摘要:

Steady state pharmacokinetics of morphine (M), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were investigated in 6 patients with intractable cancer pain administered orally with MST (Mundipharma, Limburg, Germany) and, subsequently, rectally with MSR to make a judgment whether orally administered morphine can be replaced by rectally administered morphine. The parent drug and glucuronide metabolites were measured simultaneously using high-performance liquid chromatography (HPLC) and native fluorescence detection. The mean morphine area under the curve (AUC) value (0-8 h) was smallest (434.3 ± 170.2 nmolL-1h) in the oral administration than in the rectal administration (574.8 ± 285.0 nmolL-1h) (p< 0.05). The rectal administration resulted in less production of M3G and M6G. There were no significant differences in the mean steady state concentrations (Css) of morphine, M3G, and M6G between the oral and rectal administrations (p> 0.05). The median AUC ratio-M3G/M and M6G/M, 12.58 and 1.85-following MSR rectal administration was smaller than following MST oral administration in 6 patients (19.97 and 2.59;p< 0.05), whereas the median AUC ratio M3G/M6G in the rectal dosing was 6.24 (range 5.2-7.6) was almost the same as the median ratio M3G/M6G in the oral dosing was 6.49 (range 5.8-8.5;p> 0.1). Four of the 6 patients had a greater Cmaxof M3G and M6G after oral administration than after rectal administration. The same 4 had lower fluctuation rates for morphine. M3G (p< 0.05), and M6G (p< 0.05) after rectal administration. Therefore, during chronic morphine treatment, it still seems difficult to decide whether oral administration can be replaced by rectal administration.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The accuracy and the precision with which a drug concentration is quan in the blood has a significant impact on the therapeutic drug monitoring (TDM) of the drug. In the absence of a system of accreditation of laboratories in South Africa, this study was designed to compare the accuracy and the precision of the measurement of antiepileptic drugs by 24 South African laboratories with those of non-South African laboratories that participate in the United Kingdom National External Quality Assessment Scheme (UKNEQAS). Three test samples, containing a range of concentrations of phenytoin, valproate, carbamazepine, and phenobarbitone spiked into newborn calf serum were distributed to participating laboratories, which were asked to measure the serum concentrations using their routine assay method. Coefficients of variation were used to assess precision of measurements, and the percentage difference of the consensus mean from the spike value was used as an assessment of accuracy. There was comparable precision in the measurements for both the South African and the non-South African groups. However, there appeared to be a difference in the accuracy of measurement between the two groups. It was noted that the majority (77%) of the South African laboratories used the Abbott fluorescence polarization immuno-assay (FPIA) with TDx analyzers (Abbott Laboratories, Abbott Park, IL, USA). Further analysis of the results of the South African and UKNEQAS subgroups using the FPIA technique showed a reduction in statistic bias, suggesting that part of the explanation for the statistic difference in the accuracy may be an intertechnique bias related to the use of a nonhuman matrix for sample preparation. Additional studies are required to determine other causes for the statistic differences in accuracy. However, the differences in accuracy are unlikely to be of clinical significance.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The active entity of the new antiepileptic drug, oxcarbazepine (OXC), is 10-hydroxycarbazepine (MHD). In humans, OXC undergoes rapid presystemic (first-pass) metabolic reduction to MHD. MHD is a chiral molecule with an asymmetric carbon at position 10. Previous reports have shown that in humans, the first-pass metabolic reduction of OXC into MHD is stereoselective, resulting in a 1-to-4 AUC ratio of R(-) and S(+) enantiomers. The objective of the current study was to investigate whether the pharmacokinetics of MHD was stereoselective. Racemic MHD was thus administered intravenously (IV) and orally to six dogs, and plasma samples were analyzed by a stereospecific, high-performance liquid chromatographic (HPLC) assay. We found that R(-)-MHD had a clearance similar to that of S(+)-MHD; however, a difference was found between the volume of distribution (Vd) and consequently, between the half-lives of the two MHD enantiomers. The main pharmacokinetic parameters of R(-)- and S(+)-MHD were as follows: A terminal half-life (t½) of 2.2 ± 0.4 hours for R(-)-MHD and of 3.8 ± 0.3 hours for S(+)-MHD; a clearance (CL) of 7.8 ± 1.3 L/h for R(-)-MHD and of 8.6 ± 2.1 L/h for S(+)-MHD; a Vdof 25 ± 6 L for R(-)-MHD and of 47 ± 14 L for S(+)-MHD; and a Vdat steady state (Vss) of 22.8 ± 3.6 for R(-)-MHD and of 29.9 ± 4.1 for S(+)-MHD. After its oral administration to dogs, the absolute bioavailability was 78.4 ± 20.9% for R(-)-MHD and 78.5 ± 27.3% for S(+)-MHD; t½was 2.7 ± 0.6 hours for R(-)-MHD and 4.1 ± 0.8 hours for S(+)-MHD. These results showed stereoselectivity in the volume of distribution and consequently, the t½of S(+)-MHD was longer than that of R(-)-MHD after both IV and oral administration to dogs.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The individualization of anticonvulsant therapy regimens can contribute to the implementation of appropriate carbamazepine (CBZ) maintenance doses in epileptic patients. An accurate method for the prediction of concentrations based on a determination of parameters and serum concentrations could be of clinical relevance in the management of epilepsy. In this study, we retrospectively evaluated the predictive performance in an adult outpatient population of six different methods, representing six sets of CBZ pharmacokinetic parameters selected according to the literature using a Bayesian computer program (PKS System; Abbott Laboratories, Abbott Park, IL, USA). The study involved 50 patients with two or more available concentrations selected under several inclusion criteria. The patients were taking CBZ (between 200 and 1600 mg/d) in monotherapy or polytherapy regimens and had no hepatic or renal disease. Steady state concentrations were predicted according to the use of prior information and using one and two feedback patient concentrations. Accuracy and precision were assessed by mean prediction error (ME), mean squared prediction error (MSE) and root mean squared prediction error (RMSE). The analysis showed CL = 0.067 L/hour/kg and Vd= 1.19 L/kg as the most accurate and precise set of pharmacokinetic parameters, presenting the highest percentage of clinically acceptable estimates (error < 2 µg/mL). Additionally, predictions based on one measured feedback concentration were found to be more accurate and precise than prior population-based predictions; the use of two previous patient concentrations further improved predictive capacity but failed to show a significant difference when compared with predictions based on one measured feedback concentration. In conclusion, the adoption of the previously mentioned set of parameters as population estimates and the use of at least one feedback concentration through the Bayesian approach seems to be essential for a better CBZ use in clinical practice. Finally, despite the obtained results, we believe that the Portuguese pharmacokinetic parameter determination of antiepileptics should be carried out to improve the rationale and cost-effectiveness of anticonvulsant therapy.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The metabolism of azathioprine (AZA) was studied by monitoring the concentrations of red blood cell (RBC) 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) in 27 renal transplantation recipients and in 10 patient subjects with glomerulonephritis (GN). Concentrations of 6-TGNs and 6-mMP metabolites were measured using high-performance liquid chromatography (HPLC). Six patients from the group of renal transplantation recipients were also administered allopurinol. Median values of RBC 6-TGN and of 6-mMP metabolites concentrations in 21 renal transplantation recipients (without allopurinol) were 122 pmol / 8×108RBCs (range, <60-298) and 280 pmol / 8×108RBC (range, <150-1330), respectively; there was no correlation between concentrations of 6-TGN and of 6-mMP metabolites. The group of 21 renal transplantation recipients received different AZA doses (100 or 50 mg/d) related to clinical symptoms of AZA intolerance. The median values of 6-TGN concentrations in these subgroups were 131 and 122 pmol / 8×108RBCs and were not significantly different. Median values of 6-TGN concentrations in patients given allopurinol were significantly higher, despite AZA dose reduction, compared with the group without allopurinol and were equal to 363 and 122 pmol / 8×108RBC,p< 0.004, respectively. No significant differences were found between the concentrations of 6-mMP metabolites in either group. In the group of renal transplantation recipients, a significant correlation between white blood cell (WBC) count and 6-TGN concentration was established (rs= -0.59,p< 0.005). In the group of GN patients, the median values of 6-TGN and of 6-mMP metabolites concentrations were 108 pmol / 8×108RBCs (range, 0-297) and 420 pmol / 8×108RBC (range, 0-1440), respectively. There were no significant correlations between either the WBC count and 6-TGN concentrations or between 6-TGN concentrations and 6-mMP metabolites. We expect the results of our study to provide indications for better individualization of AZA therapy.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Aniline, widely used as an intermediate in the synthesis of dye, is also used in the manufacture of pharmaceuticals, photographic developers, shoe polish, and other common substances. Exposure to aniline is toxic because it produces methemoglobin. Aniline levels are usually not measured in serum; in humans, blood methemoglobin levels are often measured as an index of exposure to aniline. In this article, we describe a method for the identification and the quantification of aniline by gas chromatography/mass spectrometry (GC/MS) after its extraction from human serum and derivatization with 4-carbethoxyhexafluorobutyryl chloride. Aniline, as well as the internal standard N-methyl aniline, was extracted from alkaline serum using chloroform. Aniline and the internal standard were derivatized with 50 µL of 4-carbethoxyhexafluorobutyryl chloride. After evaporating the excess derivatizing reagent, the residue was reconstituted in 50 µL of ethyl acetate and injected into the GC/MS. A positive identification of derivatized aniline can be made from the strong molecular ion at m/z 343. Similarly, derivatized internal standard showed a strong molecular ion at m/z 357. The within-run and between-run precisions of the assay were 3.8% and 5.8%, respectively, at an aniline concentration of 5 mg/L. The assay was linear for serum aniline concentrations of 0.5 mg/L to 25.0 mg/L. The detection limit was 0.1 mg/L. The assay was not affected by lipemia, hemolysis, or high bilirubin concentration in serum, and the assay was applicable to whole blood. We also fed mice (C57b1/6) with various concentrations of aniline and measured methemoglobin and blood concentrations of aniline. The methemoglobin percentage and aniline concentrations in blood increased with increasing aniline doses.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Methadone treatment programs commonly monitor patient compliance by screening urine samples for drugs of abuse. Our experience suggests that re-submission of urine samples (for example, providing a urine sample that is either not that of the patient or was previously submitted) is often used as a method of sample tampering. We have developed an algorithm that combines urine sodium, chloride, creatinine and pH values with urine drug screening results to effectively detect resubmitted samples. Given the widespread use of urine drug screening in drug and alcohol rehabilitation programs, we believe this technique has significant practical benefits. This technique may also have an application in forensic identification of duplicate samples.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Digoxin fab antibody (Digibind; Burroughs Wellcome, Research Triangle Park, NC, USA) is used in the treatment of digoxin overdose. The effect of digibind on the measurement of total and free digoxin has been extensively studied. However, the effect of digibind on digitoxin measurements has not been studied thoroughly. The authors studied the effect of digibind on the measurement of total and free digitoxinin vitrousing the fluorescence polarization immunoassay and a new chemiluminescent immunoassay. We also studied the capability of digibind to bind digitoxigenin, the major aglycon metabolite of digitoxin. Digibind neutralized both digitoxin and digitoxigeninin vitro, as evidenced by significant reductions in free digitoxin and digitoxigenin (measured as digitoxin equivalent) concentrations. Digibind caused negative interference in the measurement of total digitoxin concentrations by both fluorescence polarization and chemiluminescent assays. However, the magnitude of negative interference was significantly higher with the chemiluminescent assay. For example, in a serum pool supplemented with 80 ng/mL of digitoxin, the concentrations of total and free digitoxin measured by the fluorescence polarization immunoassay were 82.1 ng/mL and 3.3 ng/mL respectively. In the presence of 5 µg/mL of Digibind, the corresponding total and free digitoxin concentrations were 73.9 ng/mL and none detected, respectively. In another serum pool supplemented with 70 ng/mL of digitoxin, the concentrations of total and free digitoxin as measured by the chemiluminescent assay were 69.1 ng/mL and 3.8 ng/mL, respectively. In the presence of 5 µg/mL of Digibind, the corresponding total and free digitoxin concentrations were 29.0 ng/mL and none detected, respectively. Because this effect may also occurin vivo, the progress of Digibind therapy in treating a patient with digitoxin overdose may be monitored by measuring the free digitoxin concentrations.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

A modified EMIT 2000 digoxin assay was developed on the Cobas Mira plus analyzer for the determination of very low plasma concentrations of the drug. The major modifications were a higher plasma volume withdrawn during the analysis step and calibration curves constructed in the range 0-2 ng/ml using calibrators made up with biological matrix. Assays were controlled with an internal, four-level quality control (targets: 0.15; 0.60; 1.70; 2.70 ng/mL). The within-day and day-to-day mean observed values ± SD (n = 10) of these quality controls were 0.14 ± 0.02 and 0.15 ± 0.02 ng/mL; 0.57 ± 0.01 and 00.64 ± 0.03 ng/mL; 1.55 ± 0.06 and 1.62 ± 0.04 ng/mL, 2.82 ± 0.09 and 2.82 ± 0.12 ng/mL, respectively. The detection and the quantification limits were 0.02 and 0.08 ng/mL, respectively. No significant difference was observed between digoxin plasma concentrations measured by the original and the modified EMIT 2000 digoxin assay in 25 plasma specimens, ranging from 0.4 to 3.0 ng/mL, from patients receiving the drug. This modified digoxin EMIT 2000 assay was subsequently used to study digoxin pharmacokinetics after each of 18 healthy volunteers was administered a single 0.5 mg oral dose. The pharmacokinetic parameters found in this study were in accordance with the literature in healthy subjects, using radioimmunoassay (RIA) for digoxin plasma concentration determinations. In conclusion, the lower limit of quantification of this modified EMIT 2000 digoxin assay is similar to that of RIA and can serve as a valuable screen for digoxin pharmacokinetic interactions studies.

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0163-4356    

出版商:OVID    

年代:1999

数据来源: OVID