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Biomedical subjects

S M Bryson

Publications and source records attributed to S M Bryson.

31 records · Page 2Linked to original sources
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

Pharmacokinetics of valproic acid in young and elderly subjects.

The disposition of valproic acid was studied following single dose intravenous administration in seven young male volunteers aged 20-35 years and six elderly male in-patients aged 75-87 years. Following administration of 400 mg sodium valproate, blood samples were collected for 48 h and valproic acid concentrations analysed by enzymatic immunoassay. The median elimination half-life was 7.2 h in the young subjects but 14.9 h in the elderly patients (P less than 0.01). However, clearance did not differ significantly between groups, the values for young and old being 0.69 and 0.58 1/h respectively. The prolonged half-life resulted from a greater volume of distribution in the elderly. The median values (1/kg) for young and old were 0.13 and 0.19 respectively (P less than 0.01). These pharmacokinetic changes are unlikely to be of clinical importance.

Adult↗
PubMed1982

The influence of protein binding on disopyramide clearance.

Individual disopyramide clearance is not constant and previous studies have suggested that this may be time and/or concentration dependent. Steady state disopyramide concentrations were achieved in six volunteer subjects at each of three infusion rates. Drug analysis was by HPLC and protein binding was determined by ultrafiltration. The disopyramide free fraction was concentration dependent and marked interindividual variability was observed. Disopyramide clearance was independent of time but dependent on total plasma concentration. This can be completely explained by non-linear protein binding since free disopyramide clearance was observed to be independent of free concentration.

Adult↗
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

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

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↗
PubMed1978

Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.

1 Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half-life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half-lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. 5 The absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P less than 0.005), the 5--15% difference between the two formulations should not normally be of any clinical significance.

Administration, Oral↗
PubMedDate not supplied

The renal clearance of disopyramide after bolus intravenous injection.

Following bolus intravenous injection of disopyramide in eight normal volunteers the renal clearance of the drug appeared to fall with time. In the first two hours after injection renal clearance had a mean value of 89.0 ml min-1 and fell to 29.4 ml min-1 between 48 and 72 h. In a separate study disopyramide was given by continuous intravenous (i.v.) infusion for 8 h following a loading dose of the drug. Renal clearance of disopyramide was thus estimated hourly over three narrow serum concentration ranges in a single volunteer. The estimate of renal clearance of the drug over the first hour following the start of these infusions was considerably in excess of values obtained later in the experiments. The change in disopyramide renal clearance following bolus injection is partially time-dependent. There are, however, fallacies in calculating short-term clearance values after bolus drug injection from the venous concentration-time curve and these may partially explain the change in renal clearance of disopyramide with time.

Disopyramide↗
PubMedDate not supplied

Pharmacokinetics of high-dose metoclopramide in cancer patients.

The introduction of new cytotoxic drug regimens has been associated with an increase in the incidence and severity of adverse effects. This in turn has highlighted the need for more effective adjuvant therapy. The use of metoclopramide for the prophylaxis of nausea and vomiting, in high intravenous doses (50 to 1000 mg), has become established since 1981. As a lipid-soluble drug, metoclopramide has a large volume of distribution. The reported mean values after high doses range between 2.8 and 4.6 L/kg. The mean values for total body clearance and terminal half-life range from 0.31 to 0.69 L/kg/h and from 4.5 to 8.8 hours, respectively. The values of these pharmacokinetic parameters are essentially similar to those obtained after conventional doses (less than 50mg). Pharmacokinetic parameters appear unaffected by age, although no high-dose study has been conducted in children. Bodyweight is apparently correlated with clearance. An influence of renal function indices on terminal half-life and clearance has been shown, which is rather surprising since renal clearance accounts for only 20% of the total clearance. No thorough investigations exist which examine the influence of hepatic disease, cancer type and cytotoxic drug regimen on the disposition of metoclopramide. A relationship between dose (or concentration) and therapeutic or adverse effects of metoclopramide is outlined. The therapeutic benefit of high doses (up to 14 mg/kg) may be dependent on age, and on the combination of cytotoxic drugs. The advantages of high doses of metoclopramide are most apparent when the drug is used as protection against the adverse effects of high doses of cisplatin (greater than 60 mg/m2). Despite considerable pharmacokinetic variability, intravenous administration of high doses of metoclopramide is relatively safe due to its large therapeutic index.

Adult↗
PubMedDate not supplied

The effects of age and chemotherapy on gentamicin pharmacokinetics and dosing in pediatric oncology patients.

We attempted to determine the effects of prior antineoplastic chemotherapy and age on gentamicin pharmacokinetics in children (age 1-18 yrs) with cancer and in controls, and to establish a protocol for gentamicin dosing and monitoring to ensure rapid attainment of therapeutic serum concentrations in these patients. In a prospective controlled study, patients with fever who were receiving empiric gentamicin for confirmed or suspected infections were separated into three groups: 29 with cancer who were receiving a continuing chemotherapy protocol with nonnephrotoxic antineoplastic agents; 23 with cancer who were receiving a continuing chemotherapy protocol with nephrotoxic antineoplastic agents; and 25 control patients who did not have cancer. Three blood samples (one predose, two postdose concentrations), collected between the third and sixth gentamicin doses from each patient, were analyzed by the Emit assay. Pharmacokinetic parameters were calculated and gentamicin dosages recommended based on the Sawchuk-Zaske method of serum level interpretation. When normalized by body weight, there was no significant difference in clearance, volume of distribution, and half-life between the control group and either group of patients with cancer. However, when normalized by body surface area, patients receiving prior nephrotoxic chemotherapy appeared to have a lower mean clearance (98.2 ml/min/1.73 m2) than those exposed to nonnephrotoxic chemotherapy (117.4 ml/min/1.73 m2) and controls (113.3 ml/min/1.73 m2; ANCOVA p = 0.033). When kinetic parameters were normalized by body weight, the effect of advancing age yielded a decrease in both clearance (p < 0.001) and volume of distribution (p = 0.02), and an increase in gentamicin half-life (p < 0.001). When normalized by body surface area, age had no significant effect on clearance (p = 0.579). There was no significant difference in gentamicin daily dose requirements (mg/kg) between the chemotherapy groups, which may be due to the lack of significant effects of chemotherapy on gentamicin's volume of distribution and clearance normalized by body weight. The final maintenance doses (mg/kg/day, mean +/- SD) for patients with cancer were 10.8 +/- 1.8 for those age 1-5 years, 8.9 +/- 1.1 for those age 6-12 years, and 7.9 +/- 1.9 for those age 13-18 years. However, when normalized by body surface area, the age-dependent doses became remarkably similar for children in all three age groups (ANOVA p = 0.932), approximately 250 mg/m2/day. We recommend that pediatric patients with cancer who require treatment for fever and neutropenia be given higher than standard gentamicin dosages to achieve therapeutic serum concentrations promptly. In particular, initial empiric doses of 10 mg/kg/day are appropriate for those age 1-5 years.

Adolescent↗