[Contribution of computer technology to the improvement of drug therapy].
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Bayes Theorem↗
Biomedical subjects
S Vozeh
Publications and source records attributed to S Vozeh.
Circadian changes in the absorption and elimination of theophylline in patients with bronchial obstruction.
Circadian variation in the serum concentration of theophylline has been reported in most patients receiving slow release oral preparations. To examine further the mechanism and clinical relevance of this change, an investigation has been made into the diurnal fluctuation in elimination kinetics during i.v. administration of theophylline and its serum concentration profile on oral treatment with a slow release preparation, in 8 hospitalized patients receiving it for bronchial obstruction. After reaching steady-state on a constant intravenous infusion, the total body clearance of theophylline (CL) was determined every 4-6 h from the steady-state concentration and the infusion rate. No systematic trend indicative of circadian changes in elimination kinetics was observed. The intraindividual fluctuation in CL during the observation period was small (coefficient of variation 4-11%). In contrast, on oral dosing a smaller area under the serum concentration-time curve was found during the night time (22.00-06.00). The results show that the circadian variation described in serum theophylline concentrations is due to delayed absorption at night. The elimination kinetics of theophylline do not change.
Absorption↗
Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine.
The pharmacokinetics and metabolism of quinidine were investigated in extensive and poor metabolisers of sparteine. No differences in plasma clearance, terminal half life, volume of distribution or cumulative urinary excretion of quinidine, 3-hydroxyquinidine and quinidine-N-oxide were observed between phenotypes. Thus, it is unlikely that quinidine metabolism is controlled by the sparteine/debrisoquine gene locus.
Adult↗
Coronary ligation-reperfusion arrhythmia models in anesthetized rats and isolated perfused rat hearts concentration-effect relationships of lidocaine.
A comparative study of two arrhythmia models was carried out using coronary ligation and reperfusion in anesthetized rats and in isolated rat hearts. Both models allowed evaluation of the concentration-effect relationships of lidocaine as an antiarrhythmic agent. The average free plasma-water concentration that reduced the incidence of ventricular fibrillation by 50% was comparable in both models: 1.9 mg/liter in vivo and 2.1 mg/liter in vitro, respectively. In isolated rat hearts significantly higher concentrations were required for 50% reduction of ventricular tachycardia than for the suppression of ventricular fibrillation (2.9 +/- 0.13 versus 2.1 +/- 0.11 mg/liter, p less than 0.05). The good agreement between effective lidocaine concentrations in vivo and in vitro suggests that the isolated rat heart preparation is suitable for the quantitative assessment of drug effects on occlusion-reperfusion arrhythmias. A better reproducibility and easier control of drug concentrations are the advantages of the in vitro model.
Anesthesia↗
Evaluation of a rapid ultrafiltration technique for determination of quinidine protein binding and comparison with equilibrium dialysis.
The free level ultrafiltration (UF) assay by the enzyme multiplied immunoassay technique (EMIT) for determination of unbound quinidine concentration in serum (Qf) was evaluated in 50 samples obtained from cardiac patients treated with quinidine for ventricular arrhythmias. Equilibrium dialysis (ED) at 37 degrees C and high performance liquid chromatography (HPLC) served as standard methods for comparison. A good agreement was found between EMIT and HPLC at the low range of free quinidine concentration (0.1-0.7 mg/L) observed in our patients (r = 0.959). Although the correlation between UF and ED was high (r = 0.972), Qf was systematically underestimated by UF. This bias was due to the fact that UF was performed according to the recommendations of the manufacturer at 25 degrees C. No systematic differences were found when 20 additional samples were assayed by the two methods at the same temperature (25 degrees C; r = 0.992). The quinidine binding ratio showed a correlation with the serum concentration of alpha 1-acid-glycoprotein (r = 0.61). The metabolites 3(S)-hydroxyquinidine and quinidine-N-oxide did not influence the protein binding of the parent drug. The importance of adjusting the serum pH to physiological values before measurement of Qf was confirmed in this study. Our results show that, if performed under the same conditions, ED and UF yield practically identical values. Because of easy handling, the EMIT Free Level System II should be applicable under clinical conditions.
Chromatography, High Pressure Liquid↗
Computer-assisted infusions of drugs.
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Computers↗
Performance of Bayesian feedback to forecast lidocaine serum concentration: evaluation of the prediction error and the prediction interval.
The prediction performance of the Bayesian feedback method was evaluated with respect to accuracy and precision, and efficacy and safety (width of the prediction interval) on the basis of 90 predictions in 30 patients treated with lidocaine. The mean of the prediction error (PE) and the root mean squared error (RMSE) served as a measure of accuracy and precision. The variance of the standardized prediction error (SPE) was used to evaluate the estimate of the standard deviation of the prediction error. SPE was defined as PE divided by the standard deviation of the predicted concentration. The standard error of RMSE and of the variance of SPE was determined by bootstrap. The results indicate that the lidocaine serum concentration at 12 hr (C2) after starting continuous infusion can be predicted with high accuracy and precision with a single feedback measurement obtained 2-4 hr (C1) after commencement of treatment: RMSE = 20.6%. Prediction at 24 hr (C3) was less accurate: RMSE = 31.4%. Using both C1 and C2 to predict C3 improved precision (RMSE = 23.4%). The evaluation of the prediction interval revealed that the current algorithm produces an upward biased estimate, probably due to a positive bias in the estimate of the covariance matrix of the parameter estimates. It is suggested that evaluation of prediction performance should include the estimate of the prediction interval.
Bayes Theorem↗
Kinetics and electrocardiographic changes after oral 3-OH-quinidine in healthy subjects.
3-OH-quinidine, a major quinidine metabolite, has been reported to have antiarrhythmic activity in animals and is suspected to contribute to the effect of quinidine in man. Four healthy subjects received 3-OH-quinidine in increasing oral doses (35, 100, 300 mg) to achieve serum concentrations in the range of those after quinidine dosing in patients. Blood and urine were collected up to 48 hours and blood pressure, heart rate, and averaged ECG complexes were recorded during 12 hours after dosing. Kinetic analysis revealed differences from published data for the parent drug. Renal clearance was 16 L/hr. The elimination t1/2 was 12.4 hours, substantially longer than that of quinidine. No systematic ECG changes were observed in two subjects with maximum concentrations of 55 and 215 micrograms/L. In the other two subjects who achieved higher maximum concentrations (447 and 918 micrograms/L), there was a significant relationship between the length of the corrected QT interval and the serum concentration of 3-OH-quinidine. These first dynamic results indicate that 3-OH-quinidine exerts effects in man resembling those of quinidine and may contribute to the antiarrhythmic activity of quinidine.
Absorption↗
Computer-assisted drug assay interpretation based on Bayesian estimation of individual pharmacokinetics: application to lidocaine.
A microcomputer program for individualized drug level prediction based on Bayesian forecasting is presented. It is written so that the clinician can integrate patient demographics and drug levels to design a new dosage regimen tailored to an individual patient. The program's great flexibility and robustness make it appropriate for realistic clinical settings. A validation with a data set of lidocaine concentrations measured in 18 patients revealed that the program can predict serum lidocaine levels accurately enough to enhance individual patient dosage adjustment within a few hours after a dosage regimen is started.
Bayes Theorem↗
Influence of chronic dosing on theophylline clearance.
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Half-Life↗
[Drug level determination for optimization of drug therapy. Practical significance and new trends].
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Drug Therapy↗
Influence of thyroid function on theophylline kinetics.
Theophylline kinetics were examined in five patients with hyperthyroidism before and after treatment with carbimazole. Theophylline clearance fell after carbimazole, but the apparent volume of distribution did not change. There was a correlation between reduction in theophylline clearance and decreased thyroxine serum concentration. Data suggest that maximum induction is reached at a specific level of thyroxine beyond which no further increase in drug metabolizing activity takes place. In 15 subjects treated with aminophylline for acute bronchial obstruction, there was a positive correlation between thyroxine concentration and total body theophylline clearance (r = 0.72 for nonsmokers; r = 0.44 for smokers and nonsmokers).
Adult↗
Experience with NONMEM: analysis of serum concentration data in patients treated with mexiletine and lidocaine.
The generality and flexibility of the computer package NONMEM also confront the user with the difficult task of choosing the model which best describes the data at hand. With two practical examples we show how one may proceed in building the population model for serum concentration measurements. Features of NONMEM are presented which help the user to make the choice among different models.
Computers↗
Intravenous cyclosporine kinetics in renal failure.
Kinetics of the novel immunosuppressive cyclosporine were determined in four patients with terminal renal failure. After a short intravenous infusion (2.05 to 3.5 mg/kg in 4 hr), blood and plasma concentrations were measured (HPLC and radioimmunoassay [RIA] up to 36 hr. After infusion, concentration curves of the drug were characterized by a rapid initial fall (t 1/2 alpha 0.10 +/- 0.03 hr), followed by a biphasic elimination phase with corresponding t 1/2s of 1.08 +/- 0.25 hr (t 1/2 beta) and 15.8 +/- 8.4 hr (t 1/2 gamma). The volumes of distribution, calculated from whole blood concentrations (HPLC), were 0.140 +/- 0.48 l/kg (volume of the central compartment) and 3.49 +/- 2.65 l/kg (volume of distribution at steady state), whereas systemic clearances were 0.369 +/- 0.08 l/hr/kg. Blood levels measured by RIA exceeded the HPLC values after the fourth hour by up to 100%, indicating the production of cross-reacting cyclosporine metabolites. Plasma concentrations were considerably lower than in whole blood. Elimination of unchanged cyclosporine in patients with renal failure appears to be of the same order as in those with normal kidney function. Modification of the initial dosage regimens is therefore probably not required.
Chromatography, High Pressure Liquid↗
[Slower lidocaine elimination and dose adjustment in patients with heart failure].
In 21 patients with acute coronary artery disease the influence of cardiac failure on the elimination of lidocaine (L) was evaluated by repeated serum level measurements during and after a therapeutic L-infusion. Lidocaine clearance (Cl) was less than 8 ml/min/kg in 9 of 13 cases with congestive heart failure (CHF), while in 7 out of 8 patients without CHF Cl-values were 8-12 ml/min/kg. Due to wide interindividual variability in the CHF group, however, mean values were not significantly different: 7.3 +/- 2.9 vs. 9.52 +/- 1.54 ml/min/kg (p greater than 0.05). In 3 patients receiving a simultaneous nitroglycerine infusion Cl was greater than 10 ml/min/kg despite clinical signs of CHF. The t 1/2 of L was significantly prolonged in patients with CHF: 4.29 +/- 2.14 vs. 2.43 +/- 0.58 h (p less than 0.05). It was not possible to determine individual L-dose requirements by bedside clinical examination alone. Serum level monitoring is therefore recommended in order to optimize L-therapy in patients with life-threatening arrhythmias, severe congestive heart failure and hypotension.
Arrhythmias, Cardiac↗
Population pharmacokinetic parameters in patients treated with oral mexiletine.
A new data analysis approach, NON-MEM, proposed by Sheiner and Beal, has been employed to estimate the population pharmacokinetic parameters of oral mexiletine in patients treated for arrhythmias. 452 serum concentration measurements in 58 patients were available for analysis. 27 patients had congestive heart failure and 8 had abnormal liver function tests at the time of the study. The population averages of the pharmacokinetic parameters and their interindividual variability were: oral total body clearance (Cl) 0.38 l/h/kg +/- 43% (C.V.), apparent volume of distribution (Vd) 5.3 l/kg +/- 40%, absorption rate constant 3.1 h-1 +/- 205%, absorption time-lag 0.3 h. Congestive heart failure and sex did not show a significant effect on Cl and Vd; the number of patients with severe liver function impairment was too small for a definite conclusion. Normalizing Cl and Vd for body weight significantly decreased their interindividual variability. Based on these results, a dosage regimen is recommended which is expected to produce a "therapeutic" serum concentration (0.8-2 mg/l) in over 60% of patients. Because of its unique features, which allow estimation of pharmacokinetic parameters and their variability from fragmentary patient data, the NONMEM system has great potential applicability to clinical pharmacokinetic studies.
Aged↗
Theophylline serum concentration and therapeutic effect in severe acute bronchial obstruction: the optimal use of intravenously administered aminophylline.
In 20 patients with acute exacerbation of bronchial obstruction, the therapeutic effect of high (20 mg/L) and low (10 mg/L) serum concentrations of theophylline was compared in a double-blind randomized study. The theophylline dose, administered as a continuous aminophylline infusion, was individually adjusted by means of repeated measurements of serum concentrations. At 28 h after starting therapy the high concentration group showed a significantly greater improvement in pulmonary function as assessed by FEV1 (0.57 +/- 0.52 L (mean +/- SD) versus 0.1 +/- 0.18 L, p less than 0.01) and FVC (1.0 +/- 0.65 L versus 0.01 +/- 0.66 L, p less than 0.02). As a measure of the overall clinical improvement, the time during which intravenous therapy was required was also shorter in the high-dose group (61.7 +/- 25.8 h (mean +/- SD) versus 116 +/- 49.7 h, p less than 0.02). The occurrence of side effects in the two groups was not significantly different. In patients with severe acute bronchial obstruction, serum theophylline concentrations around 20 mg/L seemed to offer a definite therapeutic advantage, thus, routine serum concentration measurements and the use of accurate infusion devices for optimal dose adjustment may be justified.
Adult↗
[Relation of dose, serum concentration and side effects in intravenous aminophylline therapy].
Routine intravenous aminophylline therapy was monitored by drug level measurements in 45 hospitalized patients with chronic obstructive bronchitis. Only 44% had theophylline serum concentrations (Cp) in the optimum range (10-20 mg/l), while in 36% of patients potentially toxic Cp values were observed. The incidence of side effects was related to theophylline serum concentration: 78% in cases with Cp greater than 30 mg/l against 24% in cases with Cp less than 20 mg/l. Theophylline toxicity occurred most frequently in elderly patients with cardiac failure, who had markedly reduced theophylline clearances. To avoid excessive drug accumulation the usual aminophylline dose should be reduced by 50% when clinical signs of cardiac failure are present. In addition, measurement of theophylline serum concentration is often necessary for optimum dosage adjustment.
Adolescent↗