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L Aarons

Publications and source records attributed to L Aarons.

At least 19 recordsLinked to original sources
PubMed1992

A comparison of the relative sensitivities of factor VII and prothrombin time measurements in detecting drug interactions with warfarin.

We have studied the comparative abilities of the prothrombin time and factor VII clotting activity, measured using a chromogenic assay, to detect drug interactions with warfarin. Pharmacokinetic and pharmacodynamic data were collected from studies involving the single administration of 25 mg of warfarin in the absence and presence of fengabin, cimetidine, ranitidine, and enoxacin. Fengabin caused changes in both the pharmacokinetics and pharmacodynamics of warfarin, whereas cimetidine and enoxacin only caused changes in its pharmacokinetics. Ranitidine had no effect on either the pharmacokinetics or pharmacodynamics of warfarin. In general, factor VII clotting activity showed greater sensitivity but also greater variability than the prothrombin time to changes in clotting activity. Consequently, factor VII clotting activity did not have greater discriminatory power than the prothrombin time in detecting drug interactions involving warfarin.

Adult↗
PubMed1992

Population pharmacokinetics.

Traditionally pharmacokinetic studies have been performed in small homogenous groups of subjects, often normal healthy, young male volunteers. These studies are well controlled and generate meaningful baseline data. However, concern has been expressed that insufficient data is collected at an early state in the target population during a drug's development. Logistically studies during Phase III are difficult, control is lacking and what data that is generated is very sparse. In recent years there has been a growing interest in techniques capable of analyzing sparse data and there is now pressure on manufacturers to obtain more kinetic and dynamic information from Phase III studies. The issues, problems and the current status of population based studies will be discussed.

Animals↗
PubMed1991

A population analysis of the pharmacokinetics and pharmacodynamics of midazolam in the rat.

The concentration-EEG effect relationship of midazolam in the rat was studied from a population perspective. Plasma concentration and EEG effect data from 27 rats were available for analysis. Effect parameters derived from aperiodic EEG analysis were used as effect parameters. The population analysis gave results that were similar to the sample theory estimates (means s and SDs) obtained from the fits to individual data sets. Reanalysis of the EEG data using mean population pharmacokinetic parameters as input to the pharmacodynamic model led to poorer estimation of the pharmacodynamic parameters: particularly EC50. Inclusion of one observed plasma concentration per individual significantly improved the estimation of the pharmacodynamic parameters and led to results that were virtually indistinguishable from those obtained using complete pharmacokinetic data.

Animals↗
PubMed1991

The kinetics of flurbiprofen in synovial fluid.

Steady state plasma and synovial fluid flurbiprofen concentrations obtained from 26 rheumatoid arthritis patients receiving 100 mg of flurbiprofen b.i.d. were analyzed using the NONMEM program. Only one synovial fluid sample per patient was available. Population estimates for the plasma parameters, clearance, volume of distribution, and elimination half-life were 1.75 L hr-1, 11.9 L, and 4.8 hr, respectively, and the corresponding interindividual variances in these parameters were 29, 19 and 23%, respectively. The apparent elimination half-life from synovial fluid was 7.1 hr. After accounting for interindividual variability there was a residual variability of approximately 40% in both the plasma and synovial fluid concentrations.

Adolescent↗
PubMed1991

The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.

Plasma and synovial fluid concentrations of the enantiomers of flurbiprofen were measured in 15 rheumatoid patients receiving 100 mg racemic flurbiprofen twice daily. Pharmacokinetic parameters showed considerable variability within the group of patients, although differences in S(+)/R(-) plasma concentration ratios were small. The average values (+/- s.d.) of oral plasma clearance, volume of distribution and elimination half-life for R(-)-flurbiprofen were 0.075 (+/- 0.066) l min-1, 12.47 (+/- 5.79) l and 138 (+/- 61) min, respectively. The average values (+/- s.d.) of oral plasma clearance, volume of distribution and elimination half-life for S(+)-flurbiprofen were 0.057 (+/- 0.035) l min-1, 12.81 (+/- 4.43) l and 155 (+/- 49) min, respectively. S(+)/R(-) ratios (+/- s.d.) rose from 1.06 (+/- 0.12) to 1.75 (+/- 0.61) at the end of the 12 h interval in plasma and from 1.18 (+/- 0.13) to 1.47 (+/- 0.24) over the measured time course in synovial fluid. Increases in S(+)/R(-) ratios may be clinically important as they demonstrate accumulation of the pharmacologically active species.

Aged↗
PubMed1990

Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin.

1. The potential interaction between racemic warfarin given as a 25 mg single oral dose and chronically administered ketorolac was studied in 12 young healthy male volunteers. 2. Ketorolac produced no major change in the pharmacokinetics of (R)- or (S)-warfarin. 3. Ketorolac did not alter the pharmacodynamic profile of racemic warfarin. 4. Ketorolac increased template bleeding time by a factor of 1.35 as compared with placebo. 5. The results suggest that the ketorolac-warfarin interaction is unlikely to be of major clinical significance; however, combined use of ketorolac and warfarin in patients should be undertaken with due caution and appropriate monitoring.

Adult↗
PubMed1989

Design and analysis of protein binding experiments.

The design and analysis of protein binding experiments for obtaining precise parameter estimates for a one-site and a two-site model treating fu, the fraction unbound as the experimentally determined quantity was investigated. Total drug concentrations were chosen at which the binding isotherm is determined to yield the most information about the parameters under study. The D-optimization information criterion was used to achieve this although other criteria are also discussed. For both the one-site and the two-site models the number of design points was always equal to the number of parameters being estimated. The results arrived at when dealing with constant variance and unconstrained total drug concentration were rather unique in that in most of the cases studied, all the optimal design points were away from the boundary conditions. For constant relative variance and unconstrained total drug concentrations, one of the design points was always placed at the smallest possible value of fu, the fraction unbound. For the one-site model the second point was always given by K(-1) + nP. The optimal designs arrived at lead to lower theoretical coefficients of variation in the parameters than the corresponding conventional ones. Simulated experiments supported these theoretical findings for both the one-site and the two-site models. For the one-site model, results from nonlinear regression were compared with Scatchard analysis and the optimal designs were also optimal in Scatchard space. We also show that using Scatchard analysis with the conventional strategy leads to poorly determined estimates particularly when the number of observations is low.

Binding Sites↗
PubMed1989

Efficiency of drug targeting: steady-state considerations using a three-compartment model.

Physiological models have often been used to investigate the processes involved in drug targeting. Such a model is used to investigate some aspects of drug targeting, including the pharmacodynamics of therapeutic and toxic effects. A simple pharmacodynamic model is incorporated in a three-compartment pharmacokinetic model. Conventional administration and drug targeting are compared at steady state for the same degree of therapeutic effect. The efficiency of drug targeting is quantified as the ratio (TA) of the rates of administration of free drug or of a drug-carrier complex required to achieve this effect. Also, the ratios of drug concentrations in the toxicity compartment (DTI) or of the consequent degree of toxic effects (TI) are used to compare conventional administration with drug targeting. The kinetic characteristics of the drug-carrier complex, rate of elimination, and rate of free drug release, influence TA but not DTI or TI. The importance of these characteristics depends on the cost and toxicity of the drug-carrier complex or of the carrier alone. The pharmacodynamics of the free drug in both the target and the toxicity compartments have an important influence on TI but not on TA or DTI. As the pharmacological selectivity of the drug increases, so does TI. However, a drug with good pharmacological selectivity may not be suitable for drug targeting. TI is also very dependent on the shape of the effect-concentration curves, particularly that for toxicity. While TA increases as the rate of elimination of free drug from either central or target compartments increases, TI may actually be reduced if release of free drug is not confined to the target compartment.

Chemistry, Pharmaceutical↗
PubMed1989

Route of administration and sex differences in the pharmacokinetics of aspirin, administered as its lysine salt.

One thousand milligrams of aspirin, as its lysine salt was administered intravenously, orally, and intramuscularly to nine male and nine female young healthy adult volunteers. After intravenous injection mean (+/- SD) values of clearance, steady-state volume of distribution, and terminal half-life were 12.2 +/- 2.2 ml/min/kg, 0.219 +/- 0.042 liter/kg, and 15.4 +/- 2.5 min, respectively, with no differences between males and females. Following administration aspirin was absorbed more quickly in females than in males (mean absorption times of 16.4 and 21.3 min, respectively although the bioavailability, 54%, was the same in both groups. In contrast, following intramuscular administration, aspirin was absorbed more slowly in females than males (mean absorption time of 97 and 53 min, respectively) but again the bioavailability, 89%, was the same in both groups. The data suggest that in the female the intramuscular injection is going into fat. Salicylic acid concentration-time profiles showed a less pronounced sex difference and were comparable among the routes of administration.

Absorption↗
PubMed1989

Population pharmacokinetics of tobramycin.

1. Population pharmacokinetic parameters of tobramycin were determined in a heterogenous group of 97 patients using serum samples drawn for the routine monitoring of tobramycin concentrations, following multiple dosing regimens. 2. To describe the accumulation kinetics of tobramycin a two-compartment pharmacokinetic model was required. The best fit to the data was obtained when drug clearance (1 h-1) was related linearly to creatinine clearance (proportionality constant: 0.059 +/- 0.002 x CLcr (ml min-1)) and initial volume of distribution (1) was related linearly to body weight (proportionality constant: 0.327 +/- 0.014 x body weight (kg)). The intersubject variability in these two parameters was 32% and 3%, respectively, whilst the residual or intrasubject variability amounted to 21% of the tobramycin concentration. The terminal half-life of tobramycin, 26.6 +/- 9.4 h, was appreciably shorter than previously reported. 3. The population pharmacokinetic model was validated against data obtained from 34 independent patients and the predicted and observed concentrations were found to be in good agreement. The population pharmacokinetic model was used to design a priori dosing recommendations for tobramycin.

Adolescent↗
PubMed1989

Rate and extent of absorption of clonidine from a transdermal therapeutic system.

The in-vivo performance of a clonidine transdermal therapeutic system (TTS 3.5 cm2, 2.5 mg) was assessed in 12 healthy normal volunteers. Particular attention was paid to the rate and extent of absorption of clonidine from the TTS dosage form by reference to a 2 h i.v. infusion of clonidine. The absolute bioavailability of clonidine from the TTS dosage form was found to be approximately 60% with clonidine being released from the TTS at a relatively reproducible and consistent rate of 4.32 micrograms h-1 over a 7-day period.

Absorption↗
PubMed1989

A note on the use of salicylate saliva concentration in clinical pharmacokinetic studies.

A sequential approach is presented to the problem of determining the minimum number of blood samples needed to calculate the plasma to saliva concentration ratio to a required precision. The method was applied to salicylate concentrations obtained from six rheumatoid arthritis patients. In order to achieve a 10 per cent coefficient of variation in the plasma to saliva salicylic acid concentration ratio, on average 9 samples were required for total plasma concentration and 8 samples for unbound concentration. In some cases it was not possible to achieve the required precision with the given number of samples. Correlation of salicylic acid concentrations in saliva with total and unbound plasma concentration were equally as good. The limitations of saliva data in clinical pharmacokinetic studies are discussed.

Humans↗
PubMed1988

Computer-assisted learning lessons in drug disposition and pharmacokinetics.

A suite of 18 computer-assisted learning (C.A.L.) lessons has been developed in drug disposition covering processes, concepts and techniques, and pharmacokinetics. Development of lesions and implementation (using CDC's PLATO Programmerless Courseware Development authoring language (Advanced Tutorial Model) for delivery on IBM-PC clones (some also using NPL's Microtext on BBC model B microcomputers) and evaluation by questionnaire proceeded in stages. Staff assessed the authoring system and library lessons for their potential usefulness. Students assessed the importance to their own learning of the features that good quality C.A.L. lessons should display. Finally, our lessons were assessed by students for the presence of these features, comparison with other forms of presentation, their teaching performance, and integration into the curriculum. The use of a programmerless authoring language allowed the authors to concentrate on lesson subject content. The students appreciated the ability to go at their own pace and that their active involvement was required. Lessons scored well in relation to private reading and lectures but less well in comparison with practical work and tutorials. Appropriate integration of C.A.L. into the curriculum was found to be important. Evaluation by questionnaire at each stage of development was valuable.

Computer-Assisted Instruction↗
PubMed1988

Intravenous phenytoin loading in patients after neurosurgery and in status epilepticus. A population pharmacokinetic study.

In 49 patients treated with intravenous phenytoin after a neurosurgical procedure or because of repetitive frequent seizures, the serum concentration was measured before and 2 hours after an intravenous bolus injection. Based on these data the apparent volume of distribution and intra- and interpatient variability were determined in this representative patient population, using the statistical package NONMEM. From 5 characteristics tested (age, sex, bodyweight, serum albumin, renal function) only bodyweight was found to significantly influence the apparent volume of distribution of phenytoin. The population average was estimated as 1.0 +/- 0.04 L/kg (estimate +/- SE) and interindividual variability, expressed as coefficient of variation, was 23 +/- 6%. By means of Monte Carlo simulations an optimal dosing scheme for phenytoin loading has been calculated. Based on these results, a dose of 15 mg/kg divided into 3 intravenous injections administered 2 hours apart at a maximum rate of 50 mg/min is recommended. This loading regimen should result in therapeutic concentrations (10 to 20 mg/L) in 90% of patients within 6 hours.

Adolescent↗