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Biomedical subjects

Peter Lees

Publications and source records attributed to Peter Lees.

12 recordsLinked to original sources
PubMed2005

Pharmacokinetic/pharmacodynamic modelling of NSAIDs in a model of reversible inflammation in the cat.

1 Data on the relationships between plasma concentration and analgesic and anti-inflammatory effects of NSAIDs are limited because most inflammation models do not permit pharmacokinetic/pharmacodynamic (PK/PD) modelling to be readily performed. 2 In this study, a kaolin-induced inflammation model in the cat was evaluated for pre-clinical characterization of the pharmacodynamic profiles of NSAIDs (determination of efficacy, potency, sensitivity (that is the slope of the concentration-effect relationship) and duration of drug response), using meloxicam as a probe article. 3 Indirect response PK/PD models described the time course and magnitude of responses produced by 0.3 mg kg(-1) meloxicam administered subcutaneously. For endpoints for which spontaneous recovery from inflammation was superimposed on drug response, a PK/PD model with a time-dependent K(in) was used to allow for the spontaneous changes of the inflammation with time. 4 The selected endpoints were suitable for studying simultaneously the analgesic, anti-inflammatory and antipyretic effects of meloxicam, allowing comparison of relative potencies for these effects. Mean+/-s.d. IC(50) or EC(50) values (ng ml(-1)) were 777+/-124 (body temperature), 841+/-187 (locomotion variable), 883+/-215 (pain score), 911+/-189 (lameness score) and 1298+/-449 (skin temperature difference). Corresponding mean times+/-s.d. of peak responses (h) were 5.6+/-1.3, 8.6+/-3.8, 5.2+/-5.0, 5.6+/-3.7 and 4.3+/-2.4, respectively. 5 As the pharmacokinetic profiles of meloxicam in cats and humans are similar, simulations of several dosage regimens in the cat provided a pre-clinical basis, illustrating the value of the cat model for predicting a clinical dose regimen for evaluation in man. The predicted loading doses (mg kg(-1)) of meloxicam in the cat producing 70% of the maximum attainable responses were 0.29 (body temperature), 0.32 (lameness score), 0.33 (overall locomotion variable), 0.36 (pain score) and 0.50 (skin temperature difference). The values are similar to or somewhat greater than the clinically recommended doses both in cats (0.3 mg kg(-1)) and humans (7.5-15 mg, that is, between 0.1 and 0.3 mg kg(-1)). 6 These findings indicate the potential value of the cat as a laboratory model, and of a PK/PD modelling approach in assisting NSAID development programs in animals and humans.

Animals↗
PubMed2005

Development of in vitro assays for the evaluation of cyclooxygenase inhibitors and predicting selectivity of nonsteroidal anti-inflammatory drugs in cats.

OBJECTIVE: To develop and validate in cats suitable in vitro assays for screening and ranking nonsteroidal antiinflammatory drugs (NSAIDs) on the basis of their inhibitory potencies for cyclooxygenase (COX)-1 and COX-2. ANIMALS: 10 cats. PROCEDURE: COX-1 and COX-2 activities in heparinized whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. For the COX-2 assay, blood was pretreated with aspirin. The COX-1 and COX-2 assays were standardized, such that time courses of incubation with the test compounds and conditions of COX expression were as similar as possible in the 2 assays. Inhibition of thromboxane B2 production, measured by use of a radioimmunoassay, was taken as a marker of COX-1 and COX-2 activities. These assays were used to test 10 to 12 concentrations of a COX-1 selective drug (SC-560) and of 2 NSAIDs currently used in feline practice, meloxicam and carprofen. Selectivities of these drugs were compared by use of classic 50% and 80% inhibitory concentration (ie, IC50 and IC80) ratios but also with alternative indices that are more clinically relevant. RESULTS: These assay conditions provide a convenient and robust method for the determination of NSAID selectivity. The S(+) enantiomeric form of carprofen was found to be COX-2 selective in cats, but meloxicam was only slightly preferential for this isoenzyme. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro pharmacodynamic and in vivo pharmacokinetic data predict that the COX-2 selectivity of both drugs for cats will be limited when used at the recommended doses. This study provides new approaches to the selection of COX inhibitors for subsequent clinical testing.

Animals↗
PubMed2004

Detection of enrofloxacin and its metabolite ciprofloxacin in equine hair.

