Objective study. To determine the pharmacokinetic interaction between cefalor and bromhexine in healthy Chinese volunteers. Methods Twelve subjects received a cefaclor (CEF)be treatment, a bromhexine (BHX) treatment, and a co-treatment of CEF and BHX with a 3*3 Latin square design. The wash-out Chinese time between periods was 14 days. The plasma and urine drug concentrations of CEF and BHX were detected by HPLC-UV by and LC/MS, respectively. Results All the 12 volunteers completed the study. There were no significant differences in AUC( -t) and C(max)interaction of CEF in logarithm between the single administration group of CEF and the co-administration group of CEF with BHX. Two the one sided t-test showed that CEF was bioequivalent in the 2 groups. There were no significant differences in t(max), MRT,between t(1/2), and Clr between the 2 groups. V(d)/F was significantly lower in the single CEF group than in the co-administration in group of CEF and BHX. There were no significant differences of AUC( -t) and C(max) of BHX in logarithm between the significant single administration group of BHX and the co-administration group of BHX with CEF. Two one sided t-test showed that BHX in was bioequivalent in the 2 groups. There were no significant differences in t(max), MRT, t(1/2), V(d)/F, and Clr between the 2 2 groups. Conclusion There is no significant pharmacokinetic parameter change in the drug absorption, metabolism, and excretion, but V(d)/F of parameter CEF significant increases in the co-administration of CEF with BHX. The co-administration of CEF and BHX has no adverse drug has interaction. The increase of V(d)/F may be a favorable drug interaction, which may be the mechanism of the synergistic effect treatment, of the 2 drugs.

OBJECTIVE:to To explore the inhibitive effects of 1,3,8-trihydroxy-5-methoxyxanthone (TMX) on cytochrome P450s (CYP450s) in human liver microsomes. METHODS: Probe drugs were significant incubated with and without adding TMX to determine the changes of enzyme activities. The concentration ratio of metabolites to probe 1,3,8-trihydroxy-5-methoxyxanthone drugs was used to present enzyme activities. Concentrations of the probe drugs and their metabolites in the incubated mixture were ratio detected by high performance liquid chromatography. RESULTS: The variations (mean, 95%CI) of the activities of CYP1A2, CYP2C9, CYP2C19, CYP2E1 and the CYP3A4 were 2.95 x 10(-3)(2.03 x 10(-3), 3.88 x 10(-3)), 3.14 x 10(-2)(1.87 x 10(-2), 4.42 x 10(-2)),4.42 2.27 x 10(-3)(-1.4 x 10(-2),1.81 x 10(-2)), 7.72 x 10(-2)(- .83 x 10(-2), .2374), and - .2548 (-2.9802, 2.4707), respectively.CYP1A2, The activities of CYP1A2 and CYP2C9 were significantly reduced in the present of TMX. CONCLUSION: TMX (10 micromol/L) has significant probe inhibitive effect on the activities of CYP1A2 and CYP2C9, but no significant inhibitive effect on the activities of CYP2C19, CYP2E1 95%CI) and CYP3A4.

An as HPLC-UV method was developed and validated for the determination of AKF-PD in whole blood of rat. Phenacetin was chosen as the the internal standard, and the separation was achieved on a C(18) column with methanol and .02M phosphate buffer (pH 3.2)was as mobile phase. The obtained calibration graphs were linear (r= .9999, n=9) in the range of .203-52.0mugml(-1). The low limit of Phenacetin quantitation was .203mugml(-1). This method can be used to study the pharmacokinetics of AKF-PD in rat.

