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The William Harvey Research Institute - Barts and The London

Professor Brendan Whittle

Brendan

Professor of Applied Pharmacology

Email: b.j.whittle@qmul.ac.uk
Telephone: +44(0) 20 7882 8110

Profile

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).

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 gastrointestinal 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

Publist Publications

  • Horváth K, Varga C, Berkó A et al. (2008). The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis.. Eur J Pharmacol Vol.581, (3) 0014-2999 315-323.
    10.1016/j.ejphar.2007.12.004
  • Whittle BJ, Varga C, Berko A et al. (2008). Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A4 hydrolase. Br J Pharmacol Vol.153, (5) 0007-1188 983-991.
    10.1038/sj.bjp.0707645
  • Varga C, Laszlo F, Fritz P et al. (2007). Modulation by heme and zinc protoporphyrin of colonic heme oxygenase-1 and experimental inflammatory bowel disease in the rat. Eur J Pharmacol Vol.561, (1-3) 0014-2999 164-171.
    10.1016/j.ejphar.2006.12.022
  • Whittle BJ, Varga C, Berko A et al. (2007). Attenuation of indomethacin-induced rat intestinal lesions, TNF alpha-production and iNOS activity by Tdzd-8, an inhibitor of glycogen synthase kinase-3p. GASTROENTEROLOGY Vol.132, (4) 0016-5085 A564-A564.
  • Whittle BJ, Varga C, Gebhard J (2007). Reduction of rat colitis and colonic TNF-alpha and IL-6 levels, and augmentation of the beneficial actions of suffasalazine by dehydroepiandrosterone (Dhea). GASTROENTEROLOGY Vol.132, (4) 0016-5085 A229-A230.
  • Dunford PJ, Varga C, Thurmond RL et al. (2006). Histamine H4 receptor antagonism attenuates toll-like receptor signaling and inhibits experimental colitis in the rat. GASTROENTEROLOGY Vol.130, (4) 0016-5085 A689-A689.
  • Whittle BJ, Varga C, Berko A et al. (2006). Modulation of rat colonic TNF-alpha, iNOS and acute colitis through down-regulation of NF-kappa B by glycogen synthase kinase-3 beta inhibition. GASTROENTEROLOGY Vol.130, (4) 0016-5085 A551-A551.
  • Dunford PJ, Vargas C, Fourie A et al. (2006). Selective inhibition of leukotriene A4 hydrolase attenuates tissue injury, cytokine production and inflammation in rat colitis. GASTROENTEROLOGY Vol.130, (4) 0016-5085 A346-A346.
  • Whittle BJ, Varga C, Pósa A et al. (2006). Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta. Br J Pharmacol Vol.147, (5) 0007-1188 575-582.
    10.1038/sj.bjp.0706509
  • Barta A, Tarján I, Kittel A et al. (2005). Endotoxin can decrease isolated rat parotid acinar cell amylase secretion in a nitric oxide-independent manner. Eur J Pharmacol Vol.524, (1-3) 0014-2999 169-173.
    10.1016/j.ejphar.2005.09.019
  • Whittle BJ (2005). Nitric oxide-modulating agents for gastrointestinal disorders.. Expert Opin Investig Drugs Vol.14, (11) 1347-1358.
    10.1517/13543784.14.11.1347
  • Varga C, Horvath K, Berko A et al. (2005). Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. Eur J Pharmacol Vol.522, (1-3) 0014-2999 130-138.
    10.1016/j.ejphar.2005.08.045
  • Parsons M, Whittle BJ (2004). A new era for gastrointestinal research - novel therapeutic targets for drug development - Editorial overview. CURR OPIN PHARMACOL Vol.4, (6) 1471-4892 535-537.
    10.1016/j.coph.2004.09.003
  • Whittle BJ (2004). Cyclooxygenase and nitric oxide systems in the gut as therapeutic targets for safer anti-inflammatory drugs.. Curr Opin Pharmacol Vol.4, (6) 1471-4892 538-545.
    10.1016/j.coph.2004.08.003
  • Whittle BJ (2004). Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors.. Eur J Pharmacol Vol.500, (1-3) 0014-2999 427-439.
    10.1016/j.ejphar.2004.07.042
  • Lamarque D, Van Nhieu JT, Breban M et al. (2003). Lymphocytic infiltration and expression of inducible nitric oxide synthase in human duodenal and colonic mucosa is a characteristic feature of ankylosing spondylitis. J RHEUMATOL Vol.30, (11) 0315-162X 2428-2436.
  • Whittle BJ (2003). New dogmas or old?. Gut Vol.52, (9) 0017-5749 1379-1381.
    10.1136/gut.52.9.1379
  • Whittle BJR (2003). The COX controversy: Viewpoint 2 - New dogmas or old?. GUT Vol.52, (9) 0017-5749 1379-1381.
    10.1136/gut.52.9.1379
  • Walker MM, Whittle BJ (2003). British Journal of Clinical Pharmacology review series. Clinical research methods in gastroenterology.. Br J Clin Pharmacol Vol.56, (2) 0306-5251 143-145.
    10.1046/j.1365-2125.2003.01940.x
  • Whittle BJ (2003). Gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Fundam Clin Pharmacol Vol.17, (3) 0767-3981 301-313.
    10.1046/j.1472-8206.2003.00135.x
  • Evans SM, Whittle BJ (2003). Role of bacteria and inducible nitric oxide synthase activity in the systemic inflammatory microvascular response provoked by indomethacin in the rat. Eur J Pharmacol Vol.461, (1) 0014-2999 63-71.
    10.1016/S0014-2999(02)02959-X
  • Whittle BJ, Cavicchi M, Lamarque D (2003). Assessment of anticolitic drugs in the trinitrobenzene sulfonic acid (TNBS) rat model of inflammatory bowel disease.. Methods Mol Biol Vol.225, () 1064-3745 209-222.
    10.1385/1-59259-374-7:209
  • Whittle BJ (2003). Nitric oxide and the gut injury induced by non-steroidal anti-inflammatory drugs. Inflammopharmacology Vol.11, (4) 0925-4692 415-422.
    10.1163/156856003322699582
  • Whittle BJ (2002). Evolution of COX isozymes and their inhibitors - William Harvey Research Conference. IDrugs Vol.5, (12) 1369-7056 1113-1117.
  • Whittle BJ (2002). COX-2 inhibitors, NO-NSAIDs and beyond. IDrugs Vol.5, (7) 1369-7056 623-625.
  • Whittle BJ (2002). ONO-1714 (Ono). IDrugs Vol.5, (6) 1369-7056 590-593.
  • Whittle BJ (2002). Safer non-steroidal anti-inflammatory drugs: are cyclo-oxygenase inhibitors or nitric oxide non-steroidal anti-inflammatory drugs the grand finale?. Dig Liver Dis Vol.34, (6) 1590-8658 393-395.
    10.1016/S1590-8658(02)80034-2
  • Whittle BJ, Varga C, Cavicchi M et al. (2002). Inhibtion of cytokine-induced nitrite production in DLD-1 human intestinal epithelial cell line by P54, a novel curcumin preparation. GASTROENTEROLOGY Vol.122, (4) 0016-5085 A149-A150.
  • Whittle BJ, Evans SM (2002). Involvement of bacteria and iNOS expression in a model of gut-origin systemic inflammatory response syndrome (SIRS). GASTROENTEROLOGY Vol.122, (4) 0016-5085 A534-A535.
  • Evans SM, Whittle BJ (2001). Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs. Eur J Pharmacol Vol.429, (1-3) 0014-2999 287-296.
    10.1016/S0014-2999(01)01327-9
  • Kiss J, Lamarque D, Moran AP et al. (2001). Helicobacter pylori lipopolysaccharide-provoked injury to rat gastroduodenal microvasculature involves inducible nitric oxide synthase. Eur J Pharmacol Vol.420, (2-3) 0014-2999 175-179.
    10.1016/S0014-2999(01)01008-1
  • Varga C, Cavicchi M, Orsi A et al. (2001). Beneficial effect of P54, a novel curcumin preparation in TNBS-induced colitis in rats. GASTROENTEROLOGY Vol.120, (5) 0016-5085 A691-A691.
    10.1016/S0016-5085(08)83440-3
  • Varga C, Cavicchi M, Lamarque D et al. (2001). Rapid induction of the antioxidant, heme oxygenase-1 (HO-1) in human intestinal epithelial cells: Interaction with glutathione levels. GASTROENTEROLOGY Vol.120, (5) 0016-5085 A696-A696.
  • Lamarque D, Whittle BJ (2001). Increase in gastric intramucosal hydrogen ion concentration following endotoxin challenge in the rat and the actions of nitric oxide synthase inhibitors. Clin Exp Pharmacol Physiol Vol.28, (3) 0305-1870 164-168.
    10.1046/j.1440-1681.2001.03432.x
  • Blanchard HS, Dernis-Labous E, Lamarque D et al. (2001). Inducible nitric oxide synthase attenuates chronic colitis in human histocompatibility antigen HLA-B27/human beta2 microglobulin transgenic rats. Eur Cytokine Netw Vol.12, (1) 1148-5493 111-118.
  • Szepes Z, Kiss J, Lamarque D et al. (2001). Attenuation of Helicobacter pylori endotoxin-provoked rat intestinal inflammation by selective inhibition of the inducible nitric oxide synthase. J Physiol Paris Vol.95, (1-6) 0928-4257 453-455.
    10.1016/S0928-4257(01)00062-6
  • Morschl E, Pavo I, Varga G et al. (2001). Endogenous bacteria-triggered inducible nitric oxide synthase activation protects the ovariectomized rat stomach. JOURNAL OF PHYSIOLOGY-PARIS Vol.95, (1-6) 0928-4257 137-140.
    10.1016/S0928-4257(01)00017-1
  • Whittle BJ, Morschl E, Pozsár J et al. (2001). Helicobacter pylori lipopolysaccharide provokes iNOS-mediated acute systemic microvascular inflammatory responses in rat cardiac, hepatic, renal and pulmonary tissues. J Physiol Paris Vol.95, (1-6) 0928-4257 257-259.
    10.1016/S0928-4257(01)00035-3
  • Emery CJ, Lal H, Marriot HM et al. (2000). Pulmonary vasodilation by airway delivered prostacyclin analogues, UT-15 & pegylated UT-15. THORAX Vol.55, () 0040-6376 A35-A35.
  • Whittle BJR (2000). Thirteenth Gaddum Memorial Lecture - St George's Hospital Medical School, London - December 1990 - Neuronal and endothelium-derived mediators in the modulation of the gastric microcirculation: integrity in the balance. BRIT J PHARMACOL Vol.131, () 0007-1188 206-220.
  • Whittle BJR (1998). Experimental basis for non-steroidal anti-inflammatory drug-induced gut injury. CLINICAL SIGNIFICANCE AND POTENTIAL OF SELECTIVE COX-2 INHIBITORS Vol., () 67-75.

Collaborators

Internal: Professor Christoph Thiemermann (WHRI)
External: Professor Lucy Clapp (University College London), Professor Csaba Varga (University of Szeged, Hungary), Professor Lenard Lichtenberger (University of Texas at Houston, USA)