摘要:

Trough concentrations of cyclosporine can be highly variable because of its poor bioavailability in current oral formulations, Sandimmune (SIM). Neoral (N-SIM) a new microemulsion of cyclosporine is more readily absorbed than SIM in healthy controls. The present study compared the pharmacokinetic profiles of SIM and N-SIM following orthotopic liver transplantation. In 16 patients with partial biliary diversion, 1 week after transplantation, the bioavailability and peak concentration of a single 300 mg dose of N-SIM were greater than SIM by 724% (p= 0.0019) and 800% (p= 0.0001), respectively. In 39 patients who were on stable doses of cyclosporine 1 month after transplantation, the bioavailability of N-SIM was higher than that of SIM under both fasting ( + 64%,p= 0.001) and fed ( + 37%,p= 0.004) conditions. Trough concentrations were similar for the two formulations. However, peak concentrations were higher for N-SIM in both fasting ( + 119%,p= 0.003) and fed ( + 53%,p= 0.003) patients. Also, time to peak was shorter for N-SIM in both fasting (-21%,p= 0.027) and fed (-59%,p= 0.0001) patients. The correlation between trough concentrations and bioavailability was greater for N-SIM than for SIM in fasted (r= 0.80,p= 0.0001 versusr= 0.75,p= 0.0001) and fed patients (r= 0.65;p= 0.002 versusr= 0.55;p= 0.012). We conclude that the rate of absorption and the bioavailability of N-SIM is significantly and consistently better than SIM and-may, therefore, improve the therapeutic index of cyclosporine after liver transplantation.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Steady state plasma carbamazepine (CBZ), carbamazepine epoxide (CBZE), and carbamazepine diol (CBZD) concentrations were quantified by HPLC in 121 specimens obtained from two groups of epileptic patients: 78 receiving CBZ monotherapy (I), and 43 receiving CBZ and valproic acid (VPA) (II). The differences of drug/metabolite ratios and concentration/dose (μmol/L/mg/kg/day or 1/clearance) ratios were calculated as a measure for the influence of VPA on CBZ metabolism. Results as means ± SD were CBZ/CBZE 5.85 ± 3.91 (I) vs. 4.22 ± 1.57 (II), p < 0.02; CBZ/CBZD 2.94 ± 1.94 (I) vs. 2.82 ± 1.15 (II); CBZE/CBZD 0.53 ± 0.24 (I) vs. 0.71 ± 0.32 (II), p < 0.001. Concentration/dose ratios: CBZ 2.32 ± 1.58 (I) vs. 3.04 ± 1.41 (II), p < 0.05; CBZE 0.41 ± 0.20 (I) vs. 0.73 ± 0.28 (II), p < 0.001; CBZD 0.82 ± 0.35 (I) vs. 1.22 ± 0.70 (II), p < 0.001. Drug/metabolite relationship data seem to support the concept for VPA as a selective inhibitor of epoxide hydrolase, but concentration/dose ratios indicate a reduced clearance for the parent drug, and especially for its two metabolites. This latter finding is in a controversy with the former concept. In addition, a considerable age-dependency of the influence of VPA on CBZ metabolism was found: compared to monotherapy, drug/metabolite and concentration/dose ratios were most changed in children. We assume that VPA is probably not a selective inhibitor of epoxide hydrolase, and affects nonspecifically all steps of the epoxide-diol pathway of CBZ metabolism.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