Hair analysis to detect drug administration has not been studied extensively in horses. This study aimed to (a) develop an analytical method for enrofloxacin and its metabolite ciprofloxacin in mane and tail hair, (b) relate measured values to doses, routes of administration, hair colour, and (c) demonstrate long-term detectability. Samples were extracted in trifluoroacetic acid at 70 degrees C. Extracts were cleaned-up by solid-phase extraction and analysed by high-performance liquid chromatography with UV-diode array detection. Analyte recoveries were > 87%. Horses were sampled after therapeutic enrofloxacin administration either orally at 7.5 mg/kg daily for 3-13 days or twice daily for 10-14 days (Group 1, n=7) or intravenously at 5.0 mg/kg daily for 12 and 15 days (Group 2, n=2). Enrofloxacin and ciprofloxacin were detected at concentrations up to 452 and 19 ng/mg, respectively, up to 10 months post-treatment. In vitro, enrofloxacin and ciprofloxacin were extensively bound to melanin (> 96%) and in vivo, their uptake was 40-fold greater in black than white hair. Enrofloxacin and ciprofloxacin concentrations correlated to enrofloxacin dose (r2=0.777 and r2=0.769). Enrofloxacin:ciprofloxacin ratios were 21:1 and 13:1 following intravenous and oral administration, respectively. Longitudinal analyte distributions correlated to treatment-sampling interval.

Administration, Oral↗
PubMed2003

Pharmacology of drugs used to treat osteoarthritis in veterinary practice.

As in humans, pain in animals may be associated with a wide range of conditions and circumstances, ranging from acute trauma to joint diseases. Joint diseases are common in companion animal medicine (horse, dog, cat) and at least 80% of cases are classified as osteoarthritis (OA). Several drug classes are available for OA therapy, including corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs), agents with potential disease modifying properties and nutraceuticals. For long-term maintenance OA treatment, particularly in the horse and dog, NSAIDs are routinely and extensively used. This review outlines the pharmacokinetics (PK) and pharmacodynamics (PD) of NSAIDs in companion and farm animal species. NSAID PK and PD have been studied in models of acute inflammation, which enable use of PK-PD modeling to facilitate (a) studies of mechanism of action at the molecular level and (b) prediction of dosages for clinical use. The PK-PD approach is a powerful but underutilized tool which also facilitates inter-species comparisons.

Journal Article↗
PubMed2002

Rational dosing of antimicrobial drugs: animals versus humans.

The rational dosing of antimicrobial drugs depends on knowledge of physiology, anatomy and pathology, including disease condition, and in major respects these differ between animals and humans and between species of animal. These differences lead to species variation in drug pharmacokinetics, which can be profound. This review highlights selected aspects of species differences in pharmacokinetics and considers underlying mechanisms by reference to ruminant and non-ruminant mammals, birds, fish and bees. For all species it is desirable and should be possible to design dosage schedules based on knowledge of drug pharmacokinetics and pharmacodynamics. There have been many attempts to integrate pharmacokinetic and pharmacodynamic data to provide dosage schedules which optimize efficacy and minimize opportunities for the development of antimicrobial resistance in both laboratory animal studies and human clinical trials. However, there have been relatively few studies in animal species of major veterinary interest. This review summarizes recent studies in four ruminant species (calf, sheep, goat and camel) which have used PK-PD integration to determine for the fluoroquinolone, danofloxacin, AUC/MIC ratios producing (a) bacteriostasis (b) bactericidal activity and (c) elimination of bacteria. Future possible developments in dosage schedule design are considered.

Animals↗
PubMed2002

Pharmacokinetic and pharmacodynamic profiles of danofloxacin administered by two dosing regimens in calves infected with Mannheimia (Pasteurella) haemolytica.

The pharmacokinetics and pharmacodynamics of danofloxacin in calves with induced Mannheimia (Pasteurella) haemolytica pneumonia were evaluated. Calves received either saline as an intravenous (IV) bolus or danofloxacin (0.738 mg/kg of body weight) administered as either a single IV bolus or a 36-h continuous IV infusion. Blood samples and bronchial secretions were collected before and at predetermined times over 48 h following the start of treatment. Calves were assessed clinically throughout, and lung consolidation was assessed at necropsy. Bronchial secretions and lung tissue were cultured for M. haemolytica. Bolus administration of danofloxacin produced a high maximum drug concentration-to-MIC ratio (C(max):MIC) of 14.5 and a time period of 9.1 h when plasma danofloxacin concentrations exceeded the MIC (T>MIC). Following danofloxacin infusion, the C(max):MIC was low (2.3), with a long T>MIC (33.3 h). The area under the curve-to-MIC ratios were 43.3 and 49.1 for the bolus and infusion administrations, respectively. The single bolus of danofloxacin was more effective than the same dose administered by continuous infusion, as indicated by a significantly lower (P < 0.05) number of animals with M. haemolytica in bronchial secretions after treatment and lower rectal temperatures in the 24 h after the start of treatment. Thus, danofloxacin exhibited concentration-dependent antimicrobial activity in cattle with respiratory disease caused by M. haemolytica.

Animals↗