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Biomedical subjects

H Chrystyn

Publications and source records attributed to H Chrystyn.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pharmacokinetics of ifosfamide and its enantiomers following a single 1 h intravenous infusion of the racemate in patients with small cell lung carcinoma.

Ifosfamide is a chiral pro-drug which is administered clinically in its racemic form. Serum concentrations of rac-ifosfamide and its enantiomers were measured in 12 patients with lung carcinoma following a mean (+/- s.d.) intravenous dose of 4.2 (0.83) g infused over 1 h. The mean (+/- s.d.) volumes of distribution (VSS) of rac, (R)- and (S)-ifosfamide were 0.61 (0.17), 0.60 (0.16) and 0.61 (0.19) l kg-1, respectively. The mean (+/- s.d.) half-lives and clearances were 6.57 (1.69), 7.12 (1.92) and 5.98 (1.52) h and 0.065 (0.013), 0.060 (0.013) and 0.072 (0.014) l h-1 kg-1 for rac, (R)- and (S)-ifosfamide, respectively. The half-life of (S)-ifosfamide was significantly (P < 0.001) shorter than that of (R)-ifosfamide and it had a significantly higher clearance (P < 0.001). There was no significant difference in the volumes of distribution of the enantiomers. The clinical significance of the faster elimination of (S)-ifosfamide is not known.

Aged↗
PubMed1995

Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary albuterol (salbutamol) assay technique.

Metered-dose inhalers (MDIs) are extensively used to deliver drugs to the lungs but are driven by chlorofluorocarbon (CFC) propellants. The worldwide phasing out of CFCs within the next 5 to 10 years presents difficulties to the pharmaceutical industry. The mean +/- SD relative lung bioavailability of albuterol to the lung following inhalation of 400 micrograms of albuterol from an MDI, the Rotahaler and Diskhaler in 10 well-trained volunteers, was 2.83 (0.78), 1.72 (0.99), and 2.64 (1.23)%, respectively, expressed as a percentage of the nominal dose. The delivery of albuterol to the lungs from the MDI and Diskhaler was similar. In nine asthmatic subjects, the relative lung bioavailability of albuterol following inhalation with the MDI and Diskhaler was 1.19 (0.79) and 2.38 (1.46)%, respectively, expressed as a percentage of the nominal dose. There was no difference in reversibility 30 min after administration of the dose by the two methods. Similar lung deposition from the Diskhaler in volunteers probably is due to efficient MDI technique, which was absent in the asthmatic subjects. The Diskhaler does not rely on coordination during inhalation and therefore is easier to use.

Adult↗
PubMed1994

Enantiomeric separation of R- and S-ifosfamide and their determination in serum from clinical subjects.

A method to measure racemic, R- and S-ifosfamide concentrations from the serum of patients receiving ifosfamide chemotherapy has been developed. The racemic ifosfamide concentrations are quantified on a separate system and then the ratio of the enantiomers is determined using an achiral-chiral coupled system. Racemic ifosfamide is separated on the achiral system using a C1 spherisorb stationary phase and the eluent containing analyte is selectively transferred to the chiral system for separation of the two enantiomers by an alpha 1 glycoprotein column. On both systems the mobile phase is 1% acetonitrite in 0.015 M phosphate buffer (pH 4) at a flow-rate of 1 ml/min. The retention times of S- and R-ifosfamide were 11.6 and 13.0 mins, respectively, with a resolution factor of 1.53. Serum concentrations at least three to four half-lives post-infusion were detected by this method. In ten patients, following a mean +/- S.D. 1-h infusion of 3.9 +/- 0.32 g racemic ifosfamide, the mean +/- S.D. clearances of R- and S-ifosfamide were 0.061 +/- 0.013 and 0.072 +/- 0.014 1 h-1 kg-1.

Aged↗
PubMed1994

Ifosfamide enantiomers: pharmacokinetics in children.

Ifosfamide, like other oxazaphosphorine drugs, is chiral and there is some evidence, mainly from animal studies, of stereo-selective differences in metabolism, excretion and cytotoxic activity between the two enantiomers. The pharmacokinetics of racemic ifosfamide (RAC-IFO), R-ifosfamide (R-IFO) and S-ifosfamide (S-IFO) were studied in five children who received intravenous therapy with racemic ifosfamide on 3 consecutive days. The clearance of S-IFO was greater than that of R-IFO. The clearance value at the end of the infusion was faster than the respective rate measured at the beginning of or during the ifosfamide regimens in four children and, therefore, suggests autoinduction of elimination of both enantiomers.

Adolescent↗
PubMed1994

Volumatic usage: some generic salbutamol metered dose inhalers can be used.

BACKGROUND: The 30 minute and 24 hour post-inhalation urinary excretion of salbutamol represents the relative amount of drug deposited in the lungs and total systemic absorption, respectively. Using this method two metered dose inhalers used with a Volumatic (Allen and Hanburys Ltd, UK) large volume spacer have been compared. METHOD: Eleven healthy volunteers inhaled 4 x 100 micrograms salbutamol from either a generic salbutamol (Baker Norton, UK) or Ventolin (Allen and Hanburys Ltd, UK) metered dose inhaler with a Volumatic. The order of administration was randomised with a seven day washout period. Urine samples were collected for 0-30 minutes and then pooled up to 24 hours after inhalation. RESULTS: The mean (SD) urinary salbutamol excretion 30 minutes after inhalation with the metered dose inhalers used with the Volumatic was 22.22 (4.63) and 21.30 (5.91) micrograms for the Baker Norton and Ventolin respectively, with a mean difference (95% confidence interval (CI)) of 0.92 (-0.65 to 2.49) micrograms. Similar amounts were excreted up to 24 hours after the dose with a mean (SD) urinary excretion of 116.1 (24.3) micrograms and 114.8 (22.3) micrograms, respectively, and a mean difference (95% CI) of 1.22 (-20.39 to 22.84) micrograms. CONCLUSION: Inhalations from generic salbutamol (Baker Norton) and Ventolin metered dose inhalers with a Volumatic inhalation aid deliver similar amounts of drug to the lungs and the total systemic absorption from the two products is the same.

Administration, Inhalation↗
PubMed1994

Relative bioavailability of salbutamol to the lung following inhalation using metered dose inhalation methods and spacer devices.

BACKGROUND: Inhalation aids do not require coordination between actuation of a metered dose inhaler (MDI) with inspiration and reduce oropharyngeal impaction. The delivery of salbutamol to the lung and systemic availability following inhalation with three commonly used spacers and an open mouth technique have been evaluated using a simple noninvasive technique based on urinary excretion 30 minutes and 24 hours after the dose. METHODS: Ten healthy subjects inhaled, on randomised study days, 4 x 100 micrograms from a Ventolin MDI and, subsequently, with the aid of a Volumatic, Bricanyl Spacer, and Nebuhaler spacer device. In addition, an open mouth inhaler technique was evaluated. Urine samples were collected 0-30 minutes and 0.5-24 hours after inhalation. From these samples the relative bioavailability to the lung (urinary salbutamol excretion 30 minutes after dosing) and the systemic bioavailability of the dose (24 hour urinary excretion of salbutamol and its metabolite) for each inhalation method was obtained. RESULTS: The mean (SD) urinary excretion of salbutamol 30 minutes after inhalation using the MDI alone and with the Volumatic, Bricanyl Spacer, Nebuhaler, and open mouth technique was 2.83 (0.78)%, 3.37 (0.69)%, 4.09 (0.91)%, 4.34 (1.60)%, and 3.49 (0.98)%, respectively, expressed as a percentage of the nominal dose. The nebuhaler and Bricanyl Spacer spacer devices were found to increase the relative bioavailability of salbutamol to the lung compared with the MDI alone. Compared with the MDI the inhalation aid increases were much greater than the intra-individual variability of the urinary excretion method. In 11 individuals who each repeated the same inhalation procedure on four separate occasions, the mean (SD) coefficient of variation was 8.24 (2.36)%. The mean (SD) 24 hour urinary excretion of salbutamol and its metabolites was 26.6 (6.79), 27.0 (7.95), and 55.6 (9.74)% of the salbutamol dose for the Volumatic, Nebuhaler, and MDI, respectively. Similar values following the open mouth method and Bricanyl Spacer were 48.9 (10.97)% and 43.8 (11.57)%. These values, representing the systemic availability of the inhaled dose, were lower when inhaling with the aid of the Volumatic and Nebuhaler than inhalation from the MDI alone. CONCLUSIONS: Spacer devices improve pulmonary bioavailability of salbutamol and reduce the systemically available dose.

Administration, Inhalation↗
PubMed1993

Investigations of an optimal inhaler technique with the use of urinary salbutamol excretion as a measure of relative bioavailability to the lung.