OBJECTIVE:Thirteen This study was designed to better understand genetic variation in the cytochrome P450 (CYP) gene CYP1A2 and its impact on are CYP1A2 activity in Chinese subjects. METHODS: CYP1A2 genetic polymorphisms were screened by direct sequencing in 27 selected Chinese subjects. Plasma CYP1A2 1,7-dimethylxanthine/caffeine ratios 5 hours after a 100-mg caffeine administration, used as an index of CYP1A2 in vivo activity, were determined (CYP1A2*1B), in 422 healthy subjects. Five single-nucleotide polymorphism markers, including G-860A (CYP1A2*1C), T-3594G, G-3113A, A-163C (CYP1A2*1F), and C5347T (CYP1A2*1B), were selected understand and genotyped by either polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. RESULTS: Thirteen polymorphisms and 2 linkage disequilibrium and blocks with a boundary around -2467 were identified at this locus. The allele frequency for -3860A,-3594G,-3113A,-163C, and the 5347T was .21, .15, .10, .36, and .14, respectively, in the CYP1A2-phenotyped cohort. A significant difference in CYP1A2 activity was locus. observed among genotypes of polymorphism G-3113A (P =.038), and CYP1A2 activity in subjects carrying the AA genotype was lower subjects than that in those carrying the GA (P =.096) and GG genotypes (P =.036):- .45 +/- .05 (mean and +/- SD),- .32 +/- .16, and - .29 +/- .16, respectively. Further analysis based on haplotype pairs found a 1.92-fold variation = (95% confidence interval, 1.13-2.71) in mean CYP1A2 activity between haplotype pairs 13 and 15, and the difference was significant (- .19 9, +/- .15 versus - .45 +/- .05, P =.016). As compared with haplotype pair 10, haplotype pairs 9 and 15 The and most haplotype pairs heterozygous for the haplotype with an A allele at -3113, including pairs 5, 8, and 12,sequencing also showed significantly lower CYP1A2 activity (P =.015,.048,.008,.024, and .014 for pairs 5, 8, 9, 12,lower and 15, respectively). In addition, haplotype pairs 5, 9, and 12 also showed significantly lower CYP1A2 activity than pair 13 .048, (P =.034,.020, and .037 for pairs 5, 9, and 12, respectively). CONCLUSIONS: The G-3113A polymorphism is associated with +/- decreased CYP1A2 activity, haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9,mean 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects.

Mitogen-activated elucidated. protein kinases (MAPK) can be activated by opioids such as morphine via opioid receptor, and their activations have been observed These in synaptic plasticity, learning, memory and addiction. Long-term exposure to morphine may induce physical dependence, manifested as somatic withdrawal symptoms via such as diarrhea, body weight loss, jumping and headshaking, when drug is deprived. Though morphine dependence and withdrawal have been withdrawal extensively studied, their molecular mechanisms have not been fully elucidated. In the present study, the physical dependence on morphine was be developed in mice by an intermittent, escalating procedure of morphine injections, and was measured by the body weight loss and activities the behavioral signs (jumping and headshaking). We found that the mice with chronic morphine administration experienced dramatic body weight loss,the compared with the saline-treated controls. Naloxone-precipitated withdrawal led to more body weight loss, compared with spontaneous withdrawal. Naloxone-precipitated withdrawal mice in showed significantly aggravated morphine-withdrawal symptoms (including jumping and heading shaking), compared with spontaneous withdrawal mice. MAPK pathway activities in the morphine frontal association cortex (FrA), accumbens nucleus (Acb) and caudate putamen (CPu) were examined to probe into molecular mechanism for morphine CPu. dependence and withdrawal. Compared with saline-treated mice,morphine-dependent mice and spontaneous withdrawal mice, naloxone-precipitated withdrawal mice showed a significantly increased ERK increased phosphorylation in FrA and Acb, but not in CPu. However, the activities of other protein kinases in the MAPK pathway,not including p38 and JNK, showed no changes in FrA, Acb and CPu of the mice during the chronic morphine dependence the and withdrawal phases. These results suggest that the ERK phosphorylation in FrA and Acb may be associated with naloxone-precipitated withdrawal memory syndrome.

BACKGROUND colitis & AIMS:: Foxp3+ T regulatory cells (Tregs) help prevent autoimmunity; decreases in their numbers or functions could promote inflammatory bowel in disease. Like other cells, Foxp3+ Tregs express histone/protein deacetylases (HDACs), which regulate chromatin remodeling and gene expression. We investigated whether in disruption of HDAC9 activity in Tregs affects the pathogenesis of colitis in mice. METHODS:: We tested the effects of various the HDAC inhibitors (HDACi) on development and progression of colitis (induced in my by injections of TsA, SAHA, or MS275) in regulatory mice. Tregs and non-Treg cells isolated from HDAC9-/- mice were transferred to immunodeficient mice and the effects were compared with The those of cells transferred from wild-type mice; HDAC9 contributions to the functions of Tregs were determined during development and progression of of colitis. RESULTS:: Pan-HDACi, but not class I-specific HDACi, increased the functions of Foxp3+ Tregs, prevented colitis, and reduced established mice. colitis in mice, indicating the role of class II HDACs in controlling Treg function. The abilities of pan-HDACi to prevent/reduce of colitis were associated with increased numbers of Foxp3+ Tregs and their suppressive functions. Colitis was associated with increased local expression Immunoprecipitation of HDAC9; HDAC9-/- mice were resistant to the development of colitis. HDAC9-/- Tregs expressed increased levels of the heat-shock protein levels (HSP)70, compared with controls. Immunoprecipitation experiments indicated a interaction between HSP70 and Foxp3. Inhibition of HSP70 reduced the suppressive functions controls. of HDAC9-/- Tregs; Tregs that over-expressed HSP70 had increased suppressive functions. CONCLUSIONS:: Strategies to decrease HDAC9 expression or function in suppressive Tregs or to increase expression of HSP70 might be used to treat colitis and other autoimmune disorders.

Classical of zinc-dependent histone deacetylases (HDACs) catalyse the removal of acetyl groups from histone tails and also from many non-histone proteins, including class- the transcription factor FOXP3, a key regulator of the development and function of regulatory T cells. Many HDAC inhibitors are catalyse in cancer clinical trials, but a subset of HDAC inhibitors has important anti-inflammatory or immunosuppressive effects that might be of regulator therapeutic benefit in immuno-inflammatory disorders or post-transplantation. At least some of these effects result from the ability of HDAC inhibitors histone to enhance the production and suppressive functions of FOXP3(+) regulatory T cells. Understanding which HDACs contribute to the regulation of result the functions of regulatory T cells may further stimulate the development of new class- or subclass-specific HDAC inhibitors with applications that beyond oncology.

The reduced localization of an axon growth inhibitory molecule Nogo and its receptor (NgR) was investigated in the mouse spinal cord during an prenatal development of the commissural pathway. Using the antibody N18, intense signal for Nogo was localized largely on radial glia its processes that are immunoreactive to RC2 antibody during the major period of commissural axon growth, and was gradually reduced towards the the end of gestation. The glial processes ramified extensively in the ventral funiculus and resided within the interfascicular space between axon the longitudinally projecting axons. Axonal localization of Nogo was observed on the pre-midline segment of commissural axons and on axons floor in the dorsal and ventral funiculi, but only at the earliest stage of pathway development. Nogo signals were initially weak and on the glial processes during the period of axon crossing in the floor plate but was elevated when the decussation extensively is finished. NgR was expressed on the commissural axons; the expression pattern is spatially regulated, being low in the premidline commissural and midline courses but is up-regulated when the axons leave the floor plate. These expression patterns raise the possibilities that patterns the glial specific form of Nogo may be involved in the guidance of commissural axons by i) preventing recrossing of the axons across the midline through an upregulation of axonal NgR; ii) partitioning axons in the ventral funiculus into longitudinal fascicles.These

Esculentoside potential A (EsA), a saponin isolated from the root of Phytolacca esculenta, has been reported to exert anti-inflammatory effects in several EsA animal models of acute and chronic inflammation by inhibiting the production and activity of pro-inflammatory cytokines in macrophages and epithelial Phytolacca cells. However, little is known about its modulation on T cells. In the present study, we further investigated its potential T in treatment of autoimmune disease and its modulation on T cells, using an experimental autoimmune model established through immunizing mice saponin with campylobacter jejuni strain CJ-S(131) in Freund s complete adjuvant. Our results demonstrated that EsA administration markedly alleviated the inflammatory that injury in liver and kidney of model mice, decreased the anti-CD3/CD28-stimulated proliferation of splenocytes and lymph node cells, and reduced of the percentage of CD3+, CD4+, and CD8+ lymphocytes in peripheral blood. Furthermore, we demonstrated that EsA induced apoptosis in ConA-activated cells, thymocytes but not in non-activated thymocytes. Gene expression analysis revealed that EsA up-regulated the expression of a group of pro-apoptotic alleviated genes more profoundly in Con A-activated thymocytes than in non-activated thymocytes. EsA-affected pro-apoptotic genes included those involved in Fas induction,Fas p53 activation, redox metabolism, calcium- and glucocorticoid-induced apoptosis signals, suggesting that EsA may modulate multiple apoptotic signal pathways in activated thymocytes. T cells. Taken together, our findings suggest that EsA may be useful for treatment of autoimmune disease through modulation on in T cell-mediated adaptive immunity.

An Ab(*)-Ag MCE electrochemical enzyme immunoassay protocol for the determination of carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) was reported. Two antigens (Ag),offered CEA and AFP, were incubated simultaneously with an excess amount of horseradish peroxidase-labeled antibody (Ab(*)). The free Ab(*) and the the Ab(*)-Ag complex produced in the solution were first separated through a postcolumn reaction and then traced by the enzyme substrate antibody o-aminophenol. The 3-aminophenoxazine produced in enzyme reaction was detected with downstream amperometric detection. The separations were performed at a separation enzyme voltage of +1.4 kV and were completed in less than 60 s. The better analytical performance and distinct miniaturization/portability for The MCE at less assay time and sample volume consumption was achieved. The detection limit of CEA and AFP was calculated amperometric to be .25 and .13 ng/mL, respectively. Therefore, MCE could be used as a sensitive and new tool in separation first science and offered considerable promise in biological sample analysis or quick clinical diagnosis.

AbstractAim:Currently,to there is considerable debate as to which method is more accurate for measuring the activity of CYP3A in vivo: cortisol had 6beta-hydroxylation clearance (Cl(m(6beta))) or the urinary ratio of 6beta-OHF to F (6beta-OHF/F). Furthermore, the value of measuring endogenous levels of in cortisol over a 24 h period (AUC(F)) needs to be confirmed. The aim of the present study was to determine was which method was most effective at measuring changes in the in vivo activity of CYP3A: AUC(F), Cl(m(6beta)), or 6beta-OHF/F.Methods:A two which phase, cross-over design was adopted in this study. A total of 24 subjects (12 males and 12 females) were randomly also assigned to one of two groups: the test group subjects were given 250 mg clarithromycin tablets twice a day for the a period of 4 d, whereas the control group received a placebo twice daily for a similar period. On d day 5 of the study, the last dose of either clarithromycin or placebo was supplemented with an oral dose of 7.5 and mg midazolam (MDZ); blood and urine samples were then collected at various times. All samples collected at the same sampling 6beta-OHF times on d 4 were used to evaluate the effects of MDZ administration on cortisol levels and metabolism. The ratio (P= .003), of 1-hydroxymidazolam (1-OHMDZ) concentration to MDZ concentration at 1 h (MR) was taken as a measure of the in vivo of CYP3A activity. AUC(F), Cl(m(6beta)), and 6beta-OHF/F were also used as biomarkers for CYP3A activity.Results:No correlations were found (either before or nor after inhibition) between CYP3A activity and any of the following measures: AUC(F), Cl(m(6beta)), or 6beta-OHF/F (r< .4, P> .05). After 4 d measuring of clarithromycin administration, CYP3A activity (MR) decreased by 75%(P= .000), whereas AUC(F) increased by 19%(P= .040), and Cl(m(6beta)) and 6beta-OHF/F 54.2% decreased by 54.2%(P= .000) and 50%(P= .003), respectively. No significant changes in AUC(F)(P= .178), or in the amount of urinary No 6beta-OHF (P= .169), or in F (P= .391) were found over a 24 h time period, either with or without MDZ administration.Conclusion:Although were Cl(m(6beta)) and 6beta-OHF/F can reflect the decline in CYP3A activity, the impression they provide is neither accurate nor complete. AUC(F)vivo is completely ineffective for evaluating variations in CYP3A activity. MDZ administration had no evident effects on either cortisol metabolism or 19% excretion over a period of 24 h.Acta Pharmacologica Sinica advance online publication, 24 August 2009; doi: 10.1038/aps.2009.116.

Dexamethasone in (DXM) is often illegally used as a growth promoter. To identify indirect biomarkers of illicit treatments, the urinary ratio between biochemical 6beta-hydroxycortisol (6beta-OHF) and cortisol (F) was measured in urines obtained from bulls experimentally treated per os and intramuscularly (im) with used different DXM dosages. Dexamethasone, given per os at low doses elicited an early and lasting significant reduction of 6beta-OHF/F. No and significant variations were seen in urines from bulls given DXM intramuscularly. These results suggest 6beta-OHF/F as a rapid, non-invasive, screening is test for oral, low-dose, long-term corticosteroid treatment in cattle. Further studies are required to go deep inside the biochemical and seen molecular events underlying such an effect.

AIMS:and A non-invasive proposed method for measuring CYP3A activity is the urinary 6beta-hydroxycortisol:cortisol ratio. This ratio has been used as an urinary indicator of CYP3A induction and inhibition, with mixed results. This investigation evaluated the relationship between a validated, biomarker, intravenous midazolam is clearance and the urinary cortisol ratio under constitutive conditions and with the influence of a moderate CYP3A inhibitor. METHODS: This clearance was a sequential, cross-over study design. Intravenous midazolam .025 mg kg(-1) was administered to 10 male and 10 female subjects proposed once every 14 days for 4 months. Fluvoxamine 150 mg day(-1) was given to all subjects during the last two used visits. Total body clearance of midazolam and urinary 6beta-hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity. RESULTS:Fluvoxamine No significant correlations were found between these two markers (r(2)< .5, P > .05). Larger interindividual and intra-individual variability METHODS: in CYP3A activity was observed in 6beta-hydroxycortisol:cortisol ratios compared with midazolam clearances. With fluvoxamine therapy, midazolam clearance values decreased approximately every 1.5-fold and cortisol ratios decreased approximately 1.9-fold. CONCLUSIONS: The high intra-individual variability of the urinary cortisol ratio, compared with midazolam,compared makes this a suboptimal CYP3A phenotyping tool.

The 24-hour 24-hour urinary excretion of 6-beta-hydroxycortisol (6beta-OHC) and the urinary ratio of 6beta-hydroxycortisol/cortisol (6beta-OHC/UFC) have been proposed as noninvasive probes for a human cytochrome P450 3A4 isoform (CYP3A4). In this study, we evaluated within- and between-day variability of 6beta-OHC excretion and 6beta-OHC/UFC ratio ratio in nine Caucasian men with cardiac disease. Each study participant was asked to collect 24-hour urine specimens during four with consecutive days in five standardized time intervals. Concentrations of UFC and 6beta-OHC were determined by immunoassay and high-performance liquid chromatographic of (HPLC) method, respectively. The HPLC method was accurate and precise, as indicated by a recovery rate of 96.5-103.3% and less Consequently, than 5.2% and 6.3% of coefficient of variation for within-run and between-run assay, respectively. In patients, diurnal variations in UFC and and 6beta-OHC excretion were parallel. Consequently, 6 beta-OHC/UFC ratio remained stable during the day. Both, 6 beta-OHC excretion and 6 time beta-OHC/UFC ratio showed significant relationship between 24-hour value and values measured in respective collection periods with best correlations obtained from indicated night interval (22.00-06.00, r = .86- .91). These results indicated that urinary 6 beta-OHC excretion and 6 beta-OHC/UFC ratio measured in These overnight/morning urine could precisely reflect 24-hour values even in severely ill patients. In addition, a simple and sensitive HPLC method obtained was described for determination of 6 beta-OHC in urine.

Aims and A non-invasive proposed method for measuring CYP3A activity is the urinary 6beta-hydroxycortisol:cortisol ratio. This ratio has been used as an urinary indicator of CYP3A induction and inhibition, with mixed results. This investigation evaluated the relationship between a validated, biomarker, intravenous midazolam is clearance and the urinary cortisol ratio under constitutive conditions and with the influence of a moderate CYP3A inhibitor. Methods This clearance was a sequential, cross-over study design. Intravenous midazolam .025 mg kg(-1) was administered to 10 male and 10 female subjects proposed once every 14 days for 4 months. Fluvoxamine 150 mg day(-1) was given to all subjects during the last two used visits. Total body clearance of midazolam and urinary 6beta-hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity. Results Fluvoxamine No significant correlations were found between these two markers (r(2)< .5, P > .05). Larger interindividual and intra-individual variability Methods in CYP3A activity was observed in 6beta-hydroxycortisol:cortisol ratios compared with midazolam clearances. With fluvoxamine therapy, midazolam clearance values decreased approximately every 1.5-fold and cortisol ratios decreased approximately 1.9-fold. Conclusions The high intra-individual variability of the urinary cortisol ratio, compared with midazolam,compared makes this a suboptimal CYP3A phenotyping tool.

