Clinical Pharmacology

Research

 

Professor Morris Brown has regrouped Clinical Pharmacology to concentrate on high impact research with a track record of changing clinical practice through papers in Lancet and Nature Genetics. Clinical research, using a novel 11C-metomidate PET CT, and laboratory research finding signature gain-of-function mutations in genes regulating calcium entry to adrenocortical cells, have identified a common curable cause of hypertension: microadenomas of the adrenal zona glomerulosa.  One of these calcium entry genes has received a GSK Fast-track award as target for development of a novel therapeutic.

Several gifted PhD students (Lalarukh Harris Shaikh, Junhua Zhou, Ada Teo, Carmela Maniero) have won national and international prizes for work addressing whether zona glomerulosa genes found on microarray to be uniquely upregulated in human adrenal, e.g. LGR5, DACH1, NPNT, regulate the disappearance of cells making aldosterone, in response to excessive salt intake, and so create a selective advantage for cells which mutate to achieve constitutive aldosterone production. Clinically, 2015 will see the reporting of results from the BHF’s landmark multicentre programme of trials, PATHWAY, which are expected to lead to the routine use of plasma renin analysis in hypertension, and influence the revision of NICE guidance for hypertension in 2016.

Clinical Pharmacology also hosts the £5.5M Wellcome Trust/GSK interdisciplinary training programme in Translational Medicine and Therapeutics, which includes a full- or part-time MPhil in Translational Medicine, and annual competitions for posts as MB/PhD, ACF, PhD Fellowship, and Clinical Lectureships.  The programme enables trainees in almost any branch of Medicine to acquire skills that bridge the bench-to-bedside divide.

Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Küsters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ.  Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.  Nat Genet 2013; 45:1055-60.

Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, Azizan EA, Aigbirhio F, Gurnell M, Brown MJ. Evaluation of the Sensitivity and Specificity of 11C-Metomidate Positron Emission Tomography (PET)-CT for Lateralizing Aldosterone Secretion by Conn’s Adenomas. J Clin Endocrinol Metab. 2012; 97: 100-9.

Azizan EA, Lam B, Newhouse S, et al. Microarray, qPCR and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. J Clin Endocrinol Metab. 2012; 97: E819-29.

Brown MJ, McInnes GM, Papst CC, Zhang J, MacDonald TM.  Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial.  Lancet 2011; 377:312-320.

 Burton TJ, Cope G, Wang J, Sim JC, Azizan EA, O’Shaughnessy KM, et al.  Expression of the epithelial Na(+) channel and other components of an aldosterone response pathway in human adrenocortical cells.  Eur J Pharmacol 2009; 613:176-81.

 Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP.  [Pyr1]apelin-13 identified as the predominant apelin isoform in human heart: vasoactive mechanisms and inotropic action in disease.  Hypertension 2009; 54:598-604.

 Pitkin SL, Maguire JJ, Kuc RE, Davenport AP.  Modulation of the apelin/APJ system in heart failure and atherosclerosis in man.  Br J Pharmacol 2010; 160:1785-95.

 Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Maki-Petaja KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB.  Inhibition of p38 MAPK improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation 2011; 123:515-523.

 McEniery CM, Yasmin, Maki-Petaja KM, McDonnell BJ, Munnery M, Hickson SS, Franklin SS, Cockcroft JR, Wilkinson IB and Investigators A-CCT.  The impact of cardiovascular risk factors on aortic stiffness and wave reflections depends on age: the Anglo-Cardiff Collaborative Trial (ACCT III). Hypertension 2010; 56:591-597.

Legend

PET-CT of a patient with right-sided aldosterone-secreting adenoma of the adrenal