摘要:

The relationship between albumin or α1-acid glycoprotein (AAG) levels and vancomycin (VCM) protein binding was studied in 44 serum samples from the 10 patients with methicillin-resistant Staphylococcus aureus (MRSA) infection receiving VCM therapy. Eighty serum samples from 80 healthy subjects were used as a control for albumin and AAG levels. The protein binding percentage of VCM in the serum of the patients varied widely from 27 to 62%. The mean albumin level (34 g/L) was significantly lower than that in healthy subjects (46 g/L). There was no correlation between the binding percentage and serum albumin level in the patients (r = −0.25, p > 0.1). The mean AAG level in the patients (1.51 g/L) was significantly higher than in healthy subjects (0.59 g/L). There was a significant correlation between the binding percentage of VCM and serum AAG level (r = 0.63, p < 0.001). The binding percentage of VCM in individual patients changed in parallel to serum AAG and C-reactive protein (CRP) levels, which is a useful marker of acute phase response. There were also significant correlations between AAG, albumin, and CRP levels. The present results indicate that the increased AAG level in serum of the patients appeared to have a significant effect on the protein-binding characteristics of VCM.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Liver metabolism may be modified after liver transplantation according to the phenotype of the donor and may be influenced by posttrans-plantation complications. The CYP2D6 phenotype was assessed in 13 patients (group I) before and after liver transplantation using debrisoquine. CYP2D6 activity was also assessed in vitro on microsomes from the liver of the recipients and the donors, using dextrpmethorphan. Twelve patients were extensive metabolizers both before and after transplantation. One apparently poor metabolizer was transplanted with the liver of another poor metabolizer. The intrinsic clearance of dextromethorphan (CLint) measured on recipient liver microsomes was significantly lower than that on donor liver microsomes (p < 0.05). In extensive metabolizers, the debrisoquine metabolic ratio was correlated with CLintbefore (r = 0.78, p < 0.05) and after (r = 0.89, p < 0.0005) transplantation. Debrisoquine phenotype was measured repeatedly in nine additional patients (group II) up to 3 years after liver transplantation. Their phenotype was stable during the follow-up observation, although the variations observed may be clinically relevant. Therefore, no change in CYP2D6 phenotype (extensive/poor metabolizer) was observed because of the liver transplantation, and the debrisoquine log metabolic ratio was largely unaffected by the liver complications observed during the posttransplantation follow-up observation.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The objective of this study was to assign metabolizer phenotype to 107 healthy adult black Americans using dextromethorphan as the substrate probe. Eligible subjects were unrelated, healthy, nonsmoking, aged 18–50 years, and taking no medications. Fifteen milliliters of dextromethorphan syrup (85 μmol, 30 mg) was administered orally at bedtime, and 8-h overnight urine was collected. Dextromethorphan and dextrorphan urinary areas and molar ratios were determined using high-performance liquid chromatography with fluorescence detection. A molar metabolic ratio of <0.3 was used to segregate poor metabolizers (PM) from extensive metabolizers (EM). Data were obtained in 99 subjects: 68 women, 31 men. (Five were lost to follow-up, three did not take the probe drug.) Six (6.1%) were PM (five women, one man), and 93 were EM. The prevalence of PM was 6.1% (95% confidence interval, 2.3–12.7%) in our sample. This compares to 5 to 10% reported in white unrelated subjects and 1.9% in 106 black children (64 healthy and 42 with cancer), and 0–8.6% in black African populations. The clinical implications of these findings warrant further investigation.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The prognostic value of a dynamic liver-function test, based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX), in predicting multiple organ failure (MOF) was prospectively investigated in 28 critically ill patients after multiple trauma. The MEGX test and conventional static liver tests (bilirubin, aspartate aminotransferase, glutamate dehydrogenase, and factor V) were performed on days 1,3,5, and 7 after trauma. Patients were classified by a modified MOF score into a group without (n = 18) and a group with the MOF syndrome (n = 10). One patient who developed MOF on the basis of a bacterial septicemia was excluded from the general evaluation. No significant differences were observed in the MEGX values of the two groups on day 1. All patients who subsequently developed MOF, however, displayed a sharp decrease in their MEGX values between days 1 and 3. Analysis of the data using receiver operating characteristic (ROC) curves revealed that the results of the MEGX test on day 3 provided the greatest discriminating power between patients with and without subsequent MOF. A cut-off MEGX value of 30 μg/L on day 3 was associated with a prognostic sensitivity of 89% and a prognostic specificity of 94%.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

During once-daily dosing regimens of aminoglycosides, administration of large single doses results in high peak levels and low 24-h trough levels. However, commercial assays for monitoring aminoglycoside levels are designed to cover the smaller range of serum concentrations usually observed during multiple daily dosing regimens. The study assessed (a) the range of serum concentrations during once-daily dosing of amikacin and (b) the performance of a widely used assay system for measuring concentrations within this range. A total of 42 dosing intervals from eight patients receiving a once-daily regimen of amikacin (20 mg/kg) were monitored. Median (and range) of peak, 8− and 24-h trough levels were 61 (25–89), 5.9 (2.2–19), and 1.3 (<0.8–6.2) mg/L, respectively. The accuracy of a fluorescence polarization immunoassay for measuring concentrations of amikacin during once-daily dosing regimens was assessed in an international multicenter study. The performance of the assay was excellent for peak and 8-h concentrations; median deviations from the target concentrations were <5%. The majority of the trough levels (26 of 42) measured in patients during once-daily treatment were within the range of 1–2 mg/L and could also be determined with an accuracy sufficient for clinical monitoring (median deviations 14%).

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Plasma concentrations of clozapine at a given dose vary considerably between patients, but drug levels are not routinely monitored during the normal 4− to 8-week dose escalation period at the beginning of therapy. We hypothesized that the dose required to give a putative threshold therapeutic concentration of 350 μg/L could be individualized using pharmacokinetic predictions made at the beginning of normal dose escalation. Low-dose clozapine (25–75 mg every 12 h) was administered to 21 treatment-resistant patients with schizophrenia who had been split into three groups. In group A (six patients), individual target doses were predicted from area under the concentration-time curve data after a single 50-mg dose. In group B (five patients), predictions were made as in group A but at steady state. In group C (10 patients), predictions were based on trough clozapine levels obtained at steady state immediately before dose increase. Dosage was increased, if tolerated, by 25 mg twice daily three times a week for 4–8 weeks according to established clinical practice. Clozapine concentrations were measured weekly, and actual target doses were determined for each patient from dose-concentration plots. In groups A and B, the correlation between actual and predicted target dose was not significant (r = 0.18, p = 0.59). In group C, however, it was significant (r = 0.86, p = 0.0016). These results suggest that individualized doses of clozapine for treatment-resistant patients with schizophrenia can be conveniently predicted from trough drug levels at the start of therapy. Such information would facilitate a more rapid, individualized, and consistent attainment of therapeutic doses than is now the case in clinical practice.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Diuretic drugs have been reported to alter the glomerular filtration rate and possibly the creatinine excretion by the kidneys. We evaluated the effects of single doses of diuretic drugs on creatinine clearance determination. Ten healthy volunteers were randomized to receive either oral hydrochloro-thiazide, oral furosemide, intravenous furosemide, or no treatment in a crossover fashion during four separate test days with 6-day washout periods. Urine and blood specimens were collected during 24 h after the treatments. Specimens were assayed for creatinine, and the creatinine clearance corresponding to the 4-, 6-, 12-, and 24-h urine collections were calculated. Analysis of variance did not show a statistically significant effect of the diuretic regimens on creatinine clearance over these periods. This study demonstrates that single doses of diuretic drugs do not have significant effect on creatinine clearance determination using urine collected during 4–24-h periods.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Since plasma protein binding of disopyramide (DP)—a class IA antiarrhythmic widely used in the prevention and treatment of various types of cardiac arrhythmias—is not only saturable within the therapeutic range but also altered under various pathophysiological conditions, the interpretation of total DP concentrations, Ctotal, measured during routine therapeutic drug monitoring (TDM) is often complicated. To circumvent this problem, we attempted to establish a comprehensive nomogram that allows estimation of unbound DP concentrations (Cu) based upon Ctotalof the drug and plasma concentration of α1-acid glycoprotein (AAG), a major DP-binding protein. The nomogram was formulated with use of the in vitro binding data retrieved from 103 subjects categorized into 10 different groups each with a different mean concentration of AAG (range: 0.14–1.54 g/L). Data analysis, using a binding model assuming one specific binding site and nonspecific binding(s), revealed that alterations in plasma DP binding are attributable mainly to those in the capacity, Bmax, rather than affinity, ka, constant of the specific binding site. In addition, plasma AAG concentration correlated significantly (r = 0.90, p < 0.001) with the Bmaxvalue over the range 0.09–2.28 g/L. For this reason, we substituted Bmaxcalculated by the regression equation as a function of AAG and the overall mean kaand nonspecific binding parameter values for the respective individual variables of the binding model, so that Cuof each plasma sample was estimated from the corresponding data on Ctotaland plasma AAG levels. Accuracy of the retrospectively established nomogram was evaluated in a prospective manner by comparing Cudata of DP estimated by the nomogram with those actually measured by a conventional ultrafiltration method in 51 plasma samples obtained on separate occasions from 16 different cardiac patients receiving chronic DP therapy. Good agreement (r = 0.91, p < 0.001) existed between Cuvalues obtained from the two different methods. Thus, the proposed nomogram appears to be a useful means to interpret Ctotalof DP under a routine TDM, particularly in patients with pathophysiological factor(s) associated with AAG concentration changes.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We describe in this report an expedient and accurate liquid chromatographic method for measurement of mesna and dimesna in plasma and urine. The separation of mesna and the internal standard (p-aminobenzoic acid, IS) was achieved on a 10-μm, 8 mm (i.d.) × 10-cm C18-Resolve cartridge in conjunction with radial compression system. An aqueous solution of sodium citrate (0.1 M), tetrabutyl ammonium phosphate (0.001 M), and triethylamine (1:10,000, vol/vol), adjusted to pH 5 with 85% phosphoric acid was used at a flow rate of 2 ml/min as a mobile phase. The compounds were detected in the effluent electrochemically at +450 mV. After an appropriate amount of IS was added, the plasma sample (100 μl or fraction thereof) was deproteinized with an equal volume of 0.0825 M sulfuric acid containing sodium hexametaphosphate (1.25% wt/vol), whereas urine was diluted 1:50 with water and mixed 1:1 with an aqueous solution of sodium hexametaphosphate (1.25% wt/vol). Dimesna was reduced back to mesna with sodium borohydride before analysis of the total mesna. The peak height ratio (drug/IS) varied linearly with the concentration, and the correlation coefficient was >0.992 for both mesna and dimesna. The intrarun precision at different concentrations of mesna was equally good and the coefficient of variation was consistently <4.5%. No interference from endogenous substances or any concomitantly used drug was observed. This assay is currently being used for measurement of mesna and dimesna in plasma of bone marrow recipients who receive high doses of cyclophosphamide.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We determined the trough blood and plasma concentrations of tacrolimus from the day of transplantation through 30 days posttransplantation in four liver and four kidney transplant patients by three different methods. The first method involved a solid phase extraction of the blood or plasma using Sep-Pak columns (SPs) followed by quantitation of tacrolimus using an enzyme-linked immunosorbent assay (ELISA); the second method involved a liquid-liquid extraction using methylene chloride (MC) followed by quantitation of tacrolimus using the ELISA, and the third method involved a high-performance liquid chromatography (HPLC) fractionation of the extract obtained from the solid-phase extraction and quantitation of tacrolimus in the fractions by ELISA. The trough plasma tacrolimus concentrations ranged from 0.1 to 5.2 ng/ml. While the trough plasma concentrations of tacrolimus were similar and independent of the method of analysis in kidney transplant patients and in liver transplant patients with normal biochemical profile, in patients with liver dysfunction, tacrolimus plasma concentrations were higher when measured by SP-ELISA and MC-ELISA methods as compared to the HPLC-ELISA method. In plasma samples obtained from liver transplant patients with liver dysfunction, the presence of some metabolites that cross-reacted with the antibody used in the ELISA could be documented in the HPLC fraction corresponding to the metabolites. This indicates that while tacrolimus metabolites that cross-react significantly with the antibody used in the ELISA do not accumulate in kidney transplant patients, they can appear in the plasma of patients with liver dysfunction. The trough blood tacrolimus concentrations in patients were significantly higher than the corresponding plasma concentrations and ranged from 1.4 to 107 ng/ml. The trough blood tacrolimus concentrations were similar and independent of the method of analysis in kidney and liver transplant patients, suggesting unchanged tacrolimus to be the major component in the blood. The HPLC fractions corresponding to the metabolites of tacrolimus did not contain any components that cross-reacted with the antibody used. This study documents that the methods used in this study for the analysis of blood concentrations of tacrolimus appear to be specific for the parent tacrolimus and can be used in future pharmacokinetic and clinical studies.

ISSN:0163-4356    

出版商:OVID    

年代:1995

数据来源: OVID