Bayesian derived predictions for twice daily theophylline under outpatient conditions and an assessment of optimal sampling times.

1. The accuracy of a computerised method of pharmacokinetic interpretation of a single serum theophylline concentration, employing the statistical technique of Bayesian analysis, has been evaluated for an oral slow release form of theophylline using twice daily dosing. 2. Twenty-four hour steady state serum theophylline concentration-time profiles of one Uniphyllin Continus 400 mg tablet (Napp Laboratories) every 12 h were measured in 15 patients. These profiles demonstrated a diurnal variation of theophylline absorption which was faster during the day. 3. Revised predictions of the profiles were generated by Bayesian analysis using a single serum theophylline concentration taken during a previous outpatient appointment. Comparing the predicted and measured profiles, the accuracy of the Bayesian method is considered more than adequate for clinical purposes. 4. The predictions produced by the revised estimates were statistically less biased and more precise than those derived by a theophylline algorithm using population data. 5. The mean prediction errors of the revised estimates of the day and night-peak drug concentrations were -0.55 mg l-1 and -0.21 mg l-1 whilst those of the evening and morning troughs were 1.17 mg l-1 and 0.41 mg l-1, respectively. 6. Analysis of the predictive and relative performance of the samples drawn during the profile revealed that the sample taken prior to a morning dose produced the most accurate predictions. 7. There was no statistical difference in the relative predictive performance of samples drawn up to 4 h before or 2 h after the morning dose. It is, therefore, recommended that all serum theophylline concentrations to be used in Bayesian analysis, should be drawn within this period.

Dose response relation to oral theophylline in severe chronic obstructive airways disease.

OBJECTIVE: To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline. DESIGN: Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data. This was followed by random assignment to four consecutive two month treatment periods--placebo and low, medium, and high dose, as assessed by serum concentrations of theophylline. Respiratory function and exercise performance was assessed at the end of each two month period. SETTING: Chest unit in district hospital. PATIENTS: Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited; 33 aged 53-73 years completed the study. INTERVENTIONS: Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted, when 400 mg was given. Targets for the steady state serum theophylline concentrations were 5-10 mg/l in the low dose period, 10-15 mg/l in the medium dose, and 15-20 mg/l in the high dose period. ENDPOINTS: Respiratory function as measured by forced expiratory volume in one second, forced vital capacity, peak expiratory flow rate, slow vital capacity, and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived. Exercise performance assessed by six minute walking test and diary cards using visual analogue scale. MEASUREMENTS AND MAIN RESULTS: The forced expiratory volume in one second, forced vital capacity, and peak expiratory flow rate changed only slightly (about 13%) over the range of doses. There was a linear dose dependent fall of trapped gas volume from 1.84 l (SE 0.157) to 1.42 l (0.152), 1.05 l (0.128), and 0.67 l (0.102) during the placebo and low, medium, and high dose treatment periods. Mean walking distance increased by up to 55.6 m (20%). There was a modest improvement in dyspnoea as the dose of theophylline was increased. Side effects were mostly minor but they became more frequent as the dose was increased. CONCLUSION: The fall in trapped gas volume may reflect an improvement in peripheral ventilation (associated with treatment with theophylline) which is less apparent in the more common tests of lung function used in patients with chronic obstructive airways disease.

Effect of dispersion on the coloring properties of aluminum dye lakes.

The effect of particle size on the coloring properties of aluminum dye lakes was studied. Lakes impart color by dispersion in the medium to be colored. Dispersion techniques were developed, using scanning electron micrographs for particle sizing. The color strength and the trichromatic colorimetric properties were calculated from reflectance values measured from "drawdown" films. The results clearly show that the coloring properties of lakes are related to the surface of lake that is wetted by the medium, and resemble results obtained in paint systems. The submicron particles are especially important, contributing greatly to the color strength. The results also agree with theoretical predictions based on certain assumptions for the refractive index of the lakes. The utility of the CIE 1976 L*a*b* color space is demonstrated by quantifying changes in hue, chroma, lightness, and total color difference with different dispersion levels.

The accuracy and stability of Bayesian theophylline predictions.

Pharmacokinetic parameters for theophylline were determined in 33 patients (3 women), mean age 61.2 years and weight 74.6 kg using the following three methods: (a) standard one-compartmental model calculations, assuming 100% bioavailability, after a single dose of theophylline syrup (mean dose 413 mg); (b) drug nomogram; and (c) Bayesian analysis. Patients entered a randomised study of three two-monthly dosage regimens using low, medium, and high theophylline twice daily doses. These doses produced mean (+/- SE) steady-state serum theophylline concentrations of 6.3 (+/- 0.4), 12.1 (+/- 0.3) and 18.3 (+/- 0.5) mg/L, respectively. A fourth period of placebo (2-month duration) was also included. At the end of each treatment period the measured serum theophylline concentration of each patient was compared with those predicted by each of the above three methods. The revised estimates derived from Bayesian analysis produced the least biased [mean prediction error (ME)] and most precise (mean squared prediction error) predictions for all three dosage periods. Statistical analysis of relative performance demonstrated that the difference in precision between the revised estimates and those of the other two methods was significant (p less than 0.05) with the magnitude of the difference increasing with dose. The revised estimates were also found to be less biased (p less than 0.05) than those of the nomogram. The ME (+/- SE) of the revised estimates for the low, medium, and high dosage periods was 0.34 (+/- 0.30), -0.02 (+/- 0.22) and -0.48 (+/- 0.31) mg/L, respectively.

Comparison of the effectiveness of midazolam and diazepam in lipid emulsion as sedation during upper gastrointestinal endoscopy.

In a study of 101 patients undergoing upper gastrointestinal endoscopy, 90% of patients had complete amnesia for the procedure after intravenous midazolam (average dose 10 mg), but only 61% had complete amnesia after intravenous diazepam in lipid emulsion (average dose 18.4 mg) (P = 0.0006). However, when assessed by two different tests, recovery within the first hour was significantly more rapid after diazepam (P less than 0.0001). Prolonged sedation (over 20 hours after injection) was reported occasionally by patients who had received either drug. Thus, as with patients who have been sedated with diazepam, those who have been sedated with midazolam should also be advised to avoid driving or operating machinery for at least 24 hours after injection.

The accuracy of a pharmacokinetic theophylline predictor using once daily dosing.

1. The accuracy of a computer based pharmacokinetic prediction method based on Bayesian analysis has been evaluated for an oral show release form of theophylline. 2. In 83 patients from seven centres 24 h serum theophylline concentration-time profiles were measured under a variety of circumstances. 3. Revised predictions of 24 h serum theophylline concentration profiles were generated by Bayesian analysis using single serum drug concentrations taken before, during and after the study days in different subgroups of those patients. Comparing the predicted and measured profiles the mean prediction error (bias) was 0.05 mg l-1 for peak concentrations and 0.04 mg l-1 for trough concentrations during once daily dosing. The corresponding root mean squared prediction errors (precision) were 2.59 and 1.17 mg l-1, respectively. 4. This accuracy is considered more than adequate for clinical purposes. 5. The technique can be used with a variety of other drugs and can form a valuable part of a routine therapeutic drug monitoring service.

Microstructure of aluminum hydroxides and the formation of aluminum dye lakes.

The effect of processing variables on the type of aluminum hydroxide and the dye content of the resultant lakes were investigated. The solid-state structure of aluminum lakes in conjunction with the associated aluminum hydroxide was studied by electron microscopy, X-ray diffraction, and IR spectroscopy. The conditions under which the aluminum hydroxide was prepared were shown to govern the amorphous/crystalline character of the product, which was reflected in changes in particle size and surface area. A hypothesis for the interaction of the dye and aluminum hydroxide is formulated in which the amount of dye adsorbed on the aluminum hydroxide is dependent on the surface area of the microstructures present.

Plasma xanthine levels in premature infants treated for apnoea with theophylline.

Evidence is presented that oral theophylline doses of 3 mg per kg per 24 h in premature babies produces plasma levels of theophylline and caffeine of about 5 and 1-2 mg/l respectively in most subjects.

Plasma concentrations and clinical effects of lorazepam after oral administration.

The relation between plasma concentrations and properties of lorazepam administered orally as premedication was studied in patients undergoing minor surgery. The drug was found to be reliably absorbed in most subjects producing plasma concentrations similar to those reported after injection. Effective concentrations were obtained within 30-60 min, maintained for 4-6 h and were closely related to the action of the drug on memory and its sedative and anxiolytic properties. Its kinetics were described in about half of the subjects by a one-compartment model, but in others two compartments were required. Variable half-lives were found (range 9.3-32.1 h, mean about 20 h). Sufficient drug remains after 24 h to suggest that residual c.n.s. effects may still be present.

Pharmacokinetics of chlorthalidone. Dependence of biological half life on blood carbonic anhydrase levels.

The relationship between the whole blood concentration of carbonic anhydrase and the biological half life of chlorthalidone has been investigated in six volunteers. A linear relationship was observed and on the basis of this, a pharmacokinetic model to explain the long and variable biological half life of chlorthalidone is proposed and discussed.

Placental transfer of chlorthalidone and its elimination in maternal milk.

A gas chromatographic method has been used to determine chlorthalidone in amniotic fluid, maternal and foetal blood at delivery, and in maternal milk and blood three days after delivery, following the administration of chlorthalidone to nine pregnant women suffering from toxaemia of pregnancy. Placental transfer of chlorthalidone and elimination in maternal milk have been shown and the implications of these factors are discussed. An explanation has been proposed for our observations that foetal blood levels of the drug are about 15% of those in maternal blood.

Formation of liquid crystal and other non-fluid phases in emulsions containing non-ionic surfactants.

The relation between the phase distribution of components and the nature and properties of dispersions formed in a four-component system containing dodecane, water and two homogeneous non-ionic surfactants has been investigated by phase-rule techniques. Phase equilibrium diagrams for the four ternary systems were investigated and the phase boundaries for the various regions formed in these systems were defined by synthetic and analytical methods. In some of the ternary diagrams a narrow three-phase region occurs where 'gel' or liquid crystal as well as two isotropic liquid phases are present. Dispersions containing the gel phase were very stable. The four-component system has not been fully investigated due to the presence of extensive liquid crystal phases and three-phase regions. However, some distribution data for the quaternary system was obtained. In the presence of sufficient amounts of the short chain non-ionic surfactant C10H21(O.CH2.CH2)3OH, a three-liquid phase region occurs where multiple drops readily form.