Anti-inflammatory effects of clenbuterol hydrochloride on leukocyte activation in the horse

© 2013 Lucy Anne CudmoreThe work reported in this thesis aimed to investigate the potential anti-inflammatory effects of clenbuterol hydrochloride in the treatment of equine endotoxaemia. Beta adrenergic agonists, such as clenbuterol hydrochloride reduce leukocyte activation and cytokine production through the up regulation of cyclic adenosine monophosphate. Investigations measured pro-inflammatory cytokine production (IL-1β and TNFα) by equine leukocytes, following stimulation with endotoxin, peptidoglycan and lipoteichoic acid and treatment with clenbuterol hydrochloride during in vitro and in vivo studies. The study also aimed to develop a model enabling correlation of pharmacokinetic and pharmacodynamic drug properties in order to predict an optimum dosing regimen for novel anti-inflammatory agents. The results of the study indicated that clenbuterol hydrochloride has significant anti-inflammatory effects on equine leukocytes challenged with Gram negative and Gram positive bacterial toxins in in vitro assays. Clenbuterol hydrochloride was most potent at inhibiting TNFα production in response to endotoxin, with the effects on peptidoglycan and lipoteichoic acid only being significantly inhibited at much higher clenbuterol hydrochloride concentrations (>10-6 M). Also a marked reduction in lipopolysaccharide stimulated IL-1β cytokine production following treatment with clenbuterol hydrochloride was recognised. In in vivo models of equine endotoxaemia, pre-treatment with oral clenbuterol hydrochloride caused a significant reduction in the peak rectal temperature and peak plasma TNFα concentrations. A model correlating clenbuterol hydrochloride pharmacodynamics and pharmacokinetics was developed. Clenbuterol may have a beneficial role alongside non-steroidal anti-inflammatory drugs and other previously investigated therapies in the treatment of inflammation associated with sepsis in horses. Further investigations in clinical cases of equine endotoxaemia are essential prior to the recommendation of clenbuterol hydrochloride as an adjuvant anti-inflammatory agent in the treatment of systemic inflammation