A linear two-compartment Bayesian pharmacokinetic model was developed using a standard two-stage population method for the novel anti-cancer agent CPT-11 from 11 adult patients with refractory cancer. The accuracy and efficiency of this Bayesian model for estimating pharmacokinetic parameters including the area under the concentration-time curve (AUC) was then evaluated using two different sampling strategies in a new study cohort of 13 patients with cancer. Sampling strategies included either one, two, or three nonsteady-state feedback levels determined empirically and from optimal sampling theory (D-optimality). All 24 patients in this study received CPT-11 (60 mg/m2) as a 90-min infusion. Pharmacokinetic parameters derived from the Bayesian model combined with these limited sampling strategies were compared with those parameters obtained from the full sample data sets (n = 10) analyzed by weighted nonlinear least squares regression (reference method). The least-bias and most precise sampling times for estimating AUC were 3.5; 3.5 and 9.5; and 0.5, 3.5, and 9.5 h, respectively. At these times, only marginal improvement in precision of the AUC estimate was observed using two versus three samples. However, the precision of the estimate of clearance was not improved using two versus three samples. The sampling times derived from optimal sampling theory were 0.25, 3.5, 8.5, and 24 h and correlated closely to the actual and best empirical sampling times of 0.5, 3.5, 9.5, and 24 h. These results strongly suggest that Bayesian estimation combined with only two optimally timed samples accurately predicts the AUC of CPT-11 and should be useful for implementing adaptive control dosing for monitoring CPT-11 systemic exposure in patients with cancer.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Rapid and reliable measurement of acetylcholinesterase (AChE) activity is of crucial importance to the pharmacodynamic monitoring of anti-cholinesterase drugs. A new assay has been developed to measure AChE from 10 μl samples of capillary blood. AChE activity was calculated from the change in pH of the reaction medium caused by the hydrolysis of acetylcholine and measured with a highly sensitive differential pH apparatus (CL-10, Eurochem, Rome, Italy). Interference by butyrylcholinesterase was eliminated by a specific inhibitor, quinidine sulfate. The assay lasts 1 min. The coefficient of variation (CV) for replicated measurements was 2.8% (3267 U/L, n = 33). Linearity ranged from 0 to 10,000 U/L. The correlation coefficient between the new technique and Ellman's colorimetric method on washed erythrocytes wasr= 0.987 (y = 1.299x – 63, n = 29). The correlation coefficient between assays on capillary and venous samples wasr= 0.979 (y = 0.974x + 174, n = 47). A cross-laboratory validation study was performed in 10 centers using glycerol-stabilized hemolysates with normal and reduced AChE activity. Samples were assayed in triplicate. The within- and between-laboratory CVs for samples with normal AChE activity (6,018 U/L) were 2.2 and 8.1%, respectively. The new method was applied to a double-blind, placebo-controlled multicenter study of eptastigmine in Alzheimer patients and proved to be a simple, noninvasive, rapid, and reliable method for pharmacodynamic monitoring of this drug.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

A dynamic pharmacokinetic model for i.v. vancomycin administration was developed and tested in 47 neonates and infants. Twenty-nine patients (Group 1), having two or more concentrations, were used to estimate population parameters by nonlinear least-squares analysis. Multiple stepwise. linear regression techniques showed that estimated creatinine clearance,Clcr, and postnatal age were significant demographic factors related to vancomycin clearance (CL.) No strong associations were found for the apparent volume of distribution. A one-compartment model was constructed using the associations ofCLcrand postnatal age with vancomycin CL. Eighteen patients (Group 2), receiving 35 courses of vancomycin therapy, with both initial and subsequent sets of peak and trough concentrations, were used to test the predictive performance of the model with and without the use of Bayesian forecasting. Using only population-based parameters, the respective mean error (ME) (bias) and mean absolute error (MAE) (precision) for predicting subsequent peak concentrations were – 1.20 and 3.89 mg/L and for trough concentrations, 0.83 and 2.23 mg/L, respectively. For the Bayesian method, these values were, respectively, 0.45 and 4.13 mg/L for peak concentrations and 1.55 and 2.40 mg/L for trough concentrations. When predicted concentrations occurred within 30 days of feedback concentrations, the Bayesian method tended to be slightly less biased and more precise than the population-based parameters. The opposite was true >30 days of the initial set of feedback concentrations. The use of population-specific pharmacokinetic parameters and Bayesian forecasting should allow accurate dosage regimen design as well as minimize the need for monitoring serum vancomycin concentrations in neonates and young infants.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The anticonvulsant drug gabapentin and its heptaneacetic acid analog—used here as an internal standard—are isolated from serum (pH 9) with an octyldecyl (C-18) solid-phase sorbent column. To enhance analytical detection, trinitrobenzene derivatives of these extracted compounds are prepared quickly within 10 min. To furthur improve chromatographic selectivity, the derivatives are concentrated on a thin C-18 solid-phase membrane and interferences are washed away. The retained purified derivatives are eluted from the membrane with a small volume of solvent and the eluate is directly injected onto an Ultrasphere C-18 high-performance liquid chromatography column with quantification at 340 nm. No evaporation-concentration steps are necessary. Recoveries (extraction) of gabapentin and the internal standard are 94.2 ± 2.9% and 98 ± 2.0%, respectively. Analytical responses are linear from lower limit of sensitivity of 0.05 mg/L up to at least 10 mg/L. Between-run coefficients of variation (CV) range from 2.3 to 2.9% through the concentration range 0.5–4.0 mg/L. To illustrate the rationale for selection of test parameters for a robust method, we present optimization graphs for these processes. Moreover, we discuss the advantage of the packed cartridge and membrane sorbents as companion extraction devices.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In this assay of the nonsteroidal antiestrogen droloxifene and two metabolites in human serum, the serum samples were deproteinized with an equal volume of acetonitrile and then injected into an analytical octadecylsilane column. The analytical column was equilibrated with acetonitrile/water (1/1, vol/vol) containing acetic acid and diethyl amine and eluted isocratically with 66% acetonitrile in the same buffer. Droloxifene,N-desmethyldroloxifene, and 4-methoxydroloxifene were post-column converted to fluorophors by ultraviolet illumination while passing through a 10-m transparent knitted polytetrafluorethylene reaction coil. Analytical recovery was close to 100%. Within- and between-day precision corresponded to a coefficient of variation (CV) of 2–5% at serum concentrations of ≥25 ng/ml, except for 4-methoxy-droloxifene (CV 7–10% at a concentration of 25 ng/ml). By increasing the injection volume from 50 to 250 μl, the detection limits could be decreased from ∼5 to 1 ng/ml. Conjugated droloxifene could be estimated in a second run after treatment of sample with an enzyme preparation containing β-glucuronidase plus sulphatase. The recovery of droloxifene glucuronide was close to 100%. Sulphate conjugates have not been identified and were not accounted for.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The effect of storage time and temperature on the stability of FK506 in patient blood samples and quality control samples was assessed with the Abbott IMx microparticle enzyme immunoassay. Blood FK506 concentrations measured at days 0, 2, 3, 4, 7, and 14 were stable at room (22°C), refrigerator (4°C), and freezer (-70°C) temperatures for the 2-week study period. Patient samples stored at – 70°C for almost 1 year and then reanalyzed for FK506 were also found to be stable.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

A high-performance liquid chromatography (HPLC) method has been developed for the rapid evaluation of minocycline concentrations in serum after chemical pleurodesis. Elution was performed with a Nova-Pak phenyl reverse-phase column and a Waters radial compression module. No organic extraction or evaporation of samples is required. The assay is linear from 0.6–20 μg/ml with recovery rates ≥98%. Interassay variability is 8.2 ± 1.1% and intraassay variability is 2.1 ± 0.3%. Correlation coefficients were ≥0.999 for five standard curves. The technique was effective for quantitation of serum minocycline levels in a human patient who had received the drug intrapleurally on two consecutive days. This HPLC method may be useful for monitoring adverse effects related to serum concentrations of the drug during pleurodesis.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

A stereospecific high-performance liquid chromatography (HPLC) method has been developed for the analysis of the underived enantiomers of citalopram (CIT) and itsN-demethylated metabolites in plasma. Using fluorescence detection, the limit of quantification for each enantiomer is 3 ng/ml. CITN-oxide and the CIT propionic acid derivative are not extracted by the procedure used. Inter- and intraday validations of the method using reverse-phase mode HPLC on separate acetylated β-cyclobond columns showed the sensitivity of this assay to be suitable for pharmacokinetic studies of the enantiomers of these compounds. Plasma levels of the enantiomers and the demethylated metabolites of CIT have been determined during routine therapeutic drug monitoring (TDM) in 29 depressive patients treated with varying dosages (20–80 mg/day) of CIT. Concentrations ofS-( + )-CIT, which is considered the most potent selective serotonin reuptake inhibitors (SSRI) of the CIT and desmethylcitalopram (DCIT) enantiomers, varied between 24–49% (mean ± sd, 35% ± 5%) of the concentrations of total CIT. There were highly significant correlations betweenS-( + )-CIT andR-( – )-CIT levels (r= 0.866;p< 0.0001) and betweenS-( + )-DCIT andR-(-)-DCIT (r= 0.932;p< 0.0001). The co-medications seemed to have little influence on enantiomer ratios. These results suggest the need for studies on the relationships between clinical response and plasma levels of CIT enantiomers.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID