摘要:

The complexity of amiodarone disposition in blood and tissues gives rise to difficulty in determination of optimal therapeutic monitoring strategies. We have defined the within-patient variability of plasma and erythrocyte amiodarone and desethylamiodarone concentrations and electrocardiogram intervals [PR and corrected QTc)] in 27 patients each sampled on three to four occasions during long-term stable amiodarone therapy. All individual repeated measurements were included in the concentration-effect analysis. The mean within-patient coefficients of variation for amiodarone and desethylamiodarone were significantly greater in erythrocytes, 46.0 and 24.5%, respectively, compared with plasma, 12.7 and 12.3%. Amiodarone and desethylamiodarone were strongly correlated (r= 0.89 p < 0.0001) in plasma but only weakly in erythrocytes (r= 0.29 p < 0.004). There was a 10-fold variability in erythrocyte amiodarone for a given plasma level. These data emphasize the highly variable cellular distribution of amiodarone and desethylamiodarone in the same patient on stable dosage over time. Plasma amiodarone was significantly correlated with dosage (r= 0.98), and percent change in QTc, (r= 0.56, p < 0.0001), but there was a fourfold variation in plasma amiodarone for a given QTc.-Side-effect frequency was not related to plasma or erythrocyte amiodarone or desethylamiodarone concentrations. A clinically useful relationship between plasma concentration and effect could not be consistently demonstrated for amiodarone in the same individual during stable dosage.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Urinary excretion of the antiepileptic agent valproic acid (VPA) and major metabolites from its glucuronidation, β-oxidation, and ω- and ω1-hydroxylation pathways were studied under steady state conditions in 24 epileptic patients. Some 55 \pm 18% (SD) of the daily dose was recovered in urine, 33 \pm 14% in the form of VPA-glucuronide, 15 \pm 8% as β-oxidation products, and 4 \pm 2% and 2 \pm 1% as products of the ω- and ω1-hydroxylation pathways, respectively. Only 1 \pm 2% of the dose was excreted unchanged. The proportion metabolized by direct glucuronidation tended to increase with dose at the expense of the oxidative pathways, particularly β-oxidation. However, the wide variation in the patterns of urinary metabolite excretion precludes use of routinely collected urinary excretion data as a basis for detecting any but severe noncompliance with VPA therapy or abnormalities of VPA metabolism.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The relationship between free phenytoin fraction (F-PHT-F) and valproic acid (VPA) was studied under two conditions: (a) in serum samples from 43 institutionalized patients (212 serial data points) at plateau steady state, and (b) in plasma samples from 50 outpatients coming for regular visits to our clinic throughout the day. Results for both groups led to identical linear regression equations relating F-PHT-F to VPA: F-PHT-F = 0.095 + 0.001 (VPA). Nevertheless, as expected, the resulting equation gave an unreliable prediction of F-PHT-F due to a variable physiological matrix. Substituting the parameter F-PHT-F by its equivalent (F-PHT/PHT) gave the equation F-PHT = [0.095 + 0.001 (VPA)] PHT. The predictive power of this equation was evaluated by the comparison of obtained and predicted F-PHT concentrations. For the combined patient group (n = 93), an excellent agreement (r= 0.972 and F = 999.9; p < 0.001) was obtained. Although the empirically derived constants of the equation are not unique and may vary depending on the conditions of different methodologies, the fundamental relationship has been established and can be used to reliably predict F-PHT concentration from plasma VPA and PHT concentrations.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The pharmacokinetics of daunorubicin and doxorubicin were studied in plasma and leukemic cells from 16 patients with acute nonlymphoblastic leukemia during 19 courses of treatment with the unconjugated or DNA-conjugated drugs. Daunorubicin and doxorubicin are high-clearance drugs with very high apparent volumes of distribution, indicating a pronounced tissue affinity. Both clearance and distribution volume decreased when the drugs were administered as DNA-conjugates indicating a reduction in the tissue affinity. This was more pronounced in the case of doxorubicin and may explain the reduced cardiotoxicity of the DNA-complexes. Daunorubicin reached higher intracellular peak concentrations than doxorubicin, but the latter drug was retained much longer. The cell/plasma concentration ratio was higher for daunorubicin than for its reduced metabolite daunorubicinol. No doxorubicinol was found intracellularly. The observed differences in cellular pharmacokinetics between daunorubicin and doxorubicin may explain the difference between the clinical activity spectras of these two drugs. DNA-conjugation did not markedly modify the uptake of daunorubicin in the leukemic cells, whereas the mean intracellular accumulation of doxorubicin was 60% higher when the drug was administered as a DNA-conjugate. This may enhance the selectivity of doxorubicin in the treatment of acute leukemia.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Three methods for estimating maintenance dosage requirements of lithium carbonate were retrospectively evaluated in 20 inpatients who met criteria of the Diagnostic and Statistical Manual, Third Edition, for “bipolar disorder, manic phase.” Dosing methods evaluated included a pharmacokinetic method, the single-point method of Perry et al.; a population-based nomogram approach, the Zetin et al. method; and a physician-based empirical dosing procedure. The ability of each dosing procedure to produce dosing recommendations that resulted in a targeted steady-state serum lithium concentration was evaluated. The empirical dosing procedure demonstrated a significant tendency (bias) to underestimate the dose necessary to produce a desired steady-state serum lithium concentration. Comparison of the predictive accuracy of the various dosing methods failed to demonstrate any statistically significant differences among the dosing procedures. There was a strong trend, however, for the Perry method to produce predictions of steady-state lithium levels that were more frequently within 0.2 mEq/L of actual levels.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Calculated creatinine clearance (CrCL) estimates are frequently used as estimates of aminoglycoside clearance (AGCL), despite being inadequately studied. Thirty surgical intensive care unit (SICU) patients with stable serum creatinines (0.6–6.3 mg/dl) and steady-state aminoglycoside levels were studied. A one-compartment pharmacokinetic infusion model was used to calculatekandVd; AGCL = (k) (Vd). CrCLs using the equations of Cockroft-Gault (CGCL), Jelliffe (JCL), and Jelliffe uncorrected for body surface area (JCLu) were calculated, then compared to the AGCL. The JCLuwas a better fit to the data (y= 0.98x+ 0.44,r= 0.91) with a superior regression correlation (p< 0.02) than CGCL (y= 0.91x+ 6.07,R= 0.89) and JCL (y= 1.11x+ 2.11,R= 0.89) correlations. CGCL overpredicted the AGCL whereas JCL and JCLuunderpredicted the AGCL. All three methods showed a precision of approximately 20 ml/min. Relative bias and precision show JCLubetter than JCL, CGCL better than JCL only for bias, and CGCL and JCLunot different. The absolute percentage error of the CrCL estimates tended to be lower at higher AGCL and did not differ for CGCL, JCL, and JCLu. In the SICU setting, we suggest the use of the JCLufor estimating the AGCL.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Six patients undergoing diagnostic lumbar myelography were studied with respect to plasma and cerebrospinal fluid (CSF) concentrations of two xanthine drugs—enprofylline and theophylline. Three patients received enprofylline and three patients received theophylline, 200 mg t.i.d., and plasma and CSF were sampled on the morning of the third day of treatment. CSF plasma ratios averaged 0.095 with enprofylline (range of 0.094–0.097) and 0.36 with theophylline (range of 0.35–0.37). The different ratios of the two drugs contrast to their similar plasma protein binding, about 50%. Different lipophilicity or differences with regard to transport out of the CSF may explain the discrepancy.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

A high-performance liquid chromatography assay for fluoxetine and its major metabolite, norfluoxetine, was established. Serum concentrations of the two were measured in 13 depressed outpatients following a 6-week trial of the drug. No significant correlations were obvious between clinical improvement as measured by the Hamilton Rating Scale for Depression and the Clinical Global Impression scores and the serum concentrations of fluoxetine and its major metabolite, norfluoxetine, according to these initial pilot data.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

During the past decade, several patient risk factors have been identified as contributing to the development of aminoglycoside nephrotoxicity. Sawyers et al. recently published a method for estimating the probability of aminoglycoside nephrotoxicity on an individual patient basis. The present work represents a refinement of previous publications and has not been tested with the common variations used in aminoglycoside dosing. The purpose of this study was to determine both the qualitative and quantitative value of this method in predicting aminoglycoside induced nephrotoxicity. Eighty-three patients (47 male, 36 female) meeting the inclusion criteria of Sawyers et al. were entered into the study. Patient risk factors (age, sex, initial 1-h postinfusion aminoglycoside serum level, initial calculated creatinine clearance, duration of therapy, and presence of liver disease) were entered into a logistic regression analysis to determine the individual patient's risk of developing nephrotoxicity. These calculated probability scores were then compared with the observed nephrotoxicity in specific groups within our patient sample to see how effectively the model quantitatively performed. Twelve patients (14.5%) developed nephrotoxicity. The model predicted only 5 of the 12 patients developing nephrotoxicity (sensitivity or true positive = 42%). In the nonnephrotoxic group, the model accurately predicted only 38 of 71 patients (specificity or true negative = 54%). These data suggest that the model may accurately quantitate the number of patients likely to develop nephrotoxicity from a specific group but is unable to discriminate specific patients at risk of developing aminoglycoside-induced nephrotoxicity.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The effect of concomitant treatment with omeprazole (20 mg/day) on the plasma concentration and anticoagulation effect of warfarin was studied in 21 young healthy men. An initial three weeks' treatment with warfarin alone was administered to determine the doses required for the subjects' vitamin K-dependent coagulation factors to fall within 10–20% of the normal range, as determined by the Trombotest. Omeprazole and placebo were then administered concomitantly with warfarin for 2 weeks each in a double-blind, randomized, crossover fashion. Plasma concentrations of (R)- and (S)-warfarin, and Trombotest values were measured daily on weekdays throughout the crossover period. Omeprazole had no apparent effect on the mean (S)-warfarin plasma concentration (379 ng/ml with, versus 387 ng/ml without, omeprazole), but caused a slight (12%) although statistically significant increase in the mean (R)-warfarin concentration from 490 to 548 ng/ml (95% confidence interval for difference of means: 28–88). The Trombotest values exhibited large inter- and intrasubject variability during both omeprazole and placebo treatment; however, there was a small, although statistically significant decrease in the mean value from 21.1% without to 18.7% with omeprazole treatment (95% CI for difference of means: −4.6–0.1). Those subjects with Trombotest values nearest the therapeutic range (5–15%) exhibited less change during omeprazole treatment, and no changes occurred that required a change in warfarin dosing. The interaction of omeprazole with warfarin was attributed to a stereoselective inhibition of the hepatic metabolism of the less potent (R)-warfarin enantiomer. The small effect of omeprazole on the anticoagulation activity of warfarin is not likely to be of clinical importance.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID