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Biomedical subjects

B Whiting

Publications and source records attributed to B Whiting.

At least 55 records · Page 3Linked to original sources
PubMed1986

The pharmacokinetics of R- and S-tocainide in patients with acute ventricular arrhythmias.

The pharmacokinetics of R(-) and S(+)- tocainide were studied in twelve patients requiring intravenous tocainide. In all patients, a progressive increase in the S(+):R(-) ratio was observed during the infusion. Mean +/- s.d. ratios increased from 1.03 +/- 0.05 at 2 min to 1.76 +/- 0.35 at 48.5 h. Data from eight patients were fitted to a two-compartment model and there was a significant difference (Wilcoxon matched-pairs test P less than 0.01) in the clearance estimates for the two enantiomers. The median values were: S(+)-tocainide = 6.25 l h-1 and R(-)-tocainide = 9.31 l h-1. There was no differences in V1 or Vss.

Acute Disease↗
PubMed1986

Quantitation of dose and concentration-effect relationships for fenclofenac in rheumatoid arthritis.

Response to non-steroidal anti-inflammatory drugs (NSAIDs) is not usually assessed on the basis of concentration measurements: identification of a concentration-effect relationship has proved difficult to achieve. Dose and concentration-effect relationships of fenclofenac have been determined in a group of 18 patients with rheumatoid arthritis at three dose levels (600, 1200 and 1800 mg day-1). The study was double-blind and treatments were randomised according to a Latin square design. A multiple linear regression technique (GLIM) was used in the analysis. The best model to describe the change in effect in terms of dose and concentration incorporated an average slope and an individual subject intercept for each effect measurement. On average, an improvement in grip strength of 20 mm Hg could be obtained with an increase in fenclofenac (trough) concentration of 100 micrograms ml-1.

Adult↗
PubMed1985

Evaluation of nonlinear regression with extended least squares: simulation study.

A new approach to nonlinear least-squares regression analysis using extended least squares (ELS) was compared with three conventional methods: ordinary least squares (OLS); weighted least squares 1/C (WLS-1) and weighted least squares 1/C2 (WLS-2). With Monte Carlo simulation techniques, 3 X 200 data sets were constructed with constant proportional error (5, 10, and 15% error) and 3 X 200 with constant additive error (0.05, 0.10, and 0.15 g/mL) from an initial (perfect) data set based on known parameters. Two sampling strategies were employed: one with 17 time points and one with 10 time points. All data sets were fitted by each of the four methods, and parameter estimation bias was assessed by comparing the mean parameter estimate with the known value. The relative precision of each method was investigated by examination of the absolute deviations of each individual parameter estimate from the known value. ELS performed as well as the appropriate weighting scheme (WLS-2 for constant proportional error sets and OLS for constant additive error sets) and was superior with regard to both bias and precision to less appropriate methods.

Kinetics↗
PubMed1985

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].

Aged↗
PubMed1984

Clinical pharmacokinetics: a comprehensive system for therapeutic drug monitoring and prescribing.

Clinical pharmacokinetics is an expanding scientific discipline which can make an impact on treatment in coronary care, intensive care, paediatrics, general medicine and surgery, and general practice. The aim of this study was to establish a rapid system of drug assay, to report the result, to assess the influence of pathological and clinical factors on the pharmacokinetics of certain drugs, and to use a computer to determine the optimum dosage of drugs. The clinical pharmacokinetics laboratory in Stobhill is available to all clinical departments and to general practitioners in the area. Digoxin, theophylline, and phenytoin have been assessed. Initial samples of these drugs showed that only about a third were in the therapeutic range; samples obtained after the issue of the laboratory report showed an improvement. The predictive performance of the computer program improved with feedback of one or two drug concentrations. Dosages of drugs chosen on an empirical basis may not lead to optimum treatment, and by testing samples early the dosage of the drug can be adjusted. It is hoped that the results achieved will encourage other clinical, pharmaceutical, and scientific colleagues to develop laboratories along similar lines.

