摘要:

Summary:The impact of a new monitoring strategy on whole blood concentrations of cyclosporine measured by a specific monoclonal radioimmunoassay was investigated in a group of 37 renal transplant patients. Before transplantation, the patients received a standard intravenous (i.v.) and oral (p.o.) test dose of cyclosporine to calculate their individual i.v. and p.o starting dose rates to achieve a certain target steady-state cyclosporine concentration. After transplantation, the designated i.v. dose rate was continuously infused for 2 days, at which time the steady-state concentration was measured. Then, the designated oral dose for 24 h was administered while the infusion was continued at an unaltered rate. The oral absorption of cyclosporine was documented by blood samples over the following 8 h. If necessary, this overlap of i.v. and p.o. dosing was repeated until blood concentrations of cyclosporine rose at least 700 ng/ml over the steady-state concentration. By that time, the infusion was stopped and oral dosing continued. Individualized infusions led to steady-state concentrations within a range that did not exceed 1.1 times the median concentration of 472 ng/ml. Standard infusion rates in the past produced a much wider range of steady-state concentrations (9.6 times the median). Individualized infusions reached the target steady-state concentration with a significant positive bias of 17% (SEM = ≤32%, range of −36 to + 105%). Individualized oral doses reached the target average steady-state concentration (calculated by dividing the area under the concentration-time curve by the dosing interval) with an inferior precision (median = 2.6%, range of −54 to + 130%) but without a positive or negative bias. Until 14 days after transplantation, 88% of the patients showed satisfactory oral absorption of cyclosporine; the remaining 12% were kept on infusions for up to 1 month. The new monitoring strategy rendered immunosuppression with cyclosporine and prednisone a safe and effective therapy after renal transplantation.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The correlation between single plasma concentration (CP) values of 5-fluorouracil (FU) after a 10-minute i.v. infusion and the total area under the plasma concentration-time curve (AUC) has been studied in 26 cancer patients. FU dose was either 320–550 mg/m2(seven patients, 13 treatments) or 610–960 mg/m2(19 patients, 30 treatments). Linear single CP-AUC relationships were found in both dose groups with the CPs at 1, 5, 10, 15, and 30 minutes after the end of infusion. Parameters of linear regression of AUC on single CPdiffered between the two dose groups. For the high-dose group, the single CPs at repeated treatments were tested as estimators of the total AUC at these treatments, using calibration lines relating total AUC to single CP, which were derived from the data of the first (or only) treatments of all patients. The “best” AUC estimators of the total AUC were the CPs at 10 and 15 minutes after the end of infusion, with a bias of only 2% and an imprecision of only 11% of the AUC values directly determined from the complete concentration-time profiles of the repeated treatments. Because of the close correlation between these single CPs and the total AUC, these CPs should be considered equivalent to the AUC as an overall index of individual FU kinetics after brief infusion of high doses.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The concentrations of cadralazine in plasma were studied in 101 hypertensive patients treated with oral doses of 10, 15, or 20 mg of cadralazine once daily. Most of the patients received additionally a β-blocking drug (n = 87) and a diuretic (n = 52). Few blood samples were collected in each patient on several occasions during the treatment, which usually lasted for more than 6 months. No accumulation of cadralazine in plasma occurred in any of the patients and the maximum concentrations were similar to those recorded in a small sample of healthy volunteers. The terminal half-life of elimination (3.6 h) was longer than that observed in healthy subjects (approximately 2.5 h). Conversely, the total clearance (197 ml/min) was lower (285 ml/min in healthy). The half-life and the total clearance in plasma were not dose dependent. In the patients treated for more than 6 months, no change in the pharmacokinetics of cadralazine was detected. The description of the distribution of concentrations showed that one-half of the patients behaved similarly to healthy subjects concerning half-life and total clearance. The other half presented a slower elimination of the drug (t1/2= 4.4 h and ClT= 130 ml/min) and these patients were significantly older (p= 0.01) than the former. This suggests that special attention should be paid to old hypertensive patients when a dose higher than 15 mg once daily is prescribed. Though concentrations were proportional to the dose, the body weight was not found to be a determining factor for dose adjustment. The coadministration of a diuretic did not modify the kinetics of the drug. A clear advantage of this study over a conventional study in a small group was demonstrated: several parameters that could influence the pharmacokinetics were studied. The description of the pharmacokinetics in subgroups of patients was possible.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The single oral dose kinetics of carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of carbamazepine, were studied in six epileptic patients, stabilized on phenobarbital (PB) monotherapy, and in six drug-free health volunteers. The epoxide metabolite was administered as an enteric-coated tablet at the dose of 200 mg to the patients and at the dose of 100 mg to the volunteers. Patients had a significantly higher plasma clearance of CBZ-E than the control group (mean values ± SD = 220.2 ± 63.5 versus 112.5 ± 46.0 ml/h/kg,p> 0.007) and a significantly shorter plasma half-life (mean values ± SD = 4.3 ± 1.0 versus 6.7 ± 0.8 h,p> 0.0015). These results suggest that PB induces CBZ-E metabolism.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:Four digoxin radioimmunoassays (RIA) were evaluated using four antidigoxin monoclonal antibodies (MAb) with different binding specificities for digoxin metabolites and other glycosides. These RIA have been used to measure the apparent digoxin concentrations in the sera of patients treated with digoxin, in cord blood sera and in rat intestine aqueous extracts. Two MAb strongly recognized digoxin-like immunoreactive substances (DLIS) in cord blood sera and in rat intestine aqueous extract. In contrast, one MAb (2C2), which recognizes active digoxin metabolites and does not cross-react with inactive metabolites nor with digitoxin, showed no reactivity with DLIS in the cord blood sera tested. This MAb was used in a new digoxin RIA that was rapid, sensitive, reproducible, and specific for digoxin and its active metabolites.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:Stochastic simulations were used to examine the sensitivity of mean phenytoin steady state concentrations (Css) to changes in the effective dosing rate produced by differences in average product content or bioavailability. Changes of +4%, + 6%, + 8% and + 10% in the effective dosing rate (based on a starting dose yielding aCssof 15 mg/L) were examined. Monte Carlo simulations were performed for each change in dosing rate assuming a one-compartment open model with parallel Michaelis-Menten and first-order elimination. Parameter sets were comprised of a combination of values for maximal rate of saturable elimination (410 or 510 mg/day), the concentration at which the rate of saturable elimination is half maximum (Km, 4.4 or 5.7 mg/L), and linear clearance (Ç, 0.15 or 1.5 L/day). These parameters were assumed to be log-normally distributed with coefficients of variation of 30%, 50%, and 15%. The percentages of “individuals” who would be predicted to haveCssof >10 mg/L following a reduction in the effective dosing rate increased with decreasingKmandÇvalues. For aKmof 5.7 mg/L andÇof 1.5 L/day, 5% of the “individuals” hadCssvalues of > 10 mg/L with an 8% decrease in the dosing rate. If the dosing rate was reduced by 10%, then 14–16% of the “individuals” were predicted to have concentrations of > 10 mg/L. All other combinations ofKmandÇvalues yielded higher percentages of “individuals” withCssof > 10 mg/L. When the effective dosing rate increased, the percentages of the “individuals” who would be predicted to have aCssof < 20 mg/L increased with decreasingKmandÇvalues. For aKmof 5.7 mg/L andÇof 1.5 L/day, 10–12%, 32–38%, and 60–64% of the replicates would be predicted to have aCssof<20 mg/L if the dosing rate increased by 6%, 8%, and 10%. The other parameter sets showed more sensitivity to changes in the dosing rate. These simulations illustrate the importance of product uniformity that must be maintained from lot to lot of the same product and from one manufacturer to another. The sensitivity ofCssto the change in effective dosing rate is influenced by a parallel, first-order elimination pathway, the magnitude of which is unknown. A definitive study is needed to substantiate these simulation-based results.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:An original, highly sensitive and specific high-performance liquid chromatographic (HPLC) assay has been developed for the measurement of oxycodone in human plasma with a detection limit of 10 ng/ml using a 1.0-ml plasma sample. Plasma samples were initially acid-washed and then extracted twice at pH 10 with butyl chloride. Oxycodone and codeine (internal standard) were eluted with a mixture of methanol, acetonitrile, and 0.01MpH 7 phosphate buffer to which 40 mg/1 of cetyltrimethylammonium bromide (cetavlon) was added at ambient temperature and detected with electrochemical detection. The addition of cetavlon to the mobile phase markedly reduced the interaction between oxycodone and Si-OH groups on the stationary phase of the HPLC column, so that the organic content of the mobile phase could be reduced from 80 to 25%. Quantitation was achieved using the peak height ratio of oxycodone to codeine. The assay is currently being used for the study of oxycodone pharmacokinetics after single oral doses of 10 and 20 mg and single rectal doses of 30 mg.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The interlaboratory variability in the assay of theophylline and various anticonvulsant drugs was evaluated in a 16-month prospective study by using two independent experimental approaches: (a) a conventional method based on the distribution of quality control (QC) lyophilized human sera spiked with the test drugs (phenytoin, phenobarbital, carbamazepine, valproic acid, primidone, theophylline); and (b) reanalysis by two to four reference laboratories of patients' samples randomly selected among those routinely assayed for phenytoin and theophylline by the 52 participating laboratories. For all tested drugs, precision as assessed by results on spiked QC samples was generally satisfactory, interlaboratory coefficients of variation (CV) being below 18.5% for all drugs tested except primidone (CV = 24.1%) at clinically relevant drug concentrations. For both phenytoin and theophylline, there was a good agreement between results obtained by individual reference laboratories (reference results) on routine samples. The correlation coefficients relating the original values to the means of the reference results were<0.94. It is concluded that interlaboratory variability in the assay of the drugs included in this survey is relatively low not only when assessed by using conventional QC material, but also under strictly routine conditions.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:Fifty-four laboratories providing a serum digoxin monitoring service participated in a 16-month prospective quality control (QC) study that involved (a) determination of spiked QC samples based on a human serum matrix and (b) reanalysis by two to four reference laboratories of patient samples randomly selected among those assayed routinely. Interlaboratory variability on spiked samples was limited, coefficients of variation being usually in the 11–21% range. Correlations between values reported by individual reference laboratories on routine samples were reasonably good irrespective of the techniques used, which were the enzyme-multiplied immunoassay technique (EMIT) or the fluorescence polarization immunoassay (FPIA). When all data were considered, the correlation between the original routine values and reference results (r= 0.93) was comparable to that observed for the other analytes (phenytoin and theophylline) included in the survey. When subsets of results were evaluated according to the technique used, the agreement between routine and reference results was good for samples originally measured by FPIA (r= 0.96), moderate for samples originally measured by non-EMIT/non-FPIA techniques (r= 0.92), and poor for the few samples originally measured by EMIT (r= 0.55). The poor correlation with EMIT results could be ascribed largely to erratic performance of two individual laboratories. It is concluded that interlaboratory variability in routine drug measurements is greater for digoxin than for other analytes such as phenytoin and theophylline, and that the analytical performance of some laboratories is grossly inaccurate.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:Two simple, precise, and selective high-performance liquid chromatographic methods are described for the simultaneous quantitation of me-floquine (MQ) plus pyrimethamine (PYR) or sulfadoxine (SDX) plus its principal metaboliteN4-acetylsulfadoxine (N4SDX) in human plasma. After a single-step extraction, MQ plus PYR and SDX plusN4SDX including internal standards were separated using ion-paired and ion-suppression chromatography. Total run times for the assays were > 12 min. Intraassay and interassay precision of the methods expressed as the coefficients of variation were > 9% in plasma for the four compounds. The extraction recovery averaged 98% for MQ, 97% for PYR, 96% for SDX, and 81% forN4SDX. Plasma concentrations of the four compounds in a pediatric patient after a single oral dose of Fansimef (MQ + SDX + PYR) were determined to demonstrate the clinical application of the methods.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID