71.7±5.3）%,停用碳青霉烯类药物后,血药浓度逐渐恢复,但增加丙戊酸钠给药剂量对血药浓度变化影响不明显。结论：碳青霉烯类药物可致丙戊酸钠血药浓度显著降低,两者不宜联用,以确保临床用药安全、有效。     

鼻饲给药对血清丙戊酸浓度的影响

目的研究鼻饲给药对血清丙戊酸浓度的影响。方法利用荧光偏振免疫分析法（FPIA）检测住院患者血丙戊酸浓度,研究不同给药方式对血丙戊酸浓度的影响。结果丙戊酸钠鼻饲给药严重影响血液药物浓度,其血药浓度和达到有效血药浓度的比例显著低于口服给药,差异有统计学意义（P＜0.01）;丙戊酸钠鼻饲患者多次测血药浓度,均低于有效血药浓度,改为口服给药后,血药浓度上升。结论鼻饲给予患者等量丙戊酸钠,与口服给药相比,无法达到口服给药同样的效果。     

丙戊酸钠对卡马西平药代动力学的影响

目的：考察丙戊酸钠对卡马西平药代动力学的影响。方法：6名健康志愿分别口服单剂量卡马西平片以及卡马西平和丙戊酸钠片，采用荧光偏振免疫法测定卡马西平血药浓度，经3p97程序处理，计算卡马西平的药代动力学参数以及丙戊酸钠对卡马西平药代动力学参数的影响。结果：合用丙戊酸钠后，卡马西平的Ke,CL/F明显增加，而T1/2Ke,AUC0-1明显减小（P＜0．05）。结论：丙戊酸钠可加速卡马西平的排泄，使卡马西平的半衰期缩短，生物利用度减小。     

临床应用丙戊酸钠治疗小儿癫痫分析

目的:分析和探讨合理应用丙戊酸钠治疗小儿癫痫。方法:根据丙戊酸钠药代学和药动学特点,并结合临床药师参与的丙戊酸钠治疗小儿癫痫的实际案例,对丙戊酸钠治疗小儿癫痫的合理应用进行分析和阐述。结果:根据患儿具体生理、病理情况选择给药剂量,综合分析和避免治疗方案中的药物相互作用,以血药浓度监测结果为依据,及时调整药物及剂量,制定动态、合理的个体化给药方案及用药监护,使丙戊酸钠治疗小儿癫痫的临床应用更加安全、有效。结论:临床应用丙戊酸钠时应考虑各种相关因素,制定个体化给药方案,避免药物间相互作用;开展药学监护,有效促进丙戊酸的合理应用。     

115例癫痫患者丙戊酸钠血药质量浓度的监测与分析

目的分析丙戊酸钠治疗癫痫患者的血药质量浓度检测结果,探讨丙戊酸钠的合理用药。方法采用高效液相色谱法检测丙戊酸钠的血药质量浓度,统计分析丙戊酸钠的血药质量浓度与癫痫控制疗效、药物不良反应和联用药物等因素的影响。结果在115例癫痫患者中,丙戊酸钠血药质量浓度在50~100μg·mL~(-1)范围内有74例(64.35%);低于50μg·mL~(-1)有31例(26.95%);高于100μg·mL~(-1)有10例(8.70%),丙戊酸钠有效治疗血药质量浓度为50~100μg·mL~(-1),在此质量浓度范围内抗癫痫的效果优于不足此质量浓度抗癫痫的效果,但丙戊酸钠血药质量浓度高于此范围,其不良反应亦增加。卡马西平和苯妥英钠可能降低丙戊酸钠的血药质量浓度从而影响疗效。结论丙戊酸钠血药质量浓度个体差异大,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,应常规监测血药质量浓度。     

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。     

基于微透析技术的丙戊酸钠与左乙拉西坦相互作用研究

目的研究丙戊酸钠与左乙拉西坦在大鼠血液及脑组织中的药代动力学相互作用。方法将SD大鼠随机分为2组,即丙戊酸钠单用组、丙戊酸钠-左乙拉西坦联用组。采用微透析技术进行血液和脑部双位点的实时取样,所得样品经衍生化后,采用高效液相色谱法测定,得到丙戊酸钠单用组和丙戊酸钠-左乙拉西坦联用组给药后不同时间点的血液和脑组织中丙戊酸钠药物浓度。数据采用DAS 3.0软件计算药代动力学参数。结果将两组的丙戊酸钠药代动力学数据进行比较,与丙戊酸钠单用组相比,丙戊酸钠-左乙拉西坦联用组在血液透析液和脑部透析液中的药物达峰浓度(C_(max))、达峰时间(t_(max))、药物浓度-时间曲线下面积(AUC_(0～∞))、平均驻留时间(MRT)、半衰期(t_(1/2))、清除率(λ_z)差异均无统计学意义。结论丙戊酸钠与左乙拉西坦合并使用时,尽管个体之间的差异较大,但与丙戊酸钠单用时相比,各药代动力学参数间差异无统计学意义。丙戊酸钠与左乙拉西坦联合使用,安全性高,相互作用小。     

丙戊酸钠在癫痫患者中的群体药动学

目的建立丙戊酸钠在癫痫患者治疗中的群体药动学模型,为临床个体化给药提供参考。方法收集我院门诊60名癫痫患者丙戊酸钠稳态血药浓度监测数据和相应的人口学数据,应用非线性混合效应模型(non linearm ixed-effectmodel,NONMEM)程序对收集的数据进行分析,建立群体药动学模型。结果建立了癫痫患者口服丙戊酸钠群体药代动力学模型:CL/F=0.959×1.04x,(x=0,1),V/F=1.35,ka=2.38 h-1,说明丙戊酸的清除率与患者性别相关,即男性患者的清除率大于女性。结论初步建立癫痫患者口服丙戊酸钠群体药动学模型,为丙戊酸钠个体化用药提供理论基础。     

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。     

应用不同抗癫痫药治疗儿童癫痫与肥胖的关系

目的　了解应用不同抗癫痫药 (AEDs)所导致癫痫患儿肥胖的情况。方法　根据患儿服用的不同AEDs,将 6 6例癫痫病人分为丙戊酸钠治疗组和非丙戊酸钠治疗组两组 ,对其体重 (Wt)及身高 (H)从服用AEDs开始进行为期 6个月的观察 ,观察肥胖指标 (BMI)的变化情况。结果　丙戊酸钠治疗组从治疗后 3个月开始出现肥胖 ,到治疗后 6个月时 ,男、女性的肥胖指标才有统计学的差异 ;丙戊酸钠治疗组的肥胖指标与非丙戊酸钠治疗组的统计学差异 ,也是从治疗后 3个月开始。结论　应用丙戊酸钠后可导致癫痫病人出现肥胖 ,其肥胖发生的时间一般在开始应用此药治疗后 3个月 ,因此 ,临床上应用丙戊酸钠时 ,要注意导致癫痫病人出现肥胖的问题。     

Chronopharmacological study of sodium valproate in mice: dose-concentration-response relationship

Effects of the time-of-day of drug administration on the pharmacokinetics electroshock seizure (ES) threshold and acute toxicity were investigated in mice with sodium valproate (VPA). ICR male mice, housed under a light-dark (12:12) cycle, were orally administered 600 mg/kg VPA for anticonvulsant effect studies and administered 1500 mg/kg VPA for acute toxicity studies. A significant circadian rhythm was demonstrated for the ES threshold at 30 min after VPA administration, with the highest value in the light phase and the lowest in the dark phase, although no rhythm was shown in the nondrugged state. A significant circadian rhythm was also shown for plasma and brain VPA concentrations. This finding nicely corresponded to the circadian rhythm in the ES threshold. The positive relationship between the brain VPA concentration and the ES threshold was not different between the light phase and the dark phase. There was also a significant circadian rhythm in the acute toxicity induced by VPA, with the highest mortality in the light phase and the lowest in the dark phase. The results suggest the importance of time in the circadian stage at which VPA is administered in the experimental studies in mice and the significance of circadian rhythm in VPA kinetics in relation to the rhythm of ES threshold.     

曲马多在小鼠体内的时间药理学

目的　研究曲马多对小鼠的急性毒性、药效学及药代动力学的昼夜节律性。方法　小鼠在08:00 ,12:00 ,16:00,20:00 ,24:00和04:00 ip曲马多后,观察其急性死亡率、对热板和压尾刺激的反应及药代动力学的变化。结果曲马多对小鼠的急性毒性有明显的昼夜节律,且与血药浓度的昼夜节律呈正相关,毒性作用峰值在暗中期;曲马多对小鼠的镇痛作用存在昼夜节律性差异,作用峰值在暗后期;曲马多在小鼠体内的药代动力学有用药时间依赖性。结论　曲马多对小鼠的急性毒性、镇痛作用及药动学均存在昼夜节律性     

小诺霉素在小鼠的时辰毒性及时辰药代动力学

小鼠自实验前２Ｗｋ置于标准的明期和暗期下饲养，自由进食饮水。急性毒性昼夜节律实验剂量为小诺霉素７５０ｍｇ．ｋｇ－１，ｉｐ，于１ｄ中６个不同时间给药；选择９：００和２１：００做昼夜ＬＤ５０实验和昼夜药动学实验（剂量为１００ｍｇ．ｋｇ－１，ｉＰ）。结果：小诺霉素的急性毒性呈昼夜节律性变化，明期毒性大于暗期，９：００死亡率（０．７）最高，１７：００死亡率（０．２５）最低。９：００组和２１：００组ＬＤ５０±Ｌ９５分别为５６２．２±４８．４ｍｇ·ｋｇ－１和６７８．１±５３．８ｍｇ·ｋｇ－１。与２１：００组比较，９：００组在用药后０．５和１ｈ血药浓度较高，ＡＵＣ较大，提示小诺霉素毒性的昼夜节律性变化与其药动学昼夜节律变化有关。     

Chronopharmacokinetics of amitriptyline in rats

The circadian changes in absorption, tissue distribution and elimination of amitriptyline after single intravenous (i.v.) and intragastric (i.g.) administration, as well as the differences in pharmacokinetic profile after multiple i.g. administration (at 10:00 and 22:00 h) during a 12 h dosing interval, were investigated. The circadian changes of pharmacokinetic parameters of amitriptyline such as AUC (serum and tissues), clearance (i.v. and i.g.), volume of distribution, biological half-life and bioavailability were estimated. Acrophases for clearance appeared between 19:00 and 21:00 h; the bioavailability was highest during the dark phase at around 04:00 h. Higher values of AUC in serum were observed at the beginning of the light phase. A circadian rhythm of tissue distribution (AUC, K(D)) of amitriptyline with acrophase in the dark phase was observed for brain (12 h period), lung and liver (24 h), but not for heart or kidney. After single (i.v. and i.g.) amitriptyline administration, concentrations of its major metabolite, nortriptyline, were negligible; however, after ten doses, nortriptyline serum and tissue levels were similar to the concentrations of the parent drug with higher values during the day (light phase).     

Pharmacokinetics of propylene glycol in the rabbit

Propylene glycol (PG) is widely used as a drug solvent in the pharmaceutical industry. However, it has produced central nervous system toxicity during chronic administration. The current study was undertaken to describe the pharmacokinetics of propylene glycol during acute and constant-rate intravenous dosing, using the rabbit as an animal model. In the acute dosing experiment, metabolism of PG was the dominant disposition pathway, characterized by concentration-dependent metabolic clearance. Renal excretion of PG accounted for only 2.4 to 14.2% of the total dose following acute administration due to significant reabsorption in the rabbit kidney. An ascending-convex relationship exists between renal clearance and urine flow. During constant-rate intravenous infusion studies, there was a disproportionate relationship between infusion rate and steady-state concentration, providing further evidence for capacity-limited disposition kinetics. The ascending-convex relationship between renal clearance and urine flow was also apparent in the long-term infusion studies.     

Pharmacokinetics of propylene glycol in the rabbit

Propylene glycol (PG) is widely used as a drug solvent in the pharmaceutical industry. However, it has produced central nervous system toxicity during chronic administration. The current study was undertaken to describe the pharmacokinetics of propylene glycol during acute and constant-rate intravenous dosing, using the rabbit as an animal model. In the acute dosing experiment, metabolism of PG was the dominant disposition pathway, characterized by concentration-dependent metabolic clearance. Renal excretion of PG accounted for only 2.4 to 14.2% of the total dose following acute administration due to significant reabsorption in the rabbit kidney. An ascending-convex relationship exists between renal clearance and urine flow. During constant-rate intravenous infusion studies, there was a disproportionate relationship between infusion rate and steady-state concentration, providing further evidence for capacity-limited disposition kinetics. The ascending-convex relationship between renal clearance and urine flow was also apparent in the long-term infusion studies.     

Pharmacokinetics of valproic acid and metabolites in mouse plasma and brain following constant-rate application of the drug and its unsaturated metabolite with an osmotic delivery system

Human therapeutic valproic acid (VPA) levels could be maintained in the mouse for a period of 1 week by constant rate application via subcutaneously implanted osmotic minipumps. Also, the concentrations of VPA metabolites observed in mouse plasma were similar to those seen in human plasma. The drug application could be prolonged by replacing exhausted pumps with freshly-filled devices. Removal of the implanted pumps and measurement of the decay of the drug levels revealed that the half-life of the main plasma metabolite 2-en(2-propyl-2-pentenoic acid) exceeded that of VPA. This result was confirmed by constant-rate application of this metabolite; the plasma clearance of 2-en (as calculated from the steady-state levels observed) was found to be lower than that of VPA. Brain levels of VPA and 2-en during steady-state were 3–10 per cent of corresponding plasma levels. The blood-brain kinetics of 2-en following administration of VPA were similar to those observed following application of 2-en itself. VPA was cleared faster from the brain than from the plasma, while 2-en was more persistent in the brain than in the plasma. Our results indicate that controlled, constant-rate application of drugs such as VPA, via implantable osmotic minipumps, may be a valuable procedure for a number of pharmacological and toxicological studies, particularly where persistent drug levels must be maintained for extended time periods.     

Circadian variations in the pharmacokinetics, tissue distribution and urinary excretion of nifedipine after a single oral administration to rats

Circadian variations in the pharmacokinetics, tissue distribution and urinary excretion of nifedipine were examined in fasted rats after administering a single oral dose at three different dosing times (08:00 am, 16:00 pm, 00:00 am). The plasma concentrations, the areas under the plasma concentration-time curve from zero to 6 h (AUC(0-6 h)) and the peak plasma concentration (C(max)) were significantly higher in the rats dosed at 08:00 am (immediately inactive), and was lower at 16:00 pm (most inactive) and 00:00 am (most active). The time to reach the C(max) (T(max)) was the shortest in the rats dosed at 08:00 am. It was very interesting to observe the double peak phenomena in the plasma concentration profiles, showing a larger peak followed by a smaller peak. There was a dosing time dependency on the tissue distribution 30 min after administration, showing a similar tendency to the pharmacokinetic behavior. However, there was no distinct dosing time dependency observed at 2 h after administration due to the extensive disposition. The cumulative urine excretion of nifedipine in the rats dosed at 08:00 am was significantly higher (about two-fold) than in those dosed at 16:00 pm and 00:00 am. The pharmacokinetics of nifedipine in the rats was consistent with that observed in human subjects in terms of the day-night clock time but the biological time was the opposite, as marked by the rest-activity cycles. These results may help to explain the circadian time-dependency of nifedipine pharmacokinetics.     

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。     

Chronopharmacological assessment identified GLUT4 as a factor responsible for the circadian variation of the hypoglycemic effect of tolbutamide in rats

The circadian relationship between the pharmacokinetics and pharmacodynamics of tolbutamide in rats was analyzed using a compartment model. The basal concentration of plasma glucose had a circadian rhythm with the acrophase at 15:19 h. After intravenous administration of tolbutamide at 06:00, 14:00, or 18:00 h, the hypoglycemic effect showed a circadian variation, with the greatest effect at 18:00 h and the lowest effect at 06:00 h. The time courses of unbound tolbutamide concentration in plasma after intravenous administration were predicted using the model-estimated total concentration of tolbutamide and the albumin concentration and resulted in profiles that did not vary with the time of administration. Significant low insulin resistance was observed at 18:00 h to i.v. glucose and insulin loads. There was no obvious time dependency in the expression of glucose transporter 4 (GLUT4) in epididymal adipocytes. The hypoglycemic rate estimated from the plasma glucose concentration was described by the conventional pharmacokinetic-pharmacodynamic model with an effect compartment. The time courses of theoretical signals in the effect compartment described the observed circadian changes in the increased expression profile of GLUT4 normalized by the increased plasma insulin (IRI) concentration (ΔGLUT4/ΔIRI) after dosing. Thus, the time dependency in glucose uptake is responsible for the circadian variation of the hypoglycemic effect of tolbutamide.