高压液相色谱法检测脑脊液中吡喹酮浓度

本文用高压液相色谱法检测CSF(脑脊液)中吡喹酮含量,测得脑囊虫病患者CSF中吡喹酮浓度为血浓度的17-22.5％,与正常人相似。慢性脑膜炎患者CSF中吡喹酮浓度仅为血浓度的4.6％,其血脑屏障透过率明显低于囊虫病患者。本文各治疗组CSF中吡喹酮浓度均可达体外杀灭血吸虫和囊虫的最低有效浓度。     

脑脊液5-羟色胺浓度对大鼠中枢性睡眠呼吸暂停的影响

目的探讨脑脊液5-羟色胺(5-HT)浓度对中枢性睡眠呼吸暂停的影响。方法对8只成年雄性SD大鼠进行连续3d的睡眠呼吸监测,第1天为空白(A组),第2天给予新鲜脑脊液(ACSF)(B组),第3天给予5-HT(C组)。记录呼吸暂停指数、睡眠效率、各期睡眠时间,进行重复测量资料的方差分析。结果 (1)C组非快速眼动期呼吸暂停指数较A组和B组明显降低(P<0.05)。(2)C组快速眼动期(REM期)叹息后呼吸暂停指数较A组明显降低(P=0.019)。(3)三组在REM期自发性呼吸暂停指数、睡眠效率、NREM期睡眠时间上差异无统计学意义。(4)C组REM期睡眠时间较A组明显减少(P=0.038)。结论提高脑脊液5-HT浓度可改善SD大鼠NREM期睡眠呼吸暂停及REM期叹气后呼吸暂停,对SD大鼠睡眠效率及NREM期睡眠时间无影响。     

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

AIMS

This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen.

METHODS

The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package.

RESULTS

Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h⁻¹ 70 kg⁻¹. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (V_ss) was 8.1 l 70 kg⁻¹. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations.

CONCLUSIONS

Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants.     

Plasma and cerebrospinal fluid pharmacokinetics of naproxen in children

The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L /70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age.     

Plasma and cerebrospinal fluid concentrations of indomethacin in humans

Summary Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling.According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7±0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF.The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.Supported by a grant from Merck-Sharp and Dohme Chibret France     

高效液相色谱荧光法测定脑脊液中丙泊酚浓度

目的建立高效液相色谱荧光检测法测定脑脊液中丙泊酚(异丙酚)浓度的方法.方法采用Hypersil ODS-C18柱为分析柱;甲醇-水-β-环糊精(68:32:0.01)为流动相,流速为1.0mL/min;激发波长为276nm,发射波长为310nm.结果异丙酚与脑脊液中其它成分分离良好,平均回收率为104.98%,日内、日间RSD均小于15%;脑脊液中异丙酚浓度在10～320ng/mL范围内线性关系良好,r=0.9992.结论该法操作简便、结果可靠,适用于脑脊液中异丙酚浓度的测定.     

Metronidazole concentration of the cerebrospinal fluid from slightly inflamed meninges

The concentrations of metronidazole (Clont i.v.) in the cerebrospinal fluid were measured in 12 patients with viral meningitis or subsiding bacterial meningitis after a single infusion of 500 mg lasting 20 min. 1 h after infusion the CSF-concentrations were between 2,3 micrograms/ml and 7,4 micrograms/ml and 2 h after infusion between 6,5 micrograms/ml and 8,6 micrograms/ml. They attained 45,9% respectively 75,9% of the corresponding serum concentrations. Because the minimal inhibitory concentrations of the most important obligate anaerobic gram-negative bacteria are attained, it appears that metronidazole can be used for the treatment of bacterial meningitis caused by these pathogens.     

Rostral-caudal concentration gradients of histamine metabolites in human cerebrospinal fluid

The metabolites of histamine, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), have a large concentration gradient between cisternal and lumbar CSF in the rhesus monkey. The possibility of a t-MH and/or t-MIAA gradient in man was studied in sequential samples of CSF withdrawn from the lumbar space from a healthy male. The mean levels of t-MH and t-MIAA in the 14-16 ml segment of CSF from 6 male volunteers was also measured. pros-Methylimidazoleacetic acid (p-MIAA), an endogenous isomer of t-MIAA that is not derived from histamine, was also measured. Levels of t-MH, t-MIAA and p-MIAA were measured by gas chromatography-mass spectrometry. With increasing volumes of CSF removed, t-MH and t-MIAA levels increased linearly (p less than 0.01) when plotted against the midpoints of each volume segment. Levels of t-MH and t-MIAA from the volunteers showed little variation; the means of the levels were within 15% of the respective regression lines of the points from the single subject. In contrast, p-MIAA levels showed no gradient (p greater than 0.6) in serially removed CSF; the individual levels in CSF from the volunteers on unrestricted diets varied widely, suggestive of a dietary influence on p-MIAA levels in the CNS. The concentration gradient of histamine metabolites in CSF confirms the rostral-caudal gradient observed in monkey and argues against plasma or spinal cord as major sources of these metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma and cerebrospinal fluid concentrations of temazepam following oral drug administration

Summary Thirteen male patients were administered 20 mg of temazepam orally 1 to 2 h prior to undergoing spinal anaesthesia for a urological procedure. Samples of blood and CSF were drawn just before insertion of the spinal and the concentration of drug estimated in these two media.The results obtained indicated that a highly significant correlation existed between the unbound concentration of temazepam in plasma and the concentration of drug present in CSF. Temazepam appeared to be an effective light pre-medicant in all of the subjects studied.     

Drug‐resistant epilepsy and topiramate: Plasma concentration and frequency of epileptic seizures

Topiramate (TPM) is a second‐generation antiepileptic drug (AED), acting on drug‐resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (C_p), and frequency of epileptic seizures. A cross‐sectional analytical study was developed with patients aged 18‐60 years, for diagnosis of drug‐resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty‐seven patients were included, 83.8% of the patients presented C_p below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 μg/mL in TPMC_p, while the use of inducers predicted a reduction of 2.97 μg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 μg/mL in TPMC_p decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with C_p below the therapeutic range, the mean number of seizures per month was greater than those with C_p within the therapeutic range. The prescribed dose and the use of AED inducers influence C_p of TPM, likewise the low C_p of first‐line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures.     

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.     

阿米替林对SNI大鼠脑脊液中EAAs-IAAs浓度的影响

目的观察阿米替林(Amitriptyline,AMI)对分支选择结扎模型(spared nerve injury,SNI)大鼠脑脊液(Cerebrospi-nal Fluid,CSF)中EAAs-IAAs的影响。方法 30只♂SD大鼠,随机分为对照组(A组)、SNI模型组(B组)、SNI+AMI组(C组),A组和B组经腹腔注射分别给予0.2ml生理盐水、C组腹腔注射给予10mg·kg-1阿米替林,每日2次。在动物模型制做前0d及后1、3、5d测量各组大鼠机械痛阈并在体测量CSF中谷氨酸(Glu)、天冬氨酸(Asp)、γ-氨基丁酸(GABA)、甘氨酸(Gly)。结果与A组相比,B组大鼠机械痛阈值随时间下降明显(P<0.01),Glu、Asp的表达随时间推移逐渐增加(P<0.01),GABA、Gly的表达在术后1d升高(P<0.01和P<0.05),在术后3d下降(P<0.01和P<0.05)、术后5d下降(P<0.01);C组大鼠较B组机械痛阈值提高(P<0.01),Glu、Asp的表达在术后3、5d下降(P<0.01),GABA、Gly的表达在术后5d升高(P<0.01)。结论 AMI可能通过纠正脊髓水平EAAs-IAAs失衡,减轻外周损害,治疗神经病理性疼痛。     

Plasma and cerebrospinal fluid concentrations of indomethacin in children after intravenous administration

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4-144 months) received indomethacin (0.35 mg/kg) as a 10-minute intravenous infusion prior to surgery under spinal anaesthesia. A single CSF and plasma sample from each individual was collected 14 to 225 minutes after the infusion. Indomethacin concentrations were determined from the CSF, plasma, and protein-free plasma. Total plasma, protein-free plasma, and CSF concentrations of indomethacin ranged between 90 and 2200 ng/mL (median, 780 ng/mL), 0.3 and 0.8 ng/mL (median, 0.5 ng/mL), and 0.2 and 5.0 ng/mL (median, 1.4 ng/mL), respectively. The CSF to plasma concentration ratio remained less than 0.01. There was no correlation between the administration time and CSF concentrations. Eleven children developed 12 nonserious adverse effects, from which 5 were central nervous system (CNS) effects (agitation). In conclusion, indomethacin permeated into the CSF of children, which enables both desired and adverse CNS effects of indomethacin.     

Methotrexate concentration in cerebrospinal fluid of the space created by tumor removal

This paper investigates the post-surgical pharmacokinetics of methotrexate (MTX) in the plasma, the cerebrospinal fluids (CSF), and the spaces created by tumor removal (STR) in patients with glioblastoma, during hyperosmotic disruption of the blood brain barrier (HODBBB) and intra-arterial chemotherapy with MTX. Eight Japanese patients with glioblastoma, three with open STRs and five with closed STRs, received a total of thirteen courses of HODBBB and intra-arterial combination chemotherapy with MTX. The patients were initially administered mannitol, then the anticancer drugs were infused into the carotid artery. Samples of blood and CSF from the STRs were obtained. MTX concentrations were measured by fluorescence polarization immunoassay and the pharmacokinetic parameters of MTX in plasma and CSF were estimated. The plasma concentrations of MTX peaked at the end of drug infusion, and then decayed bi-exponentially during the remainder of the treatment period. The CSF concentration of MTX in the STR peaked 2 h after drug administration, then mono-exponentially decreased. The area under the concentration-time curve (AUC) for plasma and CSF MTX concentrations increased in parallel with the MTX dose. In patients with open STRs, the mean AUC of MTX in CSF was 4.44% of that found in plasma, while in patients with closed STRs, the mean was 61.2% of that found in plasma. In the latter group, the MTX administered using HODBBB and intra-arterial chemotherapy was maintained in the STRs for long periods.     

Estimation of steady state antibiotic concentration in cerebrospinal fluid from single-dose kinetics

Objective: Assuming linear kinetics, the mean CSF concentrations of an antibacterial in steady state (C_ssCSF) can be estimated, when the area under the concentration-time curve in CSF after the first dose is known. For this purpose we propose the function C_ssCSF=AUC_CSF·Anticipated dose/Dosing Interval·Applied dose. Results: Together with the MIC and MBC of the causative pathogen, the estimate is of value in the choice of antibacterial drug and the dosing regimen in central nervous system infections.     

Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio.

The ratio of drug levels in cerebrospinal fluid (CSF) to plasma (CSF/plasma) at equilibrium has been viewed as in vivo free fraction (fp) in plasma [CSF/plasma = fp], if no active transport is involved in brain penetration. We determined the CSF/plasma level following oral administration in rats and in vitro rat plasma protein binding for 20 compounds that were synthesized in our institute and have similar physicochemical properties. However, results indicated that the CSF/plasma was not only poorly correlated with fp but remarkably lower than fp in most of the compounds tested, suggesting that certain transporters such as P-glycoprotein (P-gp) located in blood-brain barrier (BBB) may decrease the unbound drug concentration in the brain. We evaluated P-gp-mediated transport activity of the 20 compounds with P-gp (mdr1a)-transfected LLC-PK1 cells and calculated P-gp efflux index (PEI), indicating the extent of P-gp-mediated transport. A plot of the CSF/plasma versus fp/PEI showed a strong correlation (r = 0.93), and the absolute values were almost identical [CSF/plasma = fp/PEI]. These results suggest that P-gp quantitatively shifts the equilibrium of unbound drugs across the BBB. Although we cannot rule out the possibility that endogenous transporters other than P-gp on BBB and/or blood-CSF barrier may affect CSF levels of compounds, the present study indicated that fp and PEI measurements may be useful in predicting in vivo CSF/plasma fractions for central nervous system-targeting drugs.     

Liquid chromatography tandem mass spectrometry assay for topiramate analysis in plasma and cerebrospinal fluid: validation and comparison with fluorescence-polarization immunoassay

SUMMARY: The authors report the development and validation of a liquid chromatography tandem mass spectrometry assay (LC/MS/MS assay) for the analysis of topiramate (2,3:4,5-bis-o-(-1-methyl)-beta-D-fructopyranose sulfamate) in plasma and cerebrospinal fluid (CSF). Comparison is made with the commercially available fluorescence-polarization immunoassay (FPIA). LC/MS/MS ASSAY: Using the internal standard, 1,2:3,4-bis-o-(1-methylethylidene-alpha-D-galactopyranose sulfamate), a structural isomer, the calibration curve in plasma was linear in the concentration range of 0.02-20.0 mg/L (r(2) = 0.9998). The coefficients of variation in plasma were < or = 3%, and the accuracy ranged from 100% to 101% in the therapeutically relevant concentration range of 0.4-16.0 mg/L. In CSF, the mean recovery was 98%, and there was linearity between the nominal and the estimated concentration in the range of 1.5-20.0 mg/L (r(2)= 0.9996). FPIA: The calibration curve was linear in the concentration interval of 1.6-24.3 mg/L (r(2) = 0.9994), and the mean recovery was 96%. Accuracy in plasma was 99- 104%, and precision was 3.2-6.0%. In CSF, there was linearity between the nominal concentration and the estimated concentration in the range of 1.5-20.0 mg/L (r(2) = 0.9995), and the mean recovery was 100%. COMPARISON BETWEEN FPIA AND LC/MS/MS: There was a high correlation between the FPIA and the LC/MS/MS assay (r(2) = 0.9965 in plasma and r(2) = 0.9996 in CSF, P < 0.001 for both). In plasma and CSF, the two methods showed equal results, evaluated as the ratio between the two methods (plasma: median ratio = 1.00; 95% confidence interval [CI], 0.98-1.02, paired-sample test, P = 0.79; and CSF: median ratio = 1.00, 95% CI, 0.99-1.02, paired-sample test, P = 0.75). The coefficient of variation on the ratios between the two methods had similar levels: 5% in plasma and 3% in CSF. CONCLUSION: The new LC/MS/MS assay has favorable characteristics, being highly precise and accurate. FPIA also proved precise and accurate, and there was a high agreement with the LC/MS/MS assay in plasma and CSF. Either method displayed sufficient precision and accuracy and may thus be implemented in daily routine.     

高效液相色谱法测定人脑脊液中利奈唑胺浓度

目的:建立高效液相色谱法快速测定人脑脊液中利奈唑胺浓度并对危重患者进行药物浓度监测。方法:采用外标法,色谱柱:ZORBAX Edipse XDB-C18(4.6 mm×150 mm,5μm);流动相:乙腈-水(23∶77);流速:1.0mL·min-1;柱温:30℃;紫外检测波长:254 nm,并利用建立的方法对危重患者进行利奈唑胺脑脊液浓度的监测。结果:利奈唑胺在0.31～40 mg.L-1范围内线性关系良好(r=0.999 9),最低定量限为0.31 mg.L-1,平均绝对回收率为46.8%,平均相对回收率为96.99%,高、中、低3个浓度日内、日间精密度的RSD均小于<5%。另外,所监测的危重患者中,利奈唑胺不同时期在脑脊液中的浓度变化很大。结论:所建立的高效液相色谱法简单、快捷、灵敏、准确,可用于监测利奈唑胺在脑脊液中的浓度。     

神经外科手术对头孢吡肟脑脊液浓度的影响

目的 探讨神经外科手术对头孢吡肟脑脊液浓度的影响。方法 神经外 科术后病人,30min输入头孢吡肟2g后,经术野和脑室引流与腰穿留置导管, 引流取脑脊液,同时静脉取血,用HPLC法测定药物浓度。结果 病人脑脊液中 药物浓度脑室引流组高于腰穿引流组,峰浓度分别是(22．54±14．06)μg· mL-1和(5．61±3．73)μg·mL-1,达峰时间为1-2 h和4 h左右,达到常见细 菌的MIC90。脑脊液与血浆药物浓度比值分别为30％-214％和3％-105％, 高于儿童脑膜炎时的穿透率9％-67％。结论 神经外科手术破坏血-脑脊液 屏障,使头孢吡肟脑脊液透过度增加,可达治疗浓度。