Clinical Pharmacology and Toxicology
The Department of Clinical Pharmacology and Toxicology is affiliated with the Department of Physiology and Pharmacology and the Faculty of Medicine via the Director Professor Day and is situated on the St Vincent’s Hospital Campus. It is also affiliated with the Garvan Institute of Medical Research and incorporates the St Vincent’s Hospital Clinical Trials Centre. Its vision is to improve
the quality of the use of medicines.
Professor Day is the academic responsible for the Master programs in Drug Development, Pharmaceutical Medicine and the Pharmacology modules in the Biopharmaceuticals course.
Summary of Activities
The Department has a strong focus on therapeutics and the quality use of medicines with a particular interest in inflammation and rheumatic diseases. Studies range from investigation of basic mechanisms of inflammation to clinical trials of new therapeutic agents, and incorporate approaches to improve organ preservation for transplantation and better therapeutics by monitoring concentrations of drugs in blood.
Current Projects
Human models of inflammation
These studies seek to develop the skin blister and related techniques for use as models to investigate mechanisms of inflammation and their modulation by anti-inflammatory agents in humans.
Mechanism of action of paracetamol
The manner in which paracetamol suppresses pain and fever is surprisingly poorly understood. Related drugs, such as aspirin, inhibit the synthesis of prostaglandins which are mediators of pain, inflammation and fever. It is widely stated that paracetamol is a poor inhibitor of the synthesis of prostaglandins but we have shown that paracetamol is a potent inhibitor in cellular systems which are close to those which may operate in vivo. We are using these cellular systems to investigate the mechanism of action of this very widely used drug.
PK and PD studies of drugs in humans
Studies of the concentration-effect of drugs have generally focussed on blood concentrations because of the accessibility of this biological fluid. However, such concentrations do not always adequately reflect processes occurring in tissues. A new technique, microdialysis, allows the study of interstitial fluid concentrations of drugs and biological markers in humans. These studies are conducted in collaboration with the Pharmacy Department, University of Sydney.
NSAIDs
An interesting series of clinical studies of the efficacy and safety of COX-2 inhibitors in varying populations of patients with rheumatic complaints is being pursued in the Department. The implications for inhibiting COX-2 but not COX-1 are not fully understood but are of importance given the surprisingly high usage of these new drugs.
Allopurinol
Optimising the dosing rate with this important drug used to prevent attacks of gout is the subject of human pharmacology studies in volunteers and patients. There is considerable variability in pharmacokinetics (PK) and pharmacodynamics (PD) and population based PK-PD approaches to individualising therapy to avoid harm but maximise benefits has been a successful research initiative.
Drug Utilisation and Information
A programme of examining the quality of medicines use in hospital and the community is an important interest of the Department. We have a special interest in why particular drugs are chosen and not others, the incidence of adverse reactions and interactions, consumers understanding of their medicines, the safe use of medicines and the influence of the pharmaceutical industry on prescribing. Close collaboration with our colleagues in the Pharmacy Department of St Vincent’s Hospital occurs with this work.
Therapeutic Drug Monitoring
The Drug Monitoring laboratory continues to participate in clinical trials investigating concentration-effect relationships with the goal of optimising drug dose for individuals. Areas of research interest include HIV drug therapy, drug treatment in tuberculosis, optimal use of drug therapy in the treatment of gout, and optimising immunosuppressive drug therapy in transplantation. The unit is reviewing opportunities for concentration-effect analysis using anti-cancer agents.
Cardiac Transplantation
This project investigates novel physiological and pharmacological strategies to improve donor heart preservation for transplantation, using small and large animal models of cardiac transplantation. The focus of the study is the use of pharmacological agents to activate natural protective mechanisms against ischaemia/reperfusion damage to heart muscle and the role of naturally produced reactive oxygen and nitrogen species in modulating this process. This is a collaborative project with the Transplant Unit and Cardiology at St Vincent’s Hospital.
St. Vincent’s Clinical Trials Centre
The Centre performs trials under contract to the pharmaceutical industry. These range from first time in human trials to world-wide, multi-centre studies for registration purposes. The Centre seeks to provide special pharmacological support to see the development of new chemical entities from discovery to clinical use, termed translational research.
Research Group
People in the Group
Other Collaborators
Research associates include:
Dr Malcolm Handel (James Lance Medicines Research Unit,, Prince of Wales Hospital)
Dr Andrew McLachlan (Faculty of Pharmacy, Sydney University)
Associate Professor Peter MacDonald (Cardiopulmonary Transplant Unit, St Vincent’s Hospital)
Associate Professor Alex Wodak (Drug and Alcohol, St Vincent’s Hospital),
Dr Franziska Loehrer (James Lance Medicines Research Unit,, Prince of Wales Hospital)
Dr Kieran Scott (Garvan Institute).
Selected Publications
Du, Z.Y.,
Hicks, M., Spratt, P., Mundie, J.A., &
Macdonald, P.S. (1998). Cardioprotective effects of pinacidil pretreatment and lazaroid (U74500A) preservation in isolated rat hearts after 12-hour hypothermic storage.
Transplantation 66: 158-163.
Du, Z.Y,
Hicks, M., Janz, P., Rainer, S., Spratt, P.,
Macdonald, P. (1998). The nitric oxide donor, diethylamine NONOate enhances preservation of the donor heart.
Journal of Heart and Lung Transplantation 66: 158-163.
Hicks, M., Du, Z.Y., P Janz, P., Rainer, S., Spratt, P.,
Macdonald, P. (1999). ATP sensitive (KATP) channel activation mimics the protective effect of ischaemic preconditioning in the isolated working rat heart after prolonged hypothermic storage.
Clinical and Experimental Pharmacology and Physiology 26: 20-25.
Ryan, J.B., Wilson, M.K.,
Hicks, M., Kesteven, S.H., Nicholson, A., Mccall, A.E., Feneley, M.P., &
Macdonald, P.S. (2000). A brain dead donor model of porcine orthotopic cardiac transplantation for assessent of cardic allograft preservation.
Heart Lung and Circulation 9: 78-81.
Scheuerer, S., Hall, S.D.,
Williams, K.M., Mclachlan, A.J., Brune, K., & Geisslinger, G. (1998). Effect of clofibrate on the chiral inversion of ibu-profen in healthy volunteers. Clinical Pharmacology and Therapeutics 64: 168-176.
Browne, G., Nelson, C., Ellis, B.,
Day, R.O., &
Williams, K.M. (1999). Stereoselective and substrate-dependent inhibition of hepatic mitochondrial ß-oxidation and oxidative phosphorylation by the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen and ketorolac.
Biochemical Pharmacology 57: 837-844.
Kelly, T., Rose, H., Keegan, J.,
Williams, K.M., & Conn, C. (2000). The development of a liquid chromatography-mass spectrometry method for the detection of allopurinol and its metabolites in human hair.
Problems Forensic Sciences, XLII, 143-151.
Sasongko, L., Ramzan, I.,
Williams, K.M., &
Mclachlan, A.J. (2001). Assessment of in vitro and in vivo recovery of gallamine using microdialysis.
Journal of Pharmacological and Toxicological Methods 44: 519-525.
Sasongko, L., Ramzan, I.,
Williams, K.M.,
Mclachlan, A.J. (2001). Application of a HPLC assay for the neuromsucular blocker gallamine to analysis of rat plasma, muscle and microdialysate samples.
Journal of Chromatography B. 754: 467-475.
Ray, J.E. (1999). Itraconazole and HIV Protease Inhibitors: an important interaction.
Medical Journal of Australia 170: 46.
Ray, J.E., &
Mclachlan, A.J. (2000). Optimising antiretroviral drug therapy: the importance of drug concentration monitoring.
Journal of HIV Therapy 25: 36-41.
Smith, D., Hales, G., Roth, N., Law, M. &
Ray, J. (2001). A randomised trial of nelfinavir, ritonavir or delavirdine in combination with saquinavir-SGC and stavudine, in treatment-experienced HIV-1 infected patients.
Journal of HIV Clinical Trials, 2: 97-107.
Ray, J.E., Gardiner, I. & Marriott, D. (2001). Managing antituberculosis drug therapy by therapeutic drug monitoring of rifampicin and isoniazid.
Chest, in press.
Day, R., Morrison, B., Luza, A., Castaneda, O., Strusberg, A., Nahir, M., Helgetveit, K.B., Kress, B., Daniels, B., Bolognese, J., Krupa, D., Seidenberg, B. & Ehrich, E. (2000). A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis.
Archives of Internal Medicine 160: 1781-1787
Bombardier, C., Laine, L., Reicin, A., Shapiro, D., Burgos-Vargas, R., Davis, B.,
Day, R., Ferraz, M.B., Hawkey, C.J., Hochberg, M.C., Kvien, T.K., Schnitzer, T.J., & Weaver, A. (2000). Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.
