摘要:

SummaryThe effects of smoking, CYP2D6 genotype, and concomitant use of enzyme inducers or inhibitors on the steady state plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were evaluated in 92 schizophrenic inpatients. All but three of these patients received concomitant medication, in many cases with drugs potentially interacting with HAL. Of the 92 patients, 63 were treated orally with HAL in a daily dose of 0.4 to 50 mg; 29 patients were treated intramuscularly with a daily equivalent dose of HAL decanoate (expressed as HAL) of 1.8 to 17.9 mg. A wide interindividual variation in HAL dose and in steady state plasma concentrations of HAL and RHAL was observed. In the patients treated orally, the daily oral dose was about 4 times higher and the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers (n = 40) than in nonsmokers (n = 23) (p < 0.01). The dose-normalized RHAL (but not HAL) plasma concentrations and the RHAL/HAL ratio were significantly higher in poor metabolizers (PMs) than in extensive metabolizers (EMs). There was a trend toward an effect of potentially interacting drugs (inducers or inhibitors) on dose, dose-normalized HAL and RHAL plasma concentrations, and the RHAL/HAL ratio. In the patients treated intramuscularly, the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers than in nonsmokers, but no differences in doses were observed. This naturalistic study of modest sample size in a polymedicated population shows an effect of smoking and CYP2D6 genotype (and to a lesser extent, of interacting drugs) on the kinetics of HAL.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryMycophenolate mofetil, an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy in pediatric renal transplant recipients. However, little is known about the pharmacokinetics of MPA in this patient population in the stable transplant phase, and dosage guidelines are preliminary. The authors therefore compared the pharmacokinetics of MPA, free MPA, and the renal metabolite MPA glucuronide (MPAG) in the initial (sampling at 1 and 3 weeks) and stable phases (sampling at 3 and 6 months) posttransplant in 17 children (age, 12.0 ± 0.77 years; range, 5.9 to 15.8 years), receiving the currently recommended dose of 600 mg MMF/m2body surface area (BSA) twice a day. Plasma concentrations of MPA and MPAG were measured by reverse phase HPLC. Because MPA is extensively bound to serum albumin and only the free drug is presumed to be pharmacologically active, the authors also analyzed the MPA free fraction by HPLC after separation by ultrafiltration. The intraindividual variability of the area under the concentration–time curves (AUC0–12) of MPA throughout the 12-hour dosing interval was high in the immediate posttransplant period, but declined in the stable phase, whereas the interindividual variability remained unchanged. The median MPA–AUC0–12values increased 2-fold from 32.4 (range, 13.9 to 57.0) mg × h/L at 3 weeks to 65.1 (range, 32.6 to 114) mg × h/L at 3 months after transplantation, whereas the median AUC0–12values of free MPA did not significantly change over time. This discrepancy can be attributed to a 35% decline of the MPA free fraction from 1.4% in the initial phase posttransplant to 0.9% (p < 0.01) in the stable phase. In conclusion, pediatric renal transplant recipients given a fixed MMF dose exhibit a 2-fold increase of the AUC0–12of total MPA in the stable phase posttransplant and a 35% decrease of the MPA free fraction, whereas the AUC0–12of free MPA remains unchanged over time. Because the latter pharmacokinetic variable is theoretically best predictive of the clinical immunosuppressive efficacy of MMF, these findings may have consequences for the dosing recommendations of MMF in renal transplant recipients.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryMidazolam (MDZ) is metabolized by CYP3A. Glucocorticoids are potent inducers of CYP3A in humans. The possible interaction between intravenous MDZ and chronically administered glucocorticoids was investigated during surgery in patients. MDZ (0.2 mg/kg) was administered intravenously to 8 patients taking glucocorticoid chronically and 10 patients not taking glucocorticoid. In patients taking glucocorticoid, the AUC0-∞and CL of MDZ was decreased to 63.9% (16.3 ± 10.5 vs 25.5 ± 20.7 &mgr;g × min/mL) and increased to 127.5% (16.7 ± 10.7 vs 13.1 ± 8.3 mL/min/kg) of that in the control group, respectively. The terminal t½values of MDZ were similar in two groups. In patients taking glucocorticoid, the AUC0-∞of 1´-hydroxymidazolam (1´-OH MDZ) was 66.7% of that in the control group (7.6 ± 2.6 vs 11.4 ± 9.7 &mgr;g × min/mL), and the terminal t½of 1´-OH MDZ was significantly (p< 0.01) decreased (1.8 ± 0.5 vs 3.0 ± 0.8 hr). Accumulative urinary excretion of 1´-OH MDZ glucuronide was increased to 157.6%. These observations might be results from induction of CYP3A4 and/or UDP-glucuronosyltransferase by glucocorticoids.