Digoxin↗
PubMed1984

Estimation of gentamicin clearance and volume of distribution in neonates and young children.

Gentamicin therapy should be guided by serum level monitoring in all age groups, dosage adjustments depending on age related changes in pharmacokinetics. Population data analysed from two centres (43 infants from Glasgow and 100 infants and children from Manchester) by the computer program NONMEM showed that volume of distribution was related to body weight by a proportionality factor that decreased from the region of 0.41-0.46 l/kg in children less than 3 months to 0.25-0.32 l/kg in older children, a value which merges with that accepted for adults (0.25 l/kg). In both young and older children, clearance was also found to be dependent on body weight. Renal function (creatinine concentrations) provided no further explanatory power. When these results were used prospectively to forecast gentamicin concentrations with a Bayesian kinetic parameter estimation program, trough concentrations were more precisely predicted than peaks when a single concentration measurement was used. In clinical practice, however, two concentration measurements are usually routinely available and these should lead to greater precision of both peak and trough predictions. These results have been incorporated into a simple nomogram which can be used to determine a dose of gentamicin which will achieve target peak concentrations in infants, assuming that troughs should not exceed 2 micrograms/ml.

Age Factors↗
PubMed1984

Prediction of response to theophylline in chronic bronchitis.

In chronic bronchitis, intersubject variability in both theophylline pharmacokinetics and pharmacodynamics must be taken into account if the drug is to be used to its best advantage. Both kinds of variability can be integrated into a model which relates the steady state concentration of theophylline to simultaneously measured ventilatory response (most conveniently, the FVC). In a group of 56 patients with chronic bronchitis, the mean +/- s.d. linear response to increasing steady state concentrations of theophylline was 0.04 +/- 0.012 1 microgram-1 ml, starting from a mean +/- s.d. pretreatment FVC of 1.58 +/- 0.791. Using these population parameter values, with or without a pretreatment FVC and/or one steady state concentration -FVC observation, it was possible to predict the degree of response which would be achieved by a smaller group of 20 similar patients. These estimates were obtained using a mathematical procedure based on Bayesian Probability Theory and Maximum Likelihood Estimation. Estimates of the overall response in individual patients allowed prediction of the response at any steady state concentration. These estimates were unbiased and accurate enough for clinical use when they were based on a pretreatment FVC and/or one paired steady state concentration -FVC observation.

Aged↗
PubMed1984

Binding of [3H]mianserin to bovine serum albumin, human serum albumin and alpha 1-acid glycoprotein.

Scatchard plots which were curvilinear with negative slopes were obtained when the binding of [3H]mianserin to bovine serum albumin (BSA), human serum albumin (HSA), defatted human serum albumin (D-HSA) and alpha 1-acid glycoprotein (alpha 1-AGP) was studied with equilibrium dialysis with constant protein concentrations and various ligand concentrations. Binding parameters were estimated graphically and with a non-linear least-squares computer program, assuming two classes of independent binding sites. alpha 1-AGP had the highest binding affinity (K) and binding capacity (nK). The binding parameters, n and K were not independent of protein concentration when the BSA concentration was varied. Linear atypical Scatchard plots with positive slopes were obtained when the protein concentration was varied for BSA, HSA and D-HSA, at a fixed ligand concentration.

Animals↗
PubMed1983

Antiarrhythmic drugs.

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Adrenergic beta-Antagonists↗
PubMed1983

Kinetic predictive techniques applied to lignocaine therapeutic drug monitoring.

As lignocaine clearance is influenced by factors such as cardiac failure and liver impairment, clinical pharmacokinetic principles should be used to account for kinetic variability so that target concentrations are achieved consistently throughout the course of intravenous therapy. Two groups of patients with ischaemic heart disease, who received lignocaine, were studied: a control group with no feedback or intervention from therapeutic drug monitoring, and an intervention group in which strict guidelines for lignocaine administration were introduced. Lignocaine plasma concentrations were measured by EMIT (Syva), and rapid feedback of concentration data in the intervention group allowed adjustment of infusion rates using the Chiou equation. The mean concentration in the intervention group remained within the therapeutic range (2-5 micrograms/ml) at all times, whereas it exceeded 5 micrograms/ml after the first 7 h in the control group. The distribution of concentrations in the intervention group was always narrower than that in the control group. The study also included a comparison of the ability of the Chiou equation and a Bayesian optimisation procedure to estimate pharmacokinetic parameters and to forecast lignocaine concentrations over various periods of time. There was no significant difference between prediction errors determined by the two methods at various points throughout a 32-h period; both methods were associated with a negative prediction bias beyond the first 12 h of infusion. It is likely that this reflects assumptions made about lignocaine clearance and indicates the need for more sophisticated kinetic models.

Aged↗
PubMed1983

The pharmacokinetics of mianserin.

1 The pharmacokinetics of mianserin hydrochloride have been determined in eight normal healthy volunteers, mean age 27, and 14 elderly patients, mean age 76. 2 Mianserin was administered to volunteers by intravenous infusion (0.011 mg/kg/min for 15 min) and, on another occasion, by mouth, in a single dose of 30 mg. Elderly patients received a single oral dose of 40-60 mg. 3 The terminal elimination half-life was significantly prolonged in the elderly. In young subjects it was 9.6 +/- 1.9 (s.d.) h. In the elderly it was 27 +/- 13.1 (s.d.) h. 4 Apparent oral clearance was significantly reduced in the elderly. In young subjects it was 87.1 +/- 32 (s.d.) h. In the elderly, it was 38.1 +/- 14.8 (s.d.) h. 5 These kinetic differences may have an important bearing on the sedative effects of mianserin.

Administration, Oral↗
PubMed1983

Assessment of the interaction between mianserin and centrally-acting antihypertensive drugs.

1 The interaction between mianserin and centrally-acting antihypertensive drugs was evaluated in normal volunteers and in patients with essential hypertension receiving either clonidine or methyldopa. 2 The administration of the first dose of 20 mg mianserin to the normal volunteers was associated with a significant sedative effect and transient postural hypotension. 3 In the normal volunteers, the blood pressure responses to a single oral dose of 300 micrograms clonidine were not modified by pretreatment with mianserin. The bradycardia associated with clonidine alone, however, was significantly attenuated. 4 In the patient study, no significant changes in blood pressure control were observed, either after the first dose of 30 mg mianserin or after one and two weeks' continued treatment with mianserin. 5 There is no evidence from these studies that the addition of mianserin therapy results in a clinically significant impairment of the antihypertensive effects of clonidine or methyldopa.

Adult↗
PubMed1982

The influence of theophylline on maximal response to salbutamol in severe chronic obstructive pulmonary disease.

We have previously shown that inhaled salbutamol further increases the bronchodilator response after the maximum effect of theophylline has been obtained in patients with severe chronic bronchitis. We now report the results of adding maximally effective doses of theophylline to the maximum response obtainable from salbutamol in ten of these patients. We constructed dose response curves to ensure maximum possible effect from salbutamol. Response plateaus (in nine out of ten patients) were achieved with cumulative doses of between 200 micrograms and 3,000 micrograms salbutamol and there was a significant response (p less than 0.05) in every subject: the mean FVC response was 1.11 (ranging from 0.5 to 1.81) and the mean FEV1 response was 0.41 (ranging from 0.1 to 0.81). Theophylline, in their previously determined maximally effective doses, produced statistically significant (p less than 0.05) small further increases in both FVC (0.2 to 0.61) and FEV (0.1 to 0.61) in four patients only. The other six did not respond. In patients classified as chronic bronchitics there is clearly a wide variation in response to bronchodilators and a surprising degree of reversibility can be achieved. But because of this variation in response, conventional drug doses may be too small in some cases. Ideally, each bronchodilator should be prescribed after some form of individual dose response studies. Although this acute study shows little or no benefit in the height of the bronchodilator response the usefulness of this combination can only really be decided after similar studies including the duration of effect in long term administration.

Aged↗