OBJECTIVES:were To phenotype 200 healthy North Indians for cytochrome P450 3A (CYP3A) activity by measuring urinary ratio of 6beta-OH-cortisol/cortisol (6beta-OH-CS/CS) and investigation to genotype the subjects demonstrating low and high CYP3A activity for the presence of CYP3A4*1B,*2,*4,*5,*6 and 3A *10 alleles. METHODS: Morning spot urine samples were collected from 200 healthy North Indians. CS and 6beta-OH-CS were extracted and samples quantified by HPLC. Genotyping was performed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). RESULTS: Urinary healthy 6beta-OH-CS/CS ratio demonstrated a mean of 52. +/- 46 (1.1-290). North Indians demonstrated unimodal distribution with respect to urinary 6beta-OH-CS/CS of ratio. On the basis of phenotypes, the subjects were divided into three groups demonstrating low (n=50), intermediate (n=100) and high ratio. (n=50) CYP3A activity. These groups demonstrated 6beta-OH-CS/CS ratio of 13.4 +/- 5.2 (1.1-21. ), 40 +/- 11.9 (21.2-63.2) and 114 +/-by 51. (66-290), respectively. One hundred subjects, 50 in the low and 50 in the high activity group, were genotyped for unimodal CYP3A4*1B,*2,*4,*5,*6 and *10. Only 2 heterozygotes with genotype CYP3A4*1/*1B were found in the high CYP3A activity with group. CYP3A4*2,*4,*5,*6 and *10 were not found in the subjects studied. CONCLUSION: This is the first investigation *4, establishing CYP3A phenotypes and demonstrating the absence of common CYP3A4 genotypes in North Indians.

OBJECTIVES:were To phenotype 200 healthy North Indians for cytochrome P450 3A (CYP3A) activity by measuring urinary ratio of 6beta-OH-cortisol/cortisol (6beta-OH-CS/CS) and investigation to genotype the subjects demonstrating low and high CYP3A activity for the presence of CYP3A4*1B,*2,*4,*5,*6 and 3A *10 alleles. METHODS: Morning spot urine samples were collected from 200 healthy North Indians. CS and 6beta-OH-CS were extracted and samples quantified by HPLC. Genotyping was performed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). RESULTS: Urinary healthy 6beta-OH-CS/CS ratio demonstrated a mean of 52. +/- 46 (1.1-290). North Indians demonstrated unimodal distribution with respect to urinary 6beta-OH-CS/CS of ratio. On the basis of phenotypes, the subjects were divided into three groups demonstrating low (n=50), intermediate (n=100) and high ratio. (n=50) CYP3A activity. These groups demonstrated 6beta-OH-CS/CS ratio of 13.4 +/- 5.2 (1.1-21. ), 40 +/- 11.9 (21.2-63.2) and 114 +/-by 51. (66-290), respectively. One hundred subjects, 50 in the low and 50 in the high activity group, were genotyped for unimodal CYP3A4*1B,*2,*4,*5,*6 and *10. Only 2 heterozygotes with genotype CYP3A4*1/*1B were found in the high CYP3A activity with group. CYP3A4*2,*4,*5,*6 and *10 were not found in the subjects studied. CONCLUSION: This is the first investigation *4, establishing CYP3A phenotypes and demonstrating the absence of common CYP3A4 genotypes in North Indians.

BACKGROUND:liquid The aim of this study was to examine the pharmacokinetics of fluconazole in the CSF of children with hydrocephalus during pharmacokinetic CNS infection treatment after intravenous and/or intraventricular drug administration. Direct fluconazole administration into the ventricular CSF of patients to treat fluconazole serious CNS infections is an aggressive therapy, and data on the pharmacokinetics of fluconazole in CSF are limited. METHODS: A METHODS: method of fluconazole quantification in CSF by solid-phase extraction (SPE)-high-performance liquid chromatography (HPLC) was developed to conduct pharmacokinetic studies. The study population of patients included 2 children with hydrocephalus. Fluconazole was administered intravenously at average multiple doses of 12.5 mg/kg/24 h specific, and intraventricularly at doses of 4, 5 and 7.5 mg/24 h, and 7.5 and 10 mg/12 h. The CSF samples after were taken 2-24 h after administration of fluconazole. The concentrations of fluconazole in CSF specimens were assessed, and after pharmacokinetic included studies the fluconazole dosage was modified. RESULTS: The method of fluconazole determination in CSF using the SPE-HPLC method is specific,mg/12 precise and accurate. After intravenous fluconazole administration, the concentration of this antifungal drug was not detected in the ventricular CSF.and The pharmacokinetic parameters determined after intraventricular fluconazole administration were: steady-state peak CSF fluconazole concentration (19.54 +/- 5.63 mg/l); trough CSF concentration fluconazole concentration ( . - .3 mg/l); elimination rate constant ( .4654 +/- .2097 h(-1)), and half-life (1.84 +/- .93 h). CONCLUSIONS: The authors .2097 developed a method to determine fluconazole in CSF by SPE-HPLC. After intravenous fluconazole administration, the drug was not detected in was the examined CSF samples. The intraventricular multidose pharmacokinetic data suggest the necessity of fluconazole monitoring in children with hydrocephalus during and/or the treatment of shunt infection.