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryPopulation pharmacokinetic parameters of gentamicin in preterm neonates on a once-daily dosage regimen of 3.0 mg/kg given intravenously every 24 hours were established prospectively. In 34 preterm neonates with a mean gestational age of 32 ± 4 (SD), 182 serum gentamicin levels (91 peak/trough pairs) were determined. Individual adjustments of dose or dosage interval were calculated by computer-aided Bayesian forecasting. The parametersVd, ke, and CL for each patient were obtained by the nonparametric estimation of maximization method. The predictive power of the model was calculated and the pharmacokinetic estimates were statistically analyzed with SPSS/PC. Cluster analysis showed a division into 2 subpopulations (designated 1 and 2) on the basis of postnatal age. The mean ± SD postnatal age of subpopulation 1 (n = 29) was 6 ± 2 days (range 1–7) and of subpopulation 2 (n = 5) 15 ± 4 days (range 12–24). The mean ± SD gentamicin relative clearances of subpopulation 1 and subpopulation 2 were 0.0515 ± 0.0128 and 0.1026 ± 0.0102 L kg−1hr−1, respectively (p < 0.05). The mean ± SD values forVd(Lkg−1) in both populations 1 and 2 were 0.6916 ± 0.1670 and 0.7509 ± 0.1961, respectively (not significantly different). For kethese data were 0.0744 ± 0.0200 and 0.1366 ± 0.0522 (p < 0.05). Statistics showed that the data forVdand keof subpopulation 1 were normally distributed (Vdand keskewness 1.61 and 1.46; kurtosis 3.09 and 3.10 respectively). The model yielded a bias of −0.11 mg/L and a precision of 0.36 mg/L. It is recommended that gentamicin be started in a dosage of 3.5 mg/kg intravenously once-daily under close monitoring.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryThe use of intravenous acyclovir can be particularly complicated in pediatric patients with evolving renal impairment, because of intraindividual pharmacokinetic variability linked to the patient's clinical condition. The objective of this study was to use therapeutic drug monitoring data to assess acyclovir intraindividual pharmacokinetic variability during several types of renal replacement therapy. Bayesian adaptive control of acyclovir dosage regimen was performed in a pediatric patient with bone marrow transplant who developed severe renal impairment. Acyclovir pharmacokinetic parameter values corresponding to the different techniques and periods of renal replacement therapy were estimated using USCPACK PC Clinical Programs and therapeutic drug monitoring data. Results showed a wide intraindividual pharmacokinetic variability during CAVH, CAVHDF, and CVVHD, reflecting not only the performance of each dialysis technique but also the difficulty in making use of each one. The acyclovir elimination rate constant was higher during CVVHD compared to CAVH or CAVHDF. Bayesian method appears to be valuable in assessing intraindividual pharmacokinetic variability, as it allows the clinician to deal with sparse routine patient data.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryThe objectives of this multiple-dose study were to compare the performance of a new formulation of omeprazole (40 mg) with that of an established formulation and to assess the accuracy of CYP2C19 phenotyping during high-dose chronic administration. Twenty-eight healthy subjects were randomized (1:1) to receive 40 mg of either Gasec-40 Gastrocaps (Mepha) or Antra 40 (Astra) daily for 5 days. The pharmacokinetics of omeprazole and the omeprazole/5´-hydroxyomeprazole ratio 3 hours postdose were assessed on day 5. Subjects switched formulations starting on day 6, and all measurements were repeated on day 8. Subjects with metabolic ratios greater than 6 were genotyped for CYP2C19. Gasec-40 was found to be bioequivalent to Antra based on the 90% confidence interval for AUC (102.4–111.7) and Cmax(100.6 – 120.7). Formulation had no effect on the ratio of omeprazole to 5´-hydroxyomeprazole, which was higher than previously reported with single 20 mg doses of omeprazole. The mean ratio did not differ between day 5 and day 8 but was highly variable: 7 of 28 subjects had more than a 2-fold difference between assessments. In four individuals identified by genotype as extensive metabolizers (EMs), phenotype could not be clearly assigned. The relative bioavailability of omeprazole can be accurately assessed using this multiple-dose study design. Chronic administration of 40 mg doses of omeprazole shifts the metabolic ratio in EMs toward that in poor metabolizers (PMs), apparently because of the nonlinear metabolic clearance of the drug. The assignment of phenotype in patients receiving chronic high-dose omeprazole treatment should be interpreted with caution.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryPharmacokinetics of intravenous and oral pulsed high-dose dexamethasone were studied in four patients with pemphigus vulgaris. Doses for dexamethasone were varied from 100 to 300 mg. Serum concentrations were measured by high-performance liquid chromatographic procedure with diode assay detection. Bioavailability was assessed by comparing the areas under the serum concentration–time curves following oral administration with those of intravenous administration. Mean bioavailability of high-dose oral dexamethasone was 63.4%. Side effects were minor and were limited to temporary facial flushing both after oral and intravenous administration. Oral administration of dexamethasone in pemphigus patients showed to be more convenient and cost effective than administration by the intravenous route.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryThe possible pharmacokinetic interaction between the new immunosuppressive mycophenolate mofetil (MMF) and tacrolimus (TAC), respectively, was assessed by comparing routinely estimated mycophenolic acid (MPA) plasma trough levels of 15 consecutive renal transplant patients receiving MMF in combination with methylprednisolone (MEP) and cyclosporin A (CSA, 10 patients) or in combination with MEP and tacrolimus (TAC, 5 patients). Coadministration of TAC instead of CSA resulted in a significant increase of mean MPA plasma trough levels [3.4 ± 1.3 &mgr;g/mL (n = 22) versus 1.87 ± 1.1 &mgr;g/mL (n = 57);p< 0.001], despite lower MMF doses [1.5 ± 0.5 g/d versus 1.7 ± 0.3 g/d (not statistically significant)]. This elevation in MPA levels is possibly caused by an interaction between MMF and TAC and could lead to a recommendation to monitor MPA plasma levels with appropriate dose adjustment.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryAmikacin and tobramycin are aminoglycosides used to treat severe Gram-negative infections. Therapeutic monitoring of both drugs is essential to avoid drug toxicity. Fluorescence polarization immunoassay kits for both amikacin and tobramycin are available from Abbott Laboratories, and assays can be run using the TDx analyzer. The test code for amikacin is 3, whereas the test code for tobramycin is 2. Here the authors report that when the operator mistakenly programmed test code 3 (amikacin code) while using the tobramycin kit, the tobramycin values were falsely elevated. The instrument software does not have any mechanism to detect this error. Similarly, when the amikacin kit was used and the operator mistakenly programmed test code 2 (tobramycin code), the amikacin values were falsely lowered. For example, in a serum sample taken from a patient the true amikacin concentration was 20.9 &mgr;g/mL. When the amikacin kit was used correctly but test code 2 was programmed, the observed concentration was falsely lowered to 6.1 &mgr;g/mL. Similarly, in another specimen the true tobramycin concentration was 3.1 &mgr;g/mL. However, when the tobramycin kit was used correctly but test code 3 was used, the observed concentration was falsely elevated to 14.3 &mgr;g/mL. The authors also observed a similar effect with controls and spiked specimens containing either amikacin or tobramycin. They conclude that correct programming of the test code is vital to obtaining useful results in amikacin and tobramycin analysis using the TDx analyzer.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryThis study was designed to measure acetaminophen (paracetamol) levels in tears, and to compare it to serum levels. Paracetamol levels were measured in 20 paired tears and serum samples from 10 healthy volunteers, 1 and 2 hours after ingesting 1.5 g paracetamol. Tears were collected using glass microcapillary tubes while stimulating the conjunctiva with a small sponge placed in the lower fornix. Blood samples were taken simultaneously. The samples were analyzed for paracetamol levels using homogeneous enzyme immunoassay. Tears and serum paracetamol levels 1 hour after ingestion were 16.3 &mgr;g/mL ± 7.2 (mean ± SD), and 21.4 &mgr;g/mL ± 7.7 (mean ± SD) respectively. Tears and serum levels 2 hours after ingestion were 14.4 &mgr;g/mL ± 7.8 (mean ± SD), and 17 &mgr;g/mL ± 7.6 (mean ± SD) respectively. Tears and serum paracetamol levels of all the 20 paired samples (1 h and 2 h after ingestion) were 15.35 &mgr;g/mL ± 7.4, and 19.25 &mgr;g/mL ± 7.8, respectively (mean ± SD). There was a strong and highly significant correlation between paracetamol levels in serum and in tears 1 and 2 hours after ingestion (r= 0.8, p = 0.005,r= 0.85, p = 0.002 respectively). Mean ± SD ratio of tears/serum paracetamol levels 1 hour and 2 hours after ingestion were 0.77 ± 0.21 and 0.81 ± 0.25 respectively. &Dgr; tears (difference in mean levels at 1 and 2 hours) paracetamol levels is significantly correlated with &Dgr; serum levels (r= 0.7, p = 0.025). A reliable, convenient, and feasible noninvasive method is described for measuring paracetamol in tears. There is no information in the literature about tears paracetamol secretion, and little information of tears drugs concentration.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID