肾移植患者环孢素A血药浓度监测指标峰浓度C2与谷浓度C0的比较

目的探讨肾移植受者服用环孢素A(CsA)后C0和C2血药浓度的监测的临床意义。方法采用荧光偏振免疫方法(FPIA)同时测定肾移植后两个月内接受CsA治疗患者的CsA谷值(C0)和峰值(C2)血药浓度。回顾性分析CsA的血药浓度监测方法在预测肾移植肝毒性和急性排斥的有效性。结果肾移植术后2个月内毒性反应(包括肝毒性和肾毒性)发生率54.1%(33/61);急性排斥发生率21.3%(13/61)。同步测定C0、C2各61次,毒性反应组与不发生毒性反应组的C0、C2平均值差异都有非常的显著性(P<0.01)。急性排斥与无排斥组的C0平均值差异无显著性(P>0.05);C2平均值差异有非常的显著性(P<0.01)。环孢素的C0能预测毒性反应的发生而不能预测急性排斥的发生;C2对毒性反应和急性排斥的发生都能起到预测的作用。结论肾移植术后患者以C2为监测点预防毒性反应、急性排斥反应和调整给药剂量比C0更具有科学性和敏感性。考虑C2的适宜浓度范围在900~1200μg.L-1。     

肾移植术后监测环孢素A血药浓度峰值(C2)的临床意义

目的 探讨肾移植术后早期监测环孢素血药浓度峰值(C2)的临床意义.方法 回顾性分析28例肾移植受者,采用单抗免疫荧光偏振法(TDX)同步监测CsA全血谷浓度(C0)和峰浓度(C2),比较研究C0和C2的监测在预测肾移植术后早期急性排异反应、药物性肝损害以及肾毒性中的价值.结果 8例患者发生急性排异反应,6例发生药物性肝损害,6例发生肾中毒.术后各时间段发生急性排异患者CsA谷浓度C0与未发生的相比无统计学差异(P﹥0.05),而发生急性排斥反应患者CsA峰浓度C2明显低于正常组C2(P<0.05).结论 监测CsA峰值浓度(C2)能有效预测肾移植术后急性排异反应的发生.     

肾移植受者血药浓度监测与最佳浓度选择

目的:寻找环孢素A(CsA)在肾移植受者三联免疫抑制用药方案中的最佳浓度.方法:用特异荧光偏振免疫法测定82例患者全血环孢素A的浓度,比较不同剂量组(各41例)患者肾移植术后CsA浓度高低、急性排斥反应和毒性反应发生率以及移植患者的人/肾生存率.结果:高浓度组在1年内总的急性排斥反应发生率为16.8%,低浓度组为18.2%,两组间差异无显著性(P＞0.05),高低浓度组患者1年内毒性反应发生率分别为32.1%和16.4%(P＜0.01),人/肾生存率分别为85.2%/82.8%和92.1%/90.9%(P＜0.05).结论:实验结果表明,低浓度组并不增加急性排斥反应的发生率,但明显降低毒性反应发生率以及移植患者的人/肾死亡率.     

肾移植术后服用环孢素A2h血药浓度峰值监测及治疗窗浓度探讨

目的探讨肾移植术后国内患者服用环孢素A(CsA)2h血药浓度峰值在不同时期的监测范围。方法用荧光偏振免疫法(FPIA)同时测定92例肾移植受者CsA谷浓度(C0)和服药2h后峰浓度(C2),并观察排斥反应的发生及肝、肾毒性反应。结果肾移植术后CsA C2在不同时期监测范围建议0mo~1mo为1000~1300μg/L,2mo~3mo为950~1250μg/L,4mo~6mo为900~1100μg/L,7mo~12mo为750~1000μg/L,12mo以上为600~800μg/L。结论在上述治疗窗浓度范围,CsA既能达到满意的免疫抑制效果,又能减少排斥反应和肝、肾毒性的发生。     

霉酚酸酯和环孢素A合用预防和治疗肾移植早期急性排斥反应

目的 :考察霉酚酸酯 (MMF)预防移植肾急性排斥反应的疗效及安全性。方法 :对MMF 1.5 g·d-1联合应用环孢素A(CsA)和皮质类固醇与硫唑嘌呤 (Aza)联合应用环孢素A和皮质类固醇预防和治疗急性排斥反应进行随机比较研究。结果 :MMF组的CsA平均给药量、血药浓度与Aza组统计学检验差异有非常显著性 (P <0 .0 1)。急性排斥反应MMF组发生率为12 % (3/ 2 5 ) ,Aza组为 33% (12 / 36 ) ,急排发生时两组CsA浓度差异有显著性 (P <0 .0 1) ,但平均给药差异无显著性 (P >0 .0 5 )。结论 :MMF可有效地减少急性排斥反应的发生。     

肝、肾移植术后受者环孢素A血药浓度监测的评估

目的探讨肝、肾移植受者环孢素A(CsA)理想的血药浓度监测指标。方法采用荧光偏振免疫法,对65例肝移植受者及136例肾移植受者进行CsA谷浓度(C0)及服药后2 h血药浓度(C2)监测,并对数据进行归纳和分析。结果肝移植受者C2/C0均值为3.56,肾移植受者C2/C0均值为4.8,肝、肾移植受者C2/C0均值有极显著差异(P<0.001);肝移植受者男性CsA血药浓度较女性低。结论C0+C2和C2/C0作为CsA血药浓度监测指标,能更全面地反映CsA体内药物暴露情况和监测CsA肝、肾毒性。     

肾移植术后受者环孢素的血药浓度监测

目的 观察环孢素血药浓度与肾移植效果间关系。方法 对97例接受同种异体肾脏移植术受术后8周内206例次环孢素血药浓度监测结果进行回顾性分析，按照受术后的临床表现、生化指标将其分为术后正常组、急性排斥组、急性毒性组，采用荧光偏振免疫测定法，以单克隆抗体试剂测定环孢素血药浓度。结果 术后正常组62例移植肾功能良好，环孢素的给药剂量为5．2±1.9mg/kg·d，171例次环孢素血药浓度的平均值为309．85±131．69μg/L;术后急性排斥组26例，距发生排斥反应最近一次的环孢素血药浓度平均为165．80±123．13μg/L ,环孢素的给药剂量为4．8±1．6mg/kg·d；术后急性毒性组9例，距发生毒性反应最近一次的环孢素血药浓度平均为556．51±102．50μg/L，环孢素的给药剂量为6．2±1．0mg/kg·d。三组之间环孢素的给药剂量无显性差异（P＞0．05），但环孢素血药浓度却相差很大，两两之间有显性差异（正常组与排斥组P＜0．05；正常组与毒性组P＜0．05；排斥组与毒性组（P＜0．01）。结论 环孢素浓度较低时，出现排斥反应的可能性较大；而环孢素浓度较高时，发生毒性反应的机会较多。     

肾移植患者术后牙龈增生与环孢素A浓度的相关性

目的:研究肾移植患者术后牙龈增生与其应用环孢素A(cyclosporine A)的关系.方法:记录肾移植患者术后药物使用情况,监测环孢素A血药浓度和唾液中浓度.结果:应用环孢素A的肾移植患者术后牙龈增生的发生率为28.9%.牙龈增生发生率随着术后年限的增加而增加.患者发生牙龈增生时环孢素A血药浓度与未发生的血药浓度差异无显著性(P＞0.05);而唾液中环孢素A浓度与未发生的血药浓度差异具显著性(P＜0.05).结论:肾移植患者术后牙龈增生与使用环孢素A的时间、唾液中环孢素A高浓度有关.     

雷帕霉素联合环孢素预防肾移植急性排斥反应的随机对照前瞻性研究

目的:评价雷帕霉素(RPM)口服液联合环孢素(CsA)预防肾移植术后早期急性排斥反应的疗效。方法:首次肾移植患者20例,随机分成RPM试验组和硫唑嘌呤(Aza)对照组,每组各10例,分别接受以CsA和类固醇激素为基础的免疫抑制治疗方案6mo,比较2组人/肾存活率、急性排斥反应发生、不良事件发生等指标的差异。结果:17例完成治疗者人/肾均存活;仅Aza组1例发生2次急性排斥反应;2组各发生2例严重不良事件。结论:RPM联合CsA可有效预防移植肾急性排斥反应,并维持肾功能于良好水平,但是也可能增强CsA的肝毒性。     

3例肾移植患者口服大黄制剂后引起环孢素全血谷浓度增高

肾移植术后患者要长期服用免疫抑制剂预防或治疗移植物排斥反应,环孢素(CsA)是器官移植受者普遍应用的免疫抑制药之一.肾移植术后患者服用CsA达稳态后,服药剂量不变的情况下,其CsA的血药浓度应当差别很小,但实际监测中发现患者CsA的血药浓度与预期结果相差较大.     

Plasma concentration of topiramate correlates with cerebrospinal fluid concentration

The authors examined the ratio between the plasma and the cerebrospinal fluid (CSF) concentration of topiramate in 14 adults with epilepsy. Simultaneous trough samples of venous blood and CSF were collected and analyzed as total and unbound concentrations. Concomitant levels were also analyzed of lamotrigine (n = 5) and the relevant oxcarbazepine metabolite, 10-hydroxycarbazepine (n = 3). There was a close correlation between the plasma and the CSF concentration for both the total and unbound concentration of topiramate. The median CSF/plasma ratio of total topiramate was 0.85. The free topiramate concentration in plasma was not different from the free topiramate concentration in CSF. The CSF/plasma ratios showed little variation and were independent of the plasma level for both the total and the unbound levels. The unbound fraction of topiramate was 84% in plasma and 97% in CSF. The CSF concentrations of lamotrigine and 10-hydroxycarbazepine were 50% and 61% of the plasma concentrations, respectively. For topiramate, there is a close correlation between the plasma concentration and the CSF concentration. There does not seem to be a saturable carrier mechanism restricting topiramate transport across the blood-brain barrier. The concentration of topiramate in CSF is equal to the unbound proportion of topiramate in plasma, implying that the delivery of topiramate to the brain occurs via transfer from the unbound plasma pool. Plasma is thus a relevant matrix for therapeutic drug monitoring of topiramate.     

Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration.

This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (C(u,plasma)) to predict brain unbound concentration (C(u,brain)). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The C(u,brain) was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl-]sarcosine, had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, C(CSF) and C(u,plasma) represent C(u,brain) equally well; for efflux substrates or slow brain penetration compounds, C(CSF) appears to be equivalent to or more accurate than C(u,plasma) to represent C(u,brain). Thus, we hypothesize that C(CSF) is equivalent to or better than C(u,plasma) to predict C(u,brain). This hypothesis is supported by the literature data.     

Evaluation of the concentration difference determining the membrane transport in concentration polarization conditions

Using Kedem-Katchalsky thermodynamic formalism, the mathematical model describing concentration difference through a membrane (Ci-Ce) in concentration polarization conditions was elaborated. Concentration polarization is connected with concentration boundary layers (l(l), l(h)) creation on both sides of a polymeric membrane (M). These layers both with membrane are the complex l(1)/M/l(h). Obtaining expression, which is square equation considering volume flux (Jvm), contain the transport parameters of membrane (omega m), concentration boundary layers (omega l, omega h) and solution concentration in initial moment (Ch, Cl). Calculations performed on the basis of obtained square equation show that for a polymeric membrane with fixed transport properties, concentration difference (Ci-Ce) is nonlinear function of solution concentration (Ch-Cl). The nonlinearity is connected with appearance of the convection instability for (Ci-Ce) > 0.015 mol l(-1), breaking symmetry of complex l(h)/M/l(l) in relation to gravitational direction, what is the reason of increase (Ci-Ce) and volume and solute fluxes.     

Determination of free ceftriaxone concentration and its application in predicting lung tissue concentration

The purpose of this study was to establish a method for determining the free concentration of ceftriaxone based on hollow fiber centrifugal ultrafiltration (HFCF-UF) technology in combination with high-performance liquid chromatography (HPLC) for free pharmacokinetic studies and the prediction of ceftriaxone concentrations in lung tissue. This method only required centrifugation for a short time, and the filtrate could be injected directly for HPLC analysis without further treatment. The specificity, linearity, precision and stability of this method were validated for quantification of free ceftriaxone. Under the optimized conditions, the absolute recoveries were more than 92.5%. The intraday and interday precision RSDs were less than 3.6%. Additionally, nonspecific adsorption (NSB) between the analyte and the ultrafiltration membrane was considered. This method was successfully applied to the analysis of the free ceftriaxone concentration in rat plasma and lung tissue. The free ceftriaxone concentration of lung tissue could be predicted by using the linear formula C_fl = C_fp (0.342x – 0.0129) (x: time). This method also provides a reliable alternative for accurate monitoring of the free ceftriaxone concentration in therapeutic drug monitoring (TDM).     

Threshold hypnotic concentration of methohexitone

Summary Methohexitone was administered to 8 healthy adult volunteers as a microprocessor controlled infusion that generated 3 cycles of linearly increasing plasma levels with an anticipated slope of 0.2 µg·ml^–1·min^–1. When a deep unconscious state was obtained, as indicated by burst suppression in the EEG, the infusion was stopped and then restarted when the volunteer was fully orientated. Frequent venous blood samples were obtained during and after the infusions to evaluate the threshold concentration at induced sleep and the return of orientation, at the loss and return of the eye lid reflex and corneal reflex, and the appearance and disappearance of EEG burst suppression patterns.From the first to the third infusion cycle only a slight and insignificant increase in the mean threshold concentrations was observed so the plasma levels were averaged over all three infusion cycles. The concentrations (µg/ml) found were: asleep 3.39 and orientated 3.35, loss 4.42 and recurrence 4.32 of eye lid reflex, loss 6.51 and recurrence 5.18 of corneal reflex, and appearance 10.7 and disappearance 9.3 of burst suppression. Acute tolerance that would have led to a significant increase in threshold concentration from the first to the last infusion cycle was not demonstrated.If induced sleep and the appearance of EEG burst suppression are considered as clinical endpoints of anaesthesia, the therapeutic window of methohexitone covers a mean venous serum concentration range of 3.4 to 10.7 µg/ml.Presented in part at the 1985 Annual Meeting of the American Society of Anesthesiologists, San Francisco, California, USA     

Measurement of lidocaine free concentration

Since lidocaine exhibits significant variation in serum protein binding, the availability of a practical method for measuring free lidocaine concentration could contribute to the optimization of individual lidocaine dosage regimens. Fifty serum samples from patients receiving lidocaine were partitioned by ultrafiltration and equilibrium dialysis. The lidocaine concentration in the ultrafiltrate was measured using an enzyme multiplied immunoassay (EMIT) and a gas-liquid chromatographic assay (GLC). The lidocaine concentrations in dialysates and filtered retentates were measured by EMIT. Ultrafiltrate concentrations measured by EMIT correlated well with those measured by GLC (r2 = 0.77), but the EMIT results were approximately 10-20% higher than the GLC measurements (GLC = 0.09 + 0.79 EMIT). At least a portion of this difference could be attributed to minor calibrator differences. The concentrations in dialysate and filtered retentate agreed well (r2 = 0.93; filtered retentate = -0.05 + 1.12 X dialysate). The fraction free values obtained by ultrafiltration were slightly lower than those obtained by equilibrium dialysis (0.301 +/- 0.086 vs. 0.345 +/- 0.137; p less than 0.05). It can be concluded that sample partitioning with ultrafiltration and measurement of free lidocaine concentration by EMIT yields results similar to those obtained by equilibrium dialysis or a GLC assay procedure.     

不同浓度亚硫酸钠对HL-7702肝细胞活性的影响

目的为了对亚硫酸钠的细胞毒性研究提供实验参考,探讨不同浓度的亚硫酸钠(Na2SO3)对正常人肝细胞HL-7702的影响。方法通过不同浓度的Na2SO3对HL-7702染毒24h后,采用四甲基偶氮唑蓝微量酶比色法(MTT法)测定Na2SO3对肝细胞的活性抑制率。结果随着Na2SO3染毒剂量的增加,对细胞的活性抑制率逐渐增高,其中0.625mmol/L组和2.5mmol/L组与对阴性对照组相比,差异有统计学意义(P<0.05)。结论Na2SO3对肝细胞的活性有一定的抑制作用。