BACKGROUND: A simple non-invasive method, in which a urine sample is taken 30 minutes after drug administration, has previously been shown to be a measure of the relative bioavailability of salbutamol to the lungs. This technique has been used to determine an optimal inhaler technique with commercially available metered dose inhalers (MDI). METHODS: Ten healthy subjects were trained in the use of MDIs. Each inhaled 4 x 100 micrograms salbutamol in a series of experiments to examine the relative bioavailability to the lung after different respiratory manoeuvres. Urine collection intervals were 0-0.5 hours and 0.5-24 hours after administration. RESULTS: There was significantly greater elimination of unchanged salbutamol 30 minutes after administration, indicating a greater relative bioavailability of salbutamol to the lungs after (1) exhaling gently to residual volume rather than to functional residual capacity before inhalation; (2) slow inhalation (10 l/min) compared with fast inhalation (50 l/min); (3) breath holding for 10 seconds after inhalation compared with no breath holding. CONCLUSIONS: All patient information leaflets and healthcare personnel should standardise the instructions given to patients and should adopt the inhalation method proposed.

Administration, Inhalation↗
PubMed1992

Measurement of the (R)- and (S)-isomers of warfarin in patients undergoing anticoagulant therapy.

An achiral/chiral high-performance liquid chromatographic system for the analysis of total warfarin together with the (R)- and (S)-enantiomers in clinical samples has been developed. The achiral analysis is achieved using a C8 column, which is coupled to a chiral stationary phase, alpha 1-acid glycoprotein (AGP), thereby allowing for analysis of warfarin isomers without interfering serum peaks. A 0.015 M phosphate buffer mobile phase with 15% v/v propan-2-ol (pH 7.0) was used on the C8/AGP system. UV analysis at 308 nm was used for quantitation of total warfarin on the C8 column and fluorescence (excitation 300 nm, emission 390 nm) detection was employed for isomer quantitation on the AGP. Retention time of total warfarin on the C8 column was 5.95 min, while that of the (S)- and (R)-warfarin on the AGP column was 10.38 and 12.69 min, respectively. Peak resolution of the warfarin isomers was 1.64. All serum samples were subjected to solid-phase extraction. Data from two patients in a single dose study indicate that a two-compartmental model could represent the warfarin concentration-time data with enterohepatic circulation. In some patients studied during steady state therapy, concentrations of (S)-warfarin were greater than (R)-warfarin indicating that the clearance of the former is slower in these patients.

Chromatography, High Pressure Liquid↗
PubMed1992

Determination of the relative bioavailability of salbutamol to the lung following inhalation.

1. The urinary excretion of salbutamol and its sulphate metabolite was measured following oral (4 mg) and inhaled (4 x 100 micrograms) administration of salbutamol. 2. Total urinary recovery of salbutamol and its sulphate conjugate indicated a mean (s.d.) relative bioavailability of 92.2 (24.8) % following inhalation compared with oral administration. 3. The mean (s.d.) elimination half-lives of salbutamol and its sulphate conjugate were 5.7 (1.4) and 4.1 (2.1) h, respectively, after oral administration and following inhalation they were 6.1 (2.1) and 5.1 (1.0) h, respectively. 4. Following oral and inhaled administration it was found that in the first 30 min the mean (s.d.) percentage of the dose excreted in the urine as unchanged salbutamol was 0.18 (0.14) and 2.06 (0.80) %, respectively (P < 0.01). The drug content of a urine sample taken 30 min after inhalation is, therefore, considered to be representative of the amount of drug delivered to the lungs. It is proposed that this method can be used to evaluate the relative bioavailability of salbutamol to the lung following inhalation by different techniques and devices.

Administration, Inhalation↗
PubMed1991

Improved bioavailability from a spironolactone beta-cyclodextrin complex.

The relative bioavailabilty of spironolactone from a complex with beta-cyclodextrin has been evaluated. Capsules containing 100 mg micronised spironolactone powder were compared with 100 mg spironolactone beta-cyclodextrin complex in 8 healthy volunteers by a single dose, double blind, crossover pharmacokinetic study. Subjects were randomly allocated to each preparation and crossed over after 2 weeks. Relative bioavailability was assessed by the measurement of serum canrenone concentrations. The mean relative bioavailability of the spironolactone cyclodextrin complex, compared to the micronised spironolactone powder, was 233%. Statistical analysis (Wilcoxon signed rank test) revealed that this difference was significant with a mean area under the serum concentration time curve of 3.90 and 1.88 mg.h.l-1 for the complex and micronised spironolactone powder, respectively. Four of the volunteer also received a 100 mg spironolactone tablet (Aldactone) under identical conditions. Pharmacokinetic analysis revealed that the mean relative bioavailability of the spironolactone beta cyclodextrin complex and micronised powder when compared with spironolactone tablets (Aldactone) was 252% and 124%, respectively. There was no change in the canrenone elimination half lives of each subject.

Adult↗
PubMed1991

The prediction of steady-state plasma phenobarbitone concentrations (following low-dose phenobarbitone) to refine its use as an indicator of compliance.

1. A model for predicting the steady-state plasma concentration of phenobarbitone following low-dose phenobarbitone used as an indicator of compliance was derived using data for 10 healthy volunteers. 2. Each volunteer was given a single 30 mg oral dose of phenobarbitone and the pharmacokinetics were described. Subsequently, volunteers were given phenobarbitone 2 mg daily for 28 days and a further pharmacokinetic profile determined during and after this period. 3. An initial predicted estimate of steady-state plasma drug concentration was made using each volunteer's demographic details. This estimate was revised by Bayesian analysis using single timed samples (24, 48, 72 or 96 h) following the single dose. 4. The model was tested on a further 10 healthy volunteers given a single 8 mg dose and who were subsequently given 2 mg daily for 28 days. 5. The revised estimate of peak steady-state plasma phenobarbitone concentration utilising the 96 h post-single dose concentration (356 ng ml-1) was least biased (mean prediction error +/- 95% CI = 10.6 +/- 19.8 ng ml-1) and most precise (root mean square error +/- 95% CI = 28.3 +/- 19.0 ng ml-1). In all cases the peak or trough steady-state drug concentration was within 13% of the predicted value. 6. The model reflected compliance accurately in a further eight volunteers with simulated partial (two-thirds) compliance. 7. The use of a predictive model using Bayesian analysis to estimate expected steady-state plasma phenobarbitone concentrations could increase further the usefulness of low-dose phenobarbitone as an indicator of compliance.

Adult↗
PubMed1991

An assessment of population-based and Bayesian methods to individualize digoxin doses shortly after the start of therapy for atrial fibrillation.

The accuracy of population-based methods and of Bayesian analysis to predict individual digoxin pharmacokinetic variables have been evaluated by their ability to predict a measured peak and trough serum digoxin concentration. We studied 13 digitalized patients (three women) whose mean (range) age and weight was 65.8 (60-78) years and 76.6 (68-101.6) kg and who had stable renal function. The population-based methods (using a clearance of 48.87 + 0.87 x creatinine clearance in ml/h/kg and volume of distribution, in litres, of either 7.3 x weight (kg) or 269 + 3.12 x creatinine clearance) were more than adequate for clinical purposes. The mean prediction errors of a measured steady-state peak concentration from these two population methods were -0.074 and 0.013 microgram/l respectively, whilst those of a measured trough concentration were -0.058 and 0.005 microgram/l. Bayesian analysis, using a sample drawn 11 h after the dose on day five of therapy, gave overall the least biased and most precise of the revised estimates. The mean prediction errors of peak and trough values using this sample were 0.069 and -0.005 microgram/l respectively. As expected, the closer the sample was drawn to the time of the trough concentration the more precise were the Bayesian-derived predictions. The value of the Bayesian technique to individualize digoxin doses could not be validated because it was not possible to distinguish between this and the population methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

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.

Administration, Oral↗
PubMed1988

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.

Administration, Oral↗
PubMed1988

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.

Bayes Theorem↗
PubMed1988

Validation of the use of Bayesian analysis in the optimization of gentamicin therapy from the commencement of dosing.

A computer program based on the statistical technique of Bayesian analysis has been adapted to run on several microcomputers. The clinical application of this method for gentamicin has been validated in 13 patients with varying degrees of renal function by a comparison of the accuracy of this method to a predictive algorithm method and one using standard pharmacokinetic principles. Blood samples for serum gentamicin analysis were taken after the administration of an intravenous loading dose of gentamicin. The results produced by each method were used to predict the peak and trough values measured on day 3 of therapy. Of the three methods studied, Bayesian analysis, using a serum gentamicin concentration drawn four hours after the initial dose, was the least biased and the most precise method for predicting the observed levels. The mean prediction error of the Bayesian analysis method, using the four-hour sample, was -0.03 mg/L for the peak serum concentration and -0.07 mg/L for the trough level on day 3. Using this method the corresponding root mean squared prediction error was 0.60 mg/L and 0.36 mg/L for the peak and trough levels, respectively.

Aged↗
PubMed1987

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.

Adult↗