摘要:

Summary: The postulated therapeutic activity of nortriptyline metabolites has prompted investigation of dosage adjustments based on plasma levels of nortriptyline (NT) and its metabolites. The method assumes that metabolite concentrations vary independently of nortriptyline concentrations among patients. This study tests that assumption and investigates different means of obtaining metabolite concentrations. Forty-two psychiatric inpatients were divided into three maintenance dose groups: 50, 100, and 150 mg NT/day. After a 28-day study for each inpatient, steady-state plasma concentrations for days 14, 18, 21, 25, and 28 were determined. Concentrations were averaged for each patient. Nortriptyline concentrations did not correlate well with corresponding 10-OH(E)nortriptyline (p > 0.05) or 10-OH(Z)nortriptyline concentrations (r2= 0.31, p < 0.05). Concentrations of 10-OH(E)nortriptyline did not correlate well with corresponding 10-OH(Z)nortriptyline concentrations (r2= 0.236, p < 0.05). Neither dose/body weight nor obesity were good predictors of individual concentrations of nortriptyline, 10-OH(E)nortriptyline, or 10-OH(Z)nortriptyline or even the sum of the three. In conclusion, optimal drug therapy may involve dosage adjustments according to the combined plasma levels of nortriptyline and metabolites. Assurance of obtaining certain plasma concentrations requires plasma level monitoring.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: Nine epileptic women were followed prospectively through pregnancy on a monthly basis. At each visit, total and free serum valproic acid levels and albumin levels were obtained. Assays were done by gas-liquid chromatography, and free drug was separated by ultrafiltration. Despite an upward dose adjustment in four patients, total valproic acid levels declined as pregnancy proceeded, but free levels did not. Plasma free fractions and clearances increased, but intrinsic clearances, which were adjusted for changes in body weight, remained unchanged.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: Pharmacokinetic parameters of the distribution and elimination of intracerebroventricularly administered methotrexate (MTX) were evaluated in three patients with meningeal carcinomatosis. Abnormal cerebrospinal fluid (CSF) flow dynamics, which were not otherwise clinically evident, were diagnosed by111In-diethylenetriaminepentaacetate radionuclide imaging. Alterations in CSF flow resulted in large changes in MTX distribution. Reduced cortical convexity (type III), spinal subarachnoid (type II), or ventricular (type I) CSF flow resulted in a prolongation of the single-pass mean residence time of MTX in the peripheral compartment by as much as eightfold and a reduction in intercompartmental clearance by 94–99%. Leptomeningeal carcinomatosis can affect both CSF MTX distribution and elimination, each to a different extent, within the same patient. Total MTX clearance from the CSF was reduced by 79–93% in the patients studied. A two-compartment pharmacokinetic model, with elimination occurring from the peripheral compartment, gave values for the distribution rate constant from the central to the peripheral compartment (k12), which decreased with the extent of CSF flow abnormality. However, the elimination rate constant from the peripheral compartment (k20) was reduced to an extent apparently independent of CSF flow abnormality (percentage reduction ink12andk20, respectively: type III, 18 and 66; type II, 67 and 86; type I, 78 and 48). Inadequate distribution and locally high concentrations of MTX within the CSF may contribute to therapeutic failure and neurotoxicity. Monitoring of MTX levels in the CSF may be deceiving when samples are drawn from the site of injection, since the distribution kinetics are altered by abnormal CSF flow dynamics.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: The method of measurement of cyclosporine concentrations in renal transplant recipients varies between centers and employs either high-performance liquid chromatography (HPLC) or radioimmunoassay (RIA). The merit of using HPLC for identifying the parent compound versus the RIA technique, which also measures certain cross-reactive metabolites that accumulate during renal impairment, is controversial. As a result of the lack of uniformity among centers, an abundance of complex literature that describes the disposition of this potent immunosuppressive agent, as well as a wide range of guidelines for therapeutic monitoring, has evolved. To examine the influence of assay methodology on the repeated determination of cyclosporine in the immediate postoperative period, a time when renal function is often unstable, eight renal transplant recipients were studied after i.v. and oral administration on up to four separate occasions. Whole-blood samples were analyzed by HPLC and RIA. Intravenous kinetic analysis yielded a mean total body clearance of 0.24 \pm 0.2 L/min (RIA) and 0.31 \pm 0.1 L/min (HPLC) (p > 0.05), the mean volume of distribution was 2.17 \pm 0.6 L/kg (RIA) and 2.75 \pm 1.2L/kg (HPLC) (p > 0.05), and a mean half-life was 11.7 \pm 4.4 h (RIA) and 12.8 \pm 3.8 h (HPLC) (p > 0.05). The mean bioavailability was 0.36 \pm 0.23 (RIA) and 0.28 \pm 0.15 (HPLC) (p > 0.05). Regression of the 12-h cyclosporine (RIA versus HPLC) concentration yielded a line described by the following equation: RIA = 72 + 1.6 (HPLC). The mean ratios (RIA/HPLC) of the area under the blood cyclosporine concentration versus the time curve (AUC) were 1.6, 1.5, and 1.7 during the oral study periods and were poorly correlated with the serum cre-atinine level. Overall, the two assay methods provided similar pharmacokinetic parameter estimates. However, correlation between the 12-h cyclosporine level determined by RIA and the AUC by HPLC yielded an overestimation of the 24-h AUC determined by HPLC and indicates that therapeutic monitoring of the parent drug in the immediate postoperative period may best be accomplished by HPLC analysis.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: Trough levels (TL) of cyclosporine (CS) measured in serum by the polyclonal radioimmunoassay (SR) are useful for dissecting the etiology of clinical events, but they are a poor guide to dosage adjustments. In renal transplant patients immunosuppressed by low doses of prednisone and CS given orally, once-a-day TL (24-h) monitoring was replaced by area under the curve (AUC) monitoring, i.e., measuring the area under the concentration (SR)time curve from seven blood samples (0, 2, 4, 6, 10, 14, and 24 h) at clinical steady state, which was reached on the 3rd day after a change in the oral dose rate. The therapeutic target was an average concentration at steady state (Css av) of 200 ng/ml during the first 6 months after transplantation and 150 ng/ml thereafter. TheCss avwas calculated by dividing the AUC by the dosing interval (24 h). Two findings demonstrated the superiority of AUC monitoring over TL monitoring. First, in 71 paired observations AUC but not TL was significantly correlated with the dose expressed as total mg (r= 0.381, p = 0.001) or mg/kg body weight (r = 0.538, p = 0.0001). Second, after adjusting (n = 26) the oral dose rate (to achieve the therapeutic target) the absolute error (i.e., deviation from the target) in the AUC observation (15%) was significantly (p = 0.0005) smaller than in the TL observation (36%). Monitoring AUC at clinical steady state reduced the number of dosage adjustments by a factor of 3.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: Nine patients (3 women), aged 29–78 years, with acute asthma were treated with the antiasthma xanthine, enprofylline, in an open-design study without a reference drug. Enprofylline was administered intravenously (i.v.) over 2 h with an exponentially decreasing concentration. This alternative infusion system was found to be simple to handle. All patients but one reached a therapeutic plasma concentration of enprofylline within 20 min, but with a lower peak plasma concentration as compared to what previously has been found with a conventional i.v. injection of the same amount of drug. The plasma concentration of enprofylline remained on a stable and therapeutic level over the 2-h observation period. The effect on lung function was comparable to that found in other controlled trials with enprofylline. A system for i.v. administration of drugs with an exponentially decreasing concentration as an alternative to manually given i.v. injections should be further evaluated.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: In order to quantify the impact of therapeutic drug monitoring (TDM) services on the average number of serum drug assays (SDAs) ordered for patients, a meta-analysis was conducted on the data collected from 16 published and unpublished studies. Overall, TDM has no effect on the number of SDAs ordered per patient. However, there were a number of moderator variables that influenced the results. In studies utilizing control groups for comparison, TDM service-monitored patients were ordered fewer SDAs than nonmonitored patients. When data from the same institution were collected before and after implementation of a TDM service, there was an increase in the number of SDAs per patient. Aminoglycoside patients monitored by a TDM service were ordered more SDAs and nonaminoglycoside monitored patients were ordered fewer SDAs than nonmonitored patients. When the pharmacy department determined when the SDAs were to be collected and adjusted the dose, monitored patients were ordered fewer SDAs than nonmonitored patients. However, when the pharmacy department did not have control of these parameters, the TDM patients were ordered more SDAs than nonmonitored patients. Methodologic limitations of the studies and their possible effects on the results are discussed.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: Ten healthy male volunteers received two doses of tobramycin (2 mg/kg) in a crossover fashion, first by intravenous piggyback (IVPB), then by the CRIS infusion system after a washout period. Serum samples were drawn both during and after the infusions. Twenty-four-hour urine collections were assayed for tobramycin. Residual fluid from the lines of both delivery systems was measured and assayed for tobramycin concentration. All samples were run in duplicate, using an enzyme-multiplied immunoassay technique assay. The results indicate that there was a statistically higher amount of drug delivered via the CRIS system (98.3 \pm 0.3% versus 90.4 \pm 2.3%). No significant difference was found in urinary recovery between the two groups. Peak serum levels were significantly higher with the CRIS system, with 8/10 subjects having at least one serum level >10 mUg/ml, as compared to 0/10 when given by IVPB. Peak serum levels occurred at 30 min in all subjects given tobramycin through the CRIS system, compared to 50–60 min when delivered by IVPB. This difference in peak serum levels is primarily related to the rate of drug delivery and to the difference in the dose delivered to each subject. The significance of the serum concentration profiles is discussed.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: The application of a two-compartment Bayesian forecasting program for vancomycin was tested retrospectively in 45 adult patients with stable renal function. Serial blood samples from 25 of these patients were used to determine population-based parameter estimates. The predictive performance of the Bayesian program was assessed by using both non-steady-state and steady-state vancomycin concentrations as feedback information. Overall, the program tended to underpredict peak and trough steady-state vancomycin serum concentrations. A larger mean prediction error (ME) was seen when non-steady-state feedback serum concentrations were used compared with using population-based parameter estimates (no feedback). In contrast, a marked improvement in ME (peaks: −1.03 versus −2.61; troughs: −1.60 versus −2.07) was seen when steady-state feedback serum concentrations were used compared with no feedback data. Precision improved when either feedback serum concentrations were used to predict steady-state peak and trough vancomycin concentrations. The results from this clinical evaluation demonstrate that the initial pharmacokinetic parameter estimates for a two-compartment Bayesian model provided accurate prediction of steady-state vancomycin concentrations. Prediction bias and precision were improved when steady-state vancomycin concentrations were used to determine individualized pharmacokinetic parameters.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: The ability of a Bayesian regression program (Warfcalc) to predict warfarin response was evaluated retrospectively in 48 inpatients and prospectively in 10 inpatients. The prothrombin ratio (PR) on the last day of inpatient therapy was predicted using zero (naive) to five sequential, daily PR feedbacks. Bias and precision were measured using mean error (ME) and mean absolute error (MAE), respectively. Root mean squared error (RMSE) was used as a combined measure of bias and precision. In the retrospective group, the use of five PR feedbacks yielded the lowest ME, MAE, and RMSE (0.22, 0.30, and 0.45, respectively). The use of two and three daily PR feedbacks resulted in larger prediction errors compared with the use of naive parameters. Further evaluation of the retrospective patient data indicated that deletion of PR feedbacks associated with an activated partial thromboplastin time >100 s and exclusion of metabolic inhibitors in the estimation of warfarin clearance resulted in more reliable predictions (ME = 0.07, MAE = 0.20, RMSE = 0.28). Similarly, deletion of such PR feedbacks and metabolic inhibitors from the prospective data and use of PRs for the first 5 days of therapy yielded ME, MAE, and RMSE values of 0.07,0.21, and 0.27, respectively. The variance for prothrombin complex activity (PCA) as a function of the variance in the prothrombin time (PT) was investigated using Monte Carlo simulation assuming four different random error models for the PT measurements. These error models yielded functions that exhibit a maximum coefficient of variation at PCA values of 40–70%. Thus, the use of PR feedbacks during the first few days of warfarin therapy may yield unreliable predictions unless they are appropriately weighted.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID