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L Aarons

Publications and source records attributed to L Aarons.

88 records · Page 5Linked to original sources
PubMed1983

Dose-response study with ibuprofen in rheumatoid arthritis: clinical and pharmacokinetic findings.

Clinical response and plasma pharmacokinetics were studied in 20 rheumatoid patients receiving three dosages of ibuprofen. There was a significant response to 1600 mg daily of ibuprofen by all three clinical measurements but increasing the daily dosage to 2400 mg produced no overall increase in response. The AUC increased with increasing daily drug dosages from 800 to 2400 mg daily and the dose normalised AUC fell by 15% over the same dosage range. The fraction of ibuprofen not bound to plasma proteins increased with increasing dosage and may contribute to the fall in the dose normalised AUC. There was a considerably inter-individual variation in the AUC. There was no significant correlation between AUC and clinical response as measured by articular index and there was a weakly significant correlation between AUC and clinical response as measured by a visual analogue pain index. Pharmacokinetic variables probably account for only a small part of the inter-individual variation in response of rheumatoid patients treated with increasing dosages of the non-steroidal, anti-inflammatory drug ibuprofen.

Adult↗
PubMed1981

A chronic dose-ranging study of the pharmacokinetics of phenylbutazone in rheumatoid arthritic patients.

Phenylbutazone in doses of 200, 300 and 400 mg/day was administered chronically to six rheumatoid arthritic patients. At each steady-state the plasma levels of phenylbutazone, oxyphenbutazone and gamma-hydroxyphenylbutazone as well as the extents of binding of phenylbutazone and oxyphenbutazone to plasma proteins were measured. 2 Plasma concentrations of phenylbutazone did not increase proportionally with dose but when corrected for protein binding unbound concentrations of phenylbutazone did show a proportional increase with dose. 3 Plasma concentrations of oxyphenbutazone decreased with an increase in phenylbutazone dose suggesting either that the elimination of oxyphenbutazone is stimulated or its formation inhibited after chronic administration of phenylbutazone. 4 Binding studies with human serum albumin demonstrated the ability of phenylbutazone and oxyphenbutazone to mutually displace one another. Neither saturation of the protein binding sites nor displacement interactions could account for the changes in binding shown by phenylbutazone with increased dose. 5 gamma-hydroxyphenylbutazone concentrations increased proportionally with phenylbutazone dose reaching 68% of the phenylbutazone concentration in one patient. There was a large inter-subject variation in the gamma-hydroxyphenylbutazone concentrations.

Aged↗
PubMed1980

Aspirin binding and the effect of albumin on spontaneous and enzyme-catalysed hydrolysis.

A method of measuring the binding of aspirin to albumin without the interference of hydrolysis was developed. At concentrations of 10 mg litre-1, aspirin is about 85% bound to bovine serum albumin (4 g %), whereas its hydrolysis product, salicylic acid, is 95% bound. Salicylic acid was shown to displace aspirin from albumin binding sites. Both salicylic acid and aspirin bind more strongly to bovine serum albumin than to human serum albumin at protein concentrations of 4 g %. Protein binding protected aspirin against spontaneous hydrolysis although protein-bound aspirin still hydrolysed at a finite rate. In contrast, albumin enhanced the enzyme-catalysed hydrolysis of aspirin. By using a simple model, the rate constants for the individual processes contributing to the overall hydrolysis rate constant in the presence of albumin and esterase are calculated.

Animals↗
PubMedDate not supplied

Sparse data analysis.

In recent years there has been a growing interest in techniques capable of analyzing sparse data, particularly gathered during Phase III clinical trials, and there is now pressure on manufacturers to obtain more kinetic and dynamic information from Phase III studies. Techniques for the analysis of sparse data are reviewed drawing on a number of examples taken from pharmacokinetic and pharmacodynamic experiments.

Animals↗
PubMedDate not supplied

How can we do pharmacokinetic studies in the tropics?

Information regarding the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug provides the basis for optimizing dosing. PK-PD information should be obtained from patients representative of the overall target population, but in many tropical hospitals or health care facilities it may be medically hazardous or logistically difficult for an ill patient or a young child to be sampled repeatedly. Traditional methods used to determine the pharmacokinetic properties of a drug require analysis of a large number of blood samples per subject. However, using modern statistical methods, sparse datasets (i.e. with assay results from only a few, or as little as one blood sample per subject) can now be analysed by a method termed 'the population approach'. Modern assay techniques can often be adapted to small blood volumes allowing finger prick blood samples to be taken. One of the major aims of the population approach is to distinguish and characterize patient and disease contributors to inter-individual variance in drug pharmacokinetics. The purpose of this paper is to explain the basis of the population approach, to highlight its advantages compared to traditional methods of analysis, and to review the application of the population approach to data from field studies of antimalarial drugs. The design of population pharmacokinetic studies is also discussed briefly. The principles discussed in the paper are also applicable to pharmacodynamic data.

Antimalarials↗
PubMedDate not supplied

Plasma concentration-response relationship for cimetidine inhibition of drug metabolism in the rat.

Cimetidine inhibition of antipyrine elimination has been studied in the rat over a range of steady state cimetidine concentrations. Cimetidine is a potent inhibitor of antipyrine metabolism with a concentration of about 1.25 mg/liter causing a 50% decrease in the total plasma clearance of antipyrine. The degree of inhibition of antipyrine clearance caused by cimetidine is dependent upon its plasma concentration, but the relationship is not linear. The formation clearances of all antipyrine metabolites measured--3-hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine--are inhibited by cimetidine at all concentrations used. The susceptibility of the different metabolites to cimetidine inhibition does vary. The renal clearance of antipyrine was also decreased by cimetidine by an unknown mechanism. Analysis of the individual formation clearances suggests that the inhibition of oxidative metabolism due to cimetidine is caused by its binding to two classes of enzyme sites--a high affinity, low capacity and a low affinity, high capacity site. These two different sites would appear to be responsible for the production of different metabolites of antipyrine. The true nature of the selectivity of cimetidine inhibition of antipyrine metabolism is apparent from the formation clearances but not from the urinary metabolite patterns.

Animals↗