Clinical Pharmacology

Unlocking The Problems Of Gut Surgery

Unravelling The Secrets Of A Sneaky Protein

Research To Prevent Renal Transplant Rejection

Drug Induced Kidney Damage - Who Is At Risk?

The Elimination Process 

Unlocking The Problems Of Gut Surgery
First Published: Investigator - December 2009
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Findings from a new study at Flinders Medical Centre will improve outcomes for patients undergoing major abdominal surgery.

Chief Investigator of the study and Clinical Director of General and Digestive Surgery at Flinders Medical Centre, Dr David Wattchow explained that after surgery to remove colon cancer or other conditions there is usually a period of cessation of activity of the gastrointestinal tract, making it difficult for patient’s to eat for days.

‘In 10 percent of patients the cessation is prolonged and results in vomiting, abdominal bloating and the need for insertion of a tube into the stomach to relieve pressure on the gut,’ he said.

Research has shown that much of the cessation of activity was due to inflammation in the bowel wall following handling of the intestines.

This research also showed that the use of anti-inflammatory drugs, particularly the class of compounds known as cyclooxygenase 2 inhibitors (COX 2) blocked this inflammation and largely reduced the shutdown in gut activity.

Dr Wattchow developed a clinical trial of more than 300 patients in over three years to compare standard anti-inflammatory drugs and the COX 2 inhibitors which are available on prescription.

‘The patient’s ability to drink or eat, or restoration of early bowel function was unaffected by the drugs,’ Dr Wattchow said.

‘However, the number of patients developing paralytic ileus (paralysis of the intestine) was markedly reduced in those patients receiving the COX 2 inhibitor, but not the standard antiinflammatory drug.

‘The finding may point the way to solving what has been a very distressing condition that can affect patients after surgery.’

The Pharmacy Department at FMC has now approved the COX 2 inhibitor for use in patients undergoing major gastrointestinal surgery at FMC.

The findings of the study were published in the journal Alimentary Pharmacology and Therapeutics.

There has been a longstanding collaboration between the Departments of Surgery and Human Physiology in studying the nervous system, and motility of normal and diseased human bowel.

Unravelling The Secrets Of A Sneaky Protein
First Published: Investigator - December 2009
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Flinders researchers are unravelling the secrets of a tricky protein in their efforts to quash drug resistance in hospital strains of ‘golden staph’.

They hope that by learning more about the physiology of the protein – known as QacA – they can learn how to overcome its drug resistance.

However, the research team concedes the sneaky nature of the protein is making their task a challenge.

‘It’s a very adaptable protein that sits on the outer surface of a cell and can recognise more than 30 chemical compounds – including antiseptics and disinfectants commonly used in hospitals,’ Dr Melissa Brown, Associate Professor in the School of Biological Sciences at Flinders University said.

‘Once it recognises a chemical it sets to work pumping it out of the cell before the chemical reaches its target.’ She said its very inventiveness was probably one of the secrets behinds its success.

Staphylococcus aureus, often referred to as golden staph, is a common bacterium that lives on the skin or in the nose of human beings.

In most situations it is harmless, however if it enters the body through a cut in the skin it can cause infection and even death in extreme cases.

While most infections caused by golden staph are treatable with antibiotics, often a few bacteria will survive a course of antibiotics, perhaps due to gene mutation or obtaining genetic information from other surrounding antibiotic-resistant bacteria.

The resulting antibiotic-resistant Staphylococcus aureus bacteria that remain then flourish, since they no longer have to compete for resources with the rest of the colony.

Hospital patients with surgical or other wounds are particularly susceptible to golden staph and can become seriously ill if their golden staph infection resists treatment from antibiotics.

Dr Brown said the ultimate aim of her team’s National Health and Medical Research Council funded study was to learn enough about drug pumps like QacA so that pharmaceutical scientists could design new drugs to combat it.

‘The more basic science you have about the physiology of a bacteria the more likely you are to learn how to overcome them,’ Dr Brown said.

Research To Prevent Renal Transplant Rejection
First Published: Investigator - April 2005
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Advanced renal failure carries a very high risk of death from heart attack and stroke.

Amongst other abnormalities in blood chemicals and hormones, patients with renal failure often have a hardening of their arterial vessels which, in turn, increase the blood pressure causing further damage to the kidneys.

The Flinders Medical Centre Foundation has provided funding to Flinders Department of Clinical Pharmacology for a pilot study aimed to investigate the effects of renal transplantation on the stiffening of the arterial vessels.

Renal transplant patients will be studied before and after the transplant operation to see if they show minimal change or significant improvement in their vascular outcome.

Through this study Drs Arduino Mangoni and Jeff Barbara hope to be able to identify vascular changes if any, just after transplant and therefore be in a better position to identify those at risk.

‘Unfortunately some renal transplant patients have some degree of early vascular disease with a high risk of rejection later on. If we can pick them up at an early stage, rejection may be prevented’, said Dr Mangoni.

“We will measure the stiffness of the vessels before and shortly after the operation with a simple, safe and non invasive test. This will assist us to better identify and characterize those patients showing minimal change or improvement in stiffness post-transplant. Some people do well, some people not so well. We want to see if different degrees of improvement of the transplant could be predicted for late rejection”

Dr Mangoni’s project will hopefully lead to a larger project to test the hypothesis that arterial stiffness is an independent predictor of renal transplant rejection.

Drug Induced Kidney Damage - Who Is At Risk?
First Published: Investigator - April 2004
Updated:

Between one and five percent of people taking non-steroidal anti-inflammatory drugs (NSAIDs), used to treat inflammation and provide pain relief, will develop changes in kidney function.

NSAIDs are one of the most commonly administered groups of drugs worldwide and are used in treating many conditions, including rheumatoid arthritis, many sporting injuries and minor aches and pains.

Although NSAIDs pose little threat of kidney damage in healthy people, for those at risk a small percentage may suffer renal failure.

Associate Professor Kathie Knights and PhD student Voula Tsoutsikos from the Department of Clinical Pharmacology are working towards identifying how NSAID caused changes in normal renal function. They will also look at who might be at risk of NSAID-induced renal damage as a result of taking these drugs.

It is widely known that some people taking NSAIDs develop changes in renal function.

Changes can be as simple as fluid and salt retention right through to the more serious problem of acute renal failure. Some renal changes can occur within a week or kidneys may develop damage over a longer period of time. Fortunately these changes in kidney function are usually reversible if NSAID therapy is stopped.

NSAIDs work by blocking the production of prostaglandins (hormone-like substances that trigger pain signals to the brain and bring on inflammation). In some people prostaglandins are also involved in maintaining renal blood flow. The use of an NSAID, which inhibits the production of prostaglandins, may stop your inflammation but at the same time it stops the production of protective prostaglandins in the kidney.

Associate Professor Kathie Knights is hoping to identify a specific marker in those people with normal kidney function who might be at a particular risk of developing renal problems.

"If we can identify those factors within the kidney that increases a person’s risk then there is the potential to design better drugs and to take a different approach in using them."

"I believe we are on the track to identifying a much bigger role that the kidneys have in the metabolism of these drugs. Also the role that the kidneys play in the metabolism of the chemicals which regulate renal function and how NSAIDs actually interfere with these processes", said Assoc Prof Knights.

The Elmination Process
First Published: Investigator - January 2004
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Flinders researchers could be changing the face of drug discovery and development as they work towards generating in vitro (‘test tube’) and computational approaches that predict the efficiency of drug elimination from the body.

Humans are reliant on enzymes, located in the liver, for the elimination of drugs from the body. If we are unable to metabolise these drugs, they can accumulate causing adverse effects. Drug metabolism is the chemical modification of the drug in the body where it turns it into another chemical that the body finds easier to eliminate.

There are two main enzymes that are responsible for this metabolism and these are what Flinders researchers are most interested in.

Professor John Miners from the Department of Clinical Pharmacology at Flinders explains.

“These two enzymes are very complicated containing a whole family of closely related proteins, each of which tend to metabolise different drugs. Over recent years we have been able to clone all of these separate enzymes, making them available 'on tap' to study whenever we wish.

"With this accessibility we have been able to identify separate drugs or other chemicals that are specific for each of these individual enzymes. This provides a basis to develop models to predict the metabolism of any given drug and measure the efficiency of its elimination from the body without the need to administer it to humans

So successful is this research that pharmaceutical companies have enlisted these techniques in new drug discovery and development.

Drug discovery and development is hugely expensive. Less than 10% of chemicals that go into clinical development ever make it onto the market as drugs, with many failing because of problems with pharmacokinetics and metabolism.

This research will have potential significance with regard to the cost of new drug discovery and development, and will also be valuable in the rational use of current drugs.