New England Journal of Medicine 343: 1520-1528
Tett, S.E., Cutler, D.J., Beck, C., &
Day, R.O. (2000). Concentration effect relationship of hydroxy-chloroquine in patients with rheumatoid arthritis – A prospective, dose-ranging study.
Journal of Rheumatology 27: 1656-1660
Brooks, P.M., &
Day, R.O. (2000). COX-2 inhibitors.
Medical Journal of Australia. 173: 433-436.
Graham, G.G.,
Day, R.O., Milligan, M.K., Ziegler, J.B., & Kettle, A.J. (1999). Current concepts of the actions of paracetamol acetaminophen) and NSAIDs.
Inflammopharmacology 7: 255-264.
Day, R.O.,
Mclachlan, A.J.,
Graham, G.G., &
Williams, K.M. (1999). Pharmacokinetics of non-steroidal anti-inflammatory drugs in synovial fluid.
Clinical Pharmacokinetics 36: 191-210.
Graham, G.G., & Kettle A.J. (1998). The activation of gold complexes by cyanide produced by polymorphonuclear leukocytes. III. The formation of aurocyanide by myeloperoxidase.
Biochemical Pharmacology 56: 874-884.
Day RO, Brooks P, Conaghan PG, Petersen M. A double-blind, randomised, parallel group study of the effectiveness and tolerance of intra-articular hyaluronan in osteoarthritis of the knee.
Journal of Rheumatology 2004; 31(4):775-82,2004.
Jiang X,
Williams KM, Liauw WS, Ammit AJ, Roufogalis B, Duke C,
Day RO,
McLachlan, AJ. Effect of St John’s Wort and gingseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.
British Journal of Clinical Pharmacology 2004; 57:592-599
Pett SL, Williams LA,
Day RO, Lloyd AR, Carr AD, Clezy KR, Emery S, Kaplan E, McPhee DA,
McLachlan AJ, Gelder FB, Lewin SR, Liauw W,
Williams KM. A Phase I Study of the Pharmacokinetics and Safety of Passive Immunotherapy with Caprine Anti-HIV Antibodies, (PE)HRG214, in HIV-1-Infected Individuals.
HIV Clin Trials. 2004; 5(2):91-8.
Tan E,
Day RO, Brien JE. Stakeholder opinions on the implementation of Drug and Therapeutics Committee decisions.
Journal of Pharmacy Practice and Research 2004; 34:178-182
Jiang X,
Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC,
Day RO,
McLachlan AJ. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects
British Journal of Clinical Pharmacology 2005; 59(4):425-432
Kerridge I, Maguire D, Newby D, McNeill PM, Henry D, Hill S,
Day R, MacDonald G, Stokes B, Henderson K. Cooperative partnerships or conflicts of interest? A national survey of interactions between the pharmaceutical industry and medical organizations.
Internal Medicine Journal 2005; 35:206-210
Henry D, Kerridge I, Hill S, McNeill PM, Doran E, Newby D, Henderson K, Maguire D, Stokes B, MacDonald G,
Day R. Medical specialists and pharmaceutical industry-sponsored research: a survey of the Australian experience.
Med J Aust 2005;182(11):557-60
Hamama AK,
Ray J,
Day RO, Brien JE. Simultaneous Determination of Rofecoxib and Celecoxib in Human Plasma by High Performance Liquid Chromatography
Journal of Chromatographic Science 2005;43:1-4
Kaye KI, Welch SA, Graudins LV, Graudins A, Rotem T, Davis SR,
Day RO Pethidine in emergency departments: promoting evidence-based prescribing
Med J Aust 2005; 183 (3):129-133
Graham GG, Scott KF. (2005) Mechanism of action of paracetamol
American Journal of Therapeutics, 12: 46-55..
Graham GG, Scott KF, Day RO. (2005) Tolerability of paracetamol.
Drug Safety 28: 227-240.
Graham GG,
Williams KM. (2004) Pharmacokinetics and metabolism of ibuprofen. In Aspirin and Related Drugs pp 157–180 ed KD Rainsford.
Taylor and Francis, London.
Graham GG,
Hicks M. (2004) Pharmacokinetics and metabolism of paracetamol. In Aspirin and Related Drugs ed KD Rainsford, pp 181-213.
Taylor and Francis, London..
Sved P, Scott KF, McLeod D, King NJ, Singh J, Tsatralis T, Nikolov B, Boulas J, Nallan L, Gelb MH, Sajinovic M,
Graham GG, Russell PJ, Dong Q. (2004) Oncogenic action of secreted phospholipase A2 in prostate cancer.
Cancer Research, 64: 6934-6940