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Biomedical subjects

B Whiting

Publications and source records attributed to B Whiting.

At least 73 records · Page 4Linked to original sources
PubMed1982

Parameter optimisation in clinical pharmacokinetics.

This paper describes a package of computer programs designed to be used in Clinical Pharmacokinetics or Clinical Chemistry Laboratories to assist in the interpretation of plasma drug concentration measurements. A simple pharmacokinetic model is utilised, and values of the necessary parameters for the general population determined using standard nomograms. Parameter estimates for individual patients are obtained by a feedback process using Bayes' theorem and the principle of maximum likelihood. Thus optimal dosage regimes can be obtained for individual patients. The package can be used with a series of drugs.

Clinical Laboratory Techniques↗
PubMed1982

Disopyramide pharmacokinetics during recovery from myocardial infarction.

1 Previous pharmacokinetics studies of disopyramide in patients with ischaemic heart disease include unexplained reports of poor bioavailability and extremely long elimination half-lives which undermine accepted dosage recommendations. 2 Disopyramide pharmacokinetics were investigated after intravenous and oral administration to nine such patients. 3 Mean elimination half-life (6.82 h) and bioavailability (79.8%) were consistent with findings from a previous study in young healthy volunteers. 4 Volume of distribution was reduced by 25%: the mean +/- s.d. value was 0.61 +/- 0.17 l/kg. Total body clearance was significantly reduced: the mean +/- s.d. value was 1.02 +/- 0.16 ml min-1 kg-1. 5 These figures indicate that, in this patient group, if renal function is not significantly impaired, a standard loading dose of 2 mg/kg should be followed by the appropriate maintenance dose administered three or four times daily.

Adult↗
PubMed1982

Haemodynamic effects of BM 10.188, a new orally active inotropic agent, in healthy volunteers.

1 BM 10.188 (Doxaminol, Boehringer Mannheim, GmbH) is a recently developed beta-sympathomimetic agent which has shown promising positive inotropic activity in experimental animal models. It is a dibenzoxepine derivative. 2 The effects of 20 mg oral BM 10.188 on systolic time intervals and standard echocardiographic parameters have been studied in six normal healthy male volunteers. 3 When assessed by repeated measured analysis of variance, QS2 and LVET shortened significantly (P less than 0.005) in the 8 h period following BM 10.188. Mean maximum shortening values were: QS2, 25.7 +/- 25.6 (s.d.) ms at 155 min and LVET, 10.7 +/- 9.5 (s.d.) ms at 155 min. There was a corresponding small but significant increase of 4.2 +/- 3.9 (s.d.) ml in stroke volume at 6 h (P less than 0.025). 4 These results indicate that in normal volunteers, BM 10.188 exhibits effects on noninvasive cardiological indices similar to those observed after cardiac glycosides.

Adolescent↗
PubMed1982

OPT: a package of computer programs for parameter optimisation in clinical pharmacokinetics.

1 OPT is a series of computer programs designed to assist dose optimisation for individual patients. It is based on Bayesian Statistical Theory and Maximum Likelihood Estimation. 2 OPT uses prior information on the distribution of population pharmacokinetic parameters and plasma drug concentration measurements to obtain the "most likely' set of parameters for the individual. 3 Complex dosage regimes and non-steady state conditions can be handled. 4 OPT is designed for use in a Clinical Pharmacokinetics Laboratory where informed interpretation of results is essential. 5 The drugs for which the system is currently available include theophylline, digoxin, lignocaine, disopyramide, gentamicin and phenytoin (steady state data only).

Administration, Oral↗
PubMed1982

The effect of glyceryl trinitrate ointment on heart rate--corrected systolic time intervals in angina pectoris.

1 Individual systolic time intervals (STI) v heart rate regression equations were determined using small doses of intravenous atropine in seven patients with angina pectoris. 2 Regression lines of the form LVET = A + B.HR and QS2 = C + D.HR were calculated. There was no significant correlation between PEP and HR. The values of parameters A C and D were significantly different from a group of previously studied normal volunteers. 3 STI changes were recorded for 5 h after the application of GTN or placebo ointment. The active drug caused shortening of LVET and QS2 with the peak effect occurring between 105 and 180 min. After 180 min neither LVET nor QS2 were significantly shortened. There was no significant effect on PEP or heart rate.

Aged↗
PubMed1982

Oral disopyramide dosage regimes in ischaemic heart disease.

The serum concentration/time profiles resulting from two oral disopyramide dosage regimes were studied in ten patients with ischaemic heart disease. Conventional dosing on a 6 r 8 hourly basis consistently achieved disopyramide concentrations within the accepted therapeutic range of 2-7 micrograms/ml. In contrast, a twice daily regime was associated in some patients with trough levels below the minimum effective concentration. The mean elimination half-life was 5.8 h; this does not substantiate previous reports of significantly prolonged disopyramide half-lives in patients with ischaemic heart disease. Unless significant renal impairment or cardiac failure is present, or a sustained release preparation is used, the dosage interval for oral disopyramide should not exceed 8 h.

Administration, Oral↗
PubMed1982

Comparison of a high pressure liquid chromatographic analysis and an enzyme immunoassay technique for quantitation of disopyramide in serum or plasma.

High pressure liquid chromatographic (HPLC) and enzyme immunoassay (Emit) methods for measuring disopyramide concentrations in plasma and serum were compared. The precision of both methods was satisfactory, with all coefficients of variation in the range 1.3--6.5%. Quantitation was comparable, with a correlation coefficient of 0.991 (n = 96). There was no interference in either method from lignocaine, digoxin, propranolol, procainamide or N-monodealkylated disopyramide. HPLC was superior in terms of lower cost, the ability to quantitate metabolite concentrations, lack of interference by lipaemia or haemolysis and slightly better within-run precision. However, Emit was considered the method of choice for routine therapeutic drug monitoring because of its relative simplicity and speed of performance.

Antibody Specificity↗
PubMed1981

Effect of naproxen on glucose metabolism and tolbutamide kinetics and dynamics in maturity onset diabetics.

1 The influence of the nonsteroidal anti-inflammatory drug naproxen on glucose metabolism and on tolbutamide pharmacokinetics and pharmacodynamics has been studied in ten maturity-onset diabetics. 2 Comparison of both plasma glucose decay curves and insulin responses during an intravenous glucose tolerance test before and after eight 12 hourly doses of naproxen revealed that naproxen had no significant influence on fasting glucose levels or on rates of glucose elimination. 3 When the subjects were given a combination of naproxen and tolbutamide for 3 days naproxen had no influence on tolbutamide absorption, protein binding, disposition or pharmacological effect. 4 Treatment with tolbutamide in maturity-onset diabetics need not be modified if concurrent administration of naproxen is contemplated.

Adult↗
PubMed1981

Theophylline-salbutamol interaction: bronchodilator response to salbutamol at maximally effective plasma theophylline concentrations.

1 The effect of inhaled salbutamol following a maximally effective dose of theophylline given by intravenous infusion was determined in 12 patients with chronic bronchitis. 2 An initial single intravenous dose study was performed to estimate each patient's theophylline kinetics and to identify those patients who would respond to theophylline. 3 Pulmonary function was assessed at hourly intervals during four to five incremental steady state theophylline infusions over the concentration range 5-25 mg/l. 4 Inhaled salbutamol (400 micrograms) was administered after the maximum effect from theophylline had been achieved or when theophylline concentrations reached 25 mg/l without maximum effect: pulmonary function was again assessed. 5 Ten patients achieved a further significant improvement in pulmonary function after salbutamol: in five, predicted values for FVC were exceeded. 6 Patients with chronic bronchitis may benefit from the combination of theophylline and salbutamol if steady state theophylline concentrations of 15-20 mg/l are achieved.

Aged↗
PubMed1981

Modelling theophylline response in individual patients with chronic bronchitis.

1 In six patients with chronic bronchitis, serial changes in both ventilatory function and plasma theophylline concentrations were measured simultaneously for 8 h following 500 mg aminophylline intravenously. 2 Using empirical mathematical models which can integrate this data, parameters were estimated which can express response as a linear function of steady state plasma theophylline levels. 3 Taking Forced Vital Capacity (FVC) as the target response, the mean (+/- s.d.) increase in FVC was 0.06 +/- 0.02 l/micrograms ml-1, starting with pretreatment values in the range 1-21. 4 This analytical approach could be used to determine whether or not a patient with chronic bronchitis could obtain a satisfactory response to theophylline at plasma levels normally encountered in clinical practice.

Adult↗
PubMed1981

Systolic time interval v heart rate regression equations using atropine: reproducibility studies.

1. Systolic time intervals (STI) were recorded in six normal male subjects over a period of 3 weeks. On one day per week, each subject received incremental doses of atropine intravenously to increase heart rate, allowing the determination of individual STI v HR regression equations. On the other days STI were recorded with the subjects resting, in the supine position. 2. There were highly significant regression relationships between heart rate and both LVET and QS2, but not between heart rate and PEP. 3. The regression relationships showed little intra-subject variability, but a large degree of inter-subject variability: they proved adequate to correct the STI for the daily fluctuations in heart rate. 4. Administration of small doses of atropine intravenously provides a satisfactory and convenient method of deriving individual STI v HR regression equations which can be applied over a period of weeks.

Adult↗
PubMed1981

The prediction of individual systolic time interval v heart rate regression equations.

1. Twenty-eight sets of systolic time interval (STI) and heart rate (HR) data were available from studies in which small bolus doses of atropine had been given to alter heart rate. 2. Regression lines of the form LVET = A+B.HR and QS2 = C+D.HR were calculated. There was no significant relationship between PEP and HR. The values of the parameters A-D were normally distributed. 3. The maximum likelihood Estimation was used to obtain the most likely values of the parameters A-D for individual subjects. 4. The technique proved to be highly satisfactory and was subsequently validated with a further six sets of data.

Atropine↗
PubMed1981

The pharmacokinetics of meclofenamic acid in the horse.

The pharmacokinetics of meclofenamic acid were studied in Thoroughbred horses and in ponies. After intravenous (i.v.) administration of either 2 mg/kg or 4 mg/kg sodium meclofenamate the elimination half-life was of the order of 0.9 h while the volume of distribution was found to be 0.128 litre/kg. Elimination was in accordance with a one-compartment model. Following oral administration of either meclofenamic acid (4 mg/kg) or sodium meclofenamate (4 mg/kg) a much longer terminal half-life than that calculated for Kel from i.v. data was found. This anomaly indicated that the 'flip-flop' phenomenon was present, i.e. Ka exceeded Kel. More rapid and higher peak levels occurred following sodium meclofenamate than meclofenamic acid, although total bioavailability was similar. Studies in ponies with meclofenamic acid showed a lower absorption than that found in Thoroughbreds. Overnight fasting before meclofenamic acid administration did not alter the rate or extent of absorption. Intramuscular administration of sodium meclofenamate resulted in low plasma concentrations and after 25 h only 46% of the drug had been absorbed.

Administration, Oral↗
PubMed1981

The changing pattern of toxicity of digoxin.

Toxicity to digoxin was monitored in 437 consecutive recipients in a comprehensive drug surveillance programme, Adverse reactions developed in 19.5% and, in contrast to previous reports, were generally of a relatively benign nature. There were no drug-related deaths, but patients with adverse reactions spent longer in hospital. Low body weight, impaired renal function, old age and concurrent use of diuretics individually did not increase the risk of toxicity. This was attributed to improvements in the prescribing of digoxin. There was a highly significant excess of gastrointestinal reactions in women, which tended to occur early in the course of therapy. This susceptibility is not widely recognized. The use of loading doses may have caused many early reactions and it is suggested that this practice cold be abandoned in all but the most urgent cases.

Age Factors↗
PubMed1980

Dose dependent methotrexate elimination following bolus intravenous injection.

The pharmacokinetics of methotrexate have been assessed at two dose levels in six patients receiving the drug for treatment of malignant disease. Each patient received bolus intravenous doses of 25 mg and 100 mg given at least one week apart, the order of administration being random. Blood and urine were collected until 48 h for methotrexate analysis by radioimmunoassay and data analysed by a model-independent pharmacokinetic approach. In each patient area under the methotrexate serum concentration-time curve (o to chi) increased out of proportion to the increase in methotrexate dose. This was reflected in a mean clearance value after the 100 mg dose of 31 +/- 16 (SD ml x min(-1) compared with a mean clearance of 62 +/- 19 ml x min(-1) following injection of 25 mg methotrexate. Renal clearance of methotrexate was markedly lower following the 100 mg dose (18 +/- 6 ml x min(-1) than after 25 mg (53 +/- 19 ml x min(-1). Saturation of the proximal tubular organic acid transport system is the likely cause of methotrexate's capacity limited elimination.

Dose-Response Relationship, Drug↗
PubMed1980

Modeling of drug response in individual subjects.

Pharmacokinetic and drug response data from individual subjects are analyzed empirically by two different mathematical techniques. The drugs involved are the antiarrhythmic agent disopyramide, whose kinetics can be described by a two-compartment model, and two cardiac glycosides, digoxin and beta-methyl digoxin, for which three-compartment models are appropriate. The first analytical approach uses multiple linear regression to describe response in terms of the amount of drug in several kinetic compartments. The second approach describes response in terms of the drug concentration in an "effect" compartment. Both approaches describe the data equally well and require the same number of parameters for model specificaton.

Digoxin↗
PubMed1980

Comparative pharmacokinetics and pharmacodynamics of cardiac glycosides.

1 The pharmacokinetics and pharmacodynamics of ouabain, digoxinn and beta-methyl digoxin (medigoxin) have been investigated in a crossover study in four normal healthy volunteers. 2 Pharmacokinetics were studied using [3H]-labelled glycosides and the shortening of the left ventricular ejection time (LVET) was used as a measure of the effect of the drugs. A graded exercise protocol was used to correct for the effects of heart rate on LVET. 3 In three of the four subjects, both digoxin and beta-methyl digoxin produced a shortening in the LVET, but no such change could be detected with ouabain in any of the four subjects. 4 There was a good linear correlation between the shortening of the LVET and the amounts of digoxin or beta-methyl digoxin present in the body tissues. 5 One subject who showed no drug-related LVET shortening had greatly enhanced clearances of all three drugs studied.

Adult↗