Brendan Whittle

Professor of Applied Pharmacology

I have been Professor of Applied Pharmacology at the William Harvey Research Institute within the School of Medicine over the past 18 years, while I am also Visiting Professor for the University of Hertfordshire, and a visiting lecturer for the University of Tampere, Finland.  In addition to my three academic degrees (B.Pharm.; Ph.D., D.Sc.), I am a Fellow of the British Pharmacological Society and Fellow of the Royal Society of Medicine and was awarded both the Gaddum Lecture Prize and the Sandoz Prize by the British Pharmacological Society.

  I am a Director of the associated company, the William Harvey Research Ltd, where I am involved with sponsored, contract and collaborative pre-clinical research studies. I have previously spent some 20 years in the international pharmaceutical sector including the Wellcome Research Laboratories (part of the Wellcome Foundation)  in Beckenham, latterly as Director of Pharmacology, working in a number of research and development fields. I have also worked with Daiichi Pharmaceuticals Ltd, London to oversee their R&D project portfolio and I have been a consultant to a number of other major pharma companies.

 I have published some 350 peer-reviewed papers and reviews, and I am a ISI Highly Cited Researcher (ranked in the top 100 most cited world-wide, for all scientific citations over the 20 year period 1980 – 2000).

Summary of Research

 My research areas have included microvascular studies on the gastro-intestinal tract, particularly in relation to the adverse effects of non-steroidal anti-inflammatory drugs. I originally characterised the microcirculatory and related components of such detrimental activity of these agents. I was able to demonstrate that microvascular blood flow to the gastric mucosa was diminished, which promoted the consequences of surface injury to acid attack by these agents. We are continuing to be interested in this work as a consequence of the findings by Professor Lichtenberger at the University of Texas on the composition of this surface barrier layer and how it can be manipulated to become more resistant to acute degradation.

 All such findings have great potential to understand and hence alleviate the gastro-intestinal damage caused by these anti-inflammatory drugs, a significant clinical problem still to be resolved.

 Working on other projects with colleagues at the University of Szged in Hungary, we have identified mechanisms contributing to the therapeutic activity of agents used to control colitis, the inflammatory conditions of the large intestine. We have investigated novel approaches to regulating the production of the pro-inflammatory leukotriene mediators, as well as the role of the newly identified histamine H4 receptors in the inflammatory process. More recently, we have found that a well-established class of anti-colitic agents that includes mesalamine, promotes the colonic expression of the endogenous anti-oxidant system, heme-oxygenase-1. Up-regulation of this system results in the attenuation of all the markers of colitis, identifying a novel mechanism for this old but still effective drug.

 My work also concerns the pulmonary vascular system and I hold a number of patents in this area. I was very closely involved in the identification, selection and early development of the prostacyclin analogue, treprostinil (the chemical structure of which shown in the recent photograph), while I was working at the Wellcome Research Laboratories. This compound was subsequently developed into a number of pharmaceutical preparations by United Therapeutics, and is now one of the key therapies for the often-fatal disease of pulmonary hypertension.

 Working together with Professor Clapp and her colleagues at University College London, we have recently identified the profile of prostanoid receptors that are activated by treprostinil, which we have found to differ distinctly from a number of other prostanoids. We are currently working to identify the complex pharmacological mechanisms, including characterisation of the prostanoid receptors, involved in the regulation of pulmonary vascular smooth muscle proliferation. This is a characteristic of this devastating disease that promotes pulmonary vascular occlusion. We feel that such knowledge will improve the selection of the few therapeutic interventions currently available and will lead to the development of new clinical entities.

 

Key Publications

Whittle BJ, Silverstein AM, Mottola DM, Clapp LH. (2012).Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist. Biochem Pharmacol. 84 68-75.

 Horváth K, Varga C, Berkó A, Pósa A, László F, Whittle BJ. (2008).The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis. Eur J Pharmacol. 581 315-323.

 Whittle BJ, Varga C, Berko A, Horvath K, Posa A, Riley JP, Lundeen KA, Fourie AM, Dunford PJ. (2008). Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A4 hydrolase. Br J Pharmacol. 153 983-991.

 Whittle, B.J.R. (2004). Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors. Eur. J. Pharmacol., 500, 427-439.

 Whittle B.J.R. (2004). Cyclo-oxygenase and nitric oxide systems in  the gut as therapeutic targets for safer  non-steroidal  anti-inflammatory drugs. Current Opinion in Pharmacology 4 538-545.

 Whittle, B.J.R.  (2001). Basis for gastro-intestinal toxicity of non-steroidal anti-inflammatory.  In: Therapeutic roles of selective COX-2 inhibitors, eds. Vane J.R and Botting R.M., William Harvey Press, London, 329-354.

 Whittle, B.J.R. (1994). Nitric oxide in gastrointestinal physiology and pathology.  Physiology of  the Gastrointestinal Tract. Third Edition, ed. L.R. Johnson. Raven Press, New York, pp. 267-294.

  Whittle, B.J.R. (1993).  Thirteenth Gaddum Memorial Lecture: Neuronal and endothelium-derived mediators in the modulation of the gastric microcirculation: integrity in the balance.  Br. J. Pharmacol., 110, 3-17.

 Rosam, A-C, Wallace, J.L. and Whittle, B.J.R. (1986). Potent ulcerogenic actions of platelet-activating factor on the stomach. Nature 319 54-56.

 Whittle, B.J.R., Kauffman, G.L. and Moncada S.  (1986). Hemostatic mechanisms, independent of platelet aggregation, arrest gastric mucosal bleeding.   Proc. Natl. Acad. Sci. 83 5683-5687.

 Whittle, B.J.R., Higgs, G.A., Eakins, K.E., Moncada, S. and Vane, J.R (1980).   Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa.  Nature, 284, 271-273

 
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