Health Horizons - Issue 4

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Commentary: Making medicines safer, Professor Libby Roughead

Research spotlight: Skin deep: Sansom scientists delve into nanomedicine, Professor Mike Roberts

Five minutes with: Professor Sanjay Garg

Research in action: Natural medicines to prevent chemo-induced bone defects, Professor Cory Xian


Prof Libby Roughead

Making medicines safer

by Professor Libby Roughead

A leading figure in medicines research and policy, Professor Libby Roughead is Director of the Sansom’s Quality Use of Medicines and Pharmacy Research Centre. She is currently driving a range of research helping to detect problems associated with medicines and medical devices as head of an NHMRC-funded Centre of Research Excellence.

When we’re prescribed a medicine by our GP most of us trust that the medicine will be effective without harmful side effects. Unfortunately that is not always the case; despite the existence of extensive regulation surrounding pre-market testing of medicines, we are still not aware of all the side effects of a medicine when it first gets to market. Some estimates suggest 50 per cent of adverse events aren’t discovered until after marketing.

Problems with medicines are common. Around two million Australians experience an adverse reaction to a medicine every six months, and this has a flow-on effect, leading to 400,000 extra visits to the doctor and almost 200,000 hospital visits a year. As well as the hard-to-quantify costs to individual health and wellbeing it’s an expensive problem for taxpayers and insurance companies, estimated to cost around $1.2 billion every year.

So what is behind this problem? Why can’t we ensure medicines are safe before they reach the shelves? The truth of the matter is that in some cases it’s not possible to identify rare adverse events until a medicine has been used by many thousands of people. When a new medicine reaches the market, it has typically been tested on less than 10,000 people and the studies are designed to test the effect of the medicine only. What we don’t always test for is how that new medicine may interact with the combinations of medicines that people in the wider world may be taking. Historically we only used one medicine for one disease, and most of us only had one illness. But now it’s not unusual to find people living with multiple illnesses and on ten or more medications at the same time.

On top of drug interactions we also have disease interactions to contend with. By treating one disease you can make another disease worse and trials don’t usually test for this, trials only look at how a medication affects one disease. 

This leaves an enormous task for post-marketing surveillance of medicines. Enter the Centre of Research Excellence in Post-Marketing Surveillance of Medicines and Medical Devices. Established at the Sansom Institute in 2012, this NHMRC-funded initiative is helping to identify potential problems with medicines and medical devices by compiling and analysing a mass of health data from Australia and around the world.

The Centre is conducting a range of work around three key themes: developing methods for finding problems faster, confirming the problems and identifying those most at risk, and monitoring safe use.

It is now one year since the Centre was established, and we’ve had some satisfying results. We have written code to help us analyse health claims data in a way that lets us look at potential signals of adverse drug reactions. We’ve tested the code and sent it to our counterparts in Japan, Taiwan, the US, Korea and Sweden, who then did further tests that collectively accessed the de-identified health data of 200 million people.

This kind of analysis is invaluable. Not only does it help us pinpoint rare but noteworthy adverse reactions because of the vast amount of data at our fingertips, but it also allows us to examine adverse reactions that might differ across ethnic groups. People from different ethnic groups often metabolize medicines differently. We're also able to look at the impact of different health systems and prescribing practices across countries. The more we can learn about these nuances the better chance we have of improving prescribing practices and minimising medication harms.

One of the things we’ve looked at is the use of antipsychotics and whether they may induce acute hyperglycaemia. Other medications under the microscope, so-to-speak, include some diabetes medicines that in rare events may cause heart problems, and the association between non-steroidal anti-inflammatory agents and stroke.

We’re also looking at interactions between medicines and devices. For example, you might have a new hip, but does it make any difference if you’re taking osteoporosis medications? This is the kind of question that wouldn’t get asked in a clinical trial, but that we are now able to drill down to.

This is hard work and an enormous job, but it is vital; our results are shining a light on the crucial subtleties of modern medication management and leading the way towards safer multi-national drug safety monitoring.

My advice to the average person or health consumer concerned about the safety of their medication would be to be on the lookout for any adverse events and to report them. If you’ve started taking a new medication and have experienced new symptoms, be aware that this could be an adverse event and speak with your doctor about them.

Often people aren’t even aware or sure if they’ve had an adverse reaction, but it’s only from people reporting what’s occurred that we can identify the problem and eliminate it. A recent example that comes to mind is the case of a medicine called olmesartan, a blood pressure medication, that is used to treat hypertension but on rare occasions was causing chronic diarrhoea and weight loss in some patients. It was only because two patients asked if the medicine could be the cause of their problem that scientists were able to uncover a number of similar cases and then rule out other potential contributing factors.

People should also be aware that newer medicines are not necessarily safer medicines. We know a lot about the older medicines developed in the ‘50s and ‘60s and are more aware of their potential pitfalls, whereas that’s not always the case with newer medications. Report adverse events to the Therapeutic Goods Administration. Good advice for consumers and health professionals is available via the NPS MedicineWise website. 

Some might say examining the safety of medicines and medical devices post-marketing is a can of worms but I prefer to look at it as a giant jigsaw puzzle. By combining what we know about different medications, drug interactions, devices, diseases, disease interactions, health systems and metabolic systems, we’re providing health professionals with the data they need to ensure medications and medical devices are used safely – and, most importantly, patients with peace of mind. 

For more information on the Sansom Institute's research activities please visit our webpage

Research spotlightConfocal Microscope Image

Skin deep: Sansom scientists delve into nanomedicine

Nanotechnology – essentially the manipulation of materials on a molecular level – is a concept that’s been around since the 1950s, but it’s only in recent years that this broad field of science has found a foothold in health and medicines. While products such as antibacterial dressings infused with silver nanoparticles are being embraced by consumers and health practitioners, there are many more promising applications in development, with a group of Sansom-based scientists at the vanguard. 

Needle-less vaccines, medicines to target melanoma cells, and stains to better diagnose tumours are some of the possible applications being investigated as part of an NHMRC-funded research program into skin and nanosystems.

Led at UniSA and the Queen Elizabeth Hospital by Professor Michael Roberts, the project is being conducted in collaboration with Professor Roberts’ colleagues at the University of Queensland and the Prince Alexandra Hospital, including Eureka Prize-winning scientist Mark Kendall, and Ian Frazer, one of the scientists behind the HPV cervical cancer vaccine.

The researchers are looking at three main areas: how to deliver larger molecules through the skin to reach certain cells; how to show the molecules have reached their targets; and how to show they have been effective without other unwanted side effects.

One year into the three-year project, and Professor Roberts reports that the team has made some important discoveries that will help to ensure the safety of future nano-based skin products. “We’ve realised skin is a bit more complex than we thought – there are glitches where nanomaterials may be able to get through the skin that we haven’t realised before,” he says. “We’re exploring those glitches to see how we can use that for safer and more effective medicines delivery.”

Skin is a particularly important area for health-based nanotech applications because, as well as providing an effective barrier to many types of infection, it is also the area that you can get the most effective immune response. "Immune cells are more highly concentrated in skin than muscle, and it’s this realisation that has led to the recent development of vaccine patches where you need only a one hundredth or one thousandth of the normal vaccine dose to get the same immune response," Professor Roberts explains.

Another exciting possibility being explored is developing nanomedicine to treat melanoma. Researchers are building upon Professor Roberts' previous work on a technique called regional lymph perfusion, where a tourniquet is applied around a tumour, high dosage chemo is applied, and then flushed out of the body. The technique is a clear avenue for nanotechnology. "It's still early days but we know that nanotechnology can allow us much more control over drugs in terms of how long they stay in the body and how and whether they can get out, so combining that with existing regional chemotherapy techniques holds a lot of potential."

With the Sansom's advanced confocal and multiphoton imaging facilities allowing researchers to accurately visualise where and how drugs interact with cells in the various layers of skin, the UniSA team is also examining the potential of harnessing nanotechnology to achieve better diagnostic imaging of cancerous tumours. 

It’s an exciting field but one that is not without its critics, with questions surrounding the safety of nanotechnology persisting after some types of nanoparticles have been shown to stay in the body. While some concerns are well-founded, others have been blown out of proportion, according to Professor Roberts. "There's been a lot of fear-mongering surrounding sunscreens using zinc-oxide-based nanomaterials, but that fear has been exaggerated and the critics have ignored in vivo studies that show these sunscreens break down in water and pose no risk," he says.

"On the other hand, recent experiments have shown some forms of nanoparticles appear to stick in bodies forever and could induce cancer, so we have to keep an even keel and make sure we’re aware of the dangers. Still, those experiments have told us something useful – we know those are nanoparticles that we don’t want to use, and we’re now trying to make biodegradable nanoparticles. You can take these bad experiences and turn them into positives by redefining and redesigning your approach."

Aware of the need to rule out potential risks, Professor Roberts says many of the benefits of nanotechnology in medicines are a way off, but he’s optimistic about the possibilities. "Nanotechnology also has a role to play not just in medicine but in the technology of medicine; it can allow for miniaturisation that has massive potential in developing, for example, tiny capacitors that could be used in medical devices," he says. "In future, nanotechnology will be combined with other technologies to become more effective and I think we’ll be able to diagnose and treat diseases in a way that we never dreamed we could, allowing for more evidence-based, personalised medicine."

For more information on the Sansom Institute's research activities please visit our webpage

Five minutes with...Prof Sanjay Garg

Professor Sanjay Garg

A pharmaceutical scientist whose areas of expertise range from medicine formulation to clinical trials and regulation, Professor Sanjay Garg is leader of the Sansom Institute’s Centre for Drug Formulation and Delivery.

With a career spanning over two decades you have 26 patents to your name and have worked on everything from probiotics to polymer implants. What’s the achievement that you’re most proud of?

If there was one thing I’d have to pick, it’s my work in the area of HIV prevention; I did my PhD in the development of microbicides and I’ve been lucky to continue that work for almost 20 years, to the point where one of my formulations – Amphora, a contraceptive lubricant that has anti-HIV properties – is currently in phase three clinical trials in the US as a contraceptive.

The company that’s developing the product will market it as a contraceptive rather than an HIV-preventative because HIV trials are extremely difficult to conduct. To test such a prophylactic product, you need healthy participants, but you can’t take the risk of exposing them to HIV.

If it all goes well then Amphora will reach shelves in three to four years’ time, which would be pretty extraordinary when you consider that globally only 25-30 new drugs are approved each year. If the trials are a success and the product is approved then it will be one of that select number and will be helping people all around the world – that will make me very proud indeed!

We often hear about how new medicines take years and years and exorbitant amounts of money to reach the market. Do you think the barriers to getting a new drug to market are excessive or are they in-line with what’s required to ensure safety?

I believe the timelines and costs are in-line with what’s required. Knowing that a new drug is going to be for humans and animals, you have to be absolutely sure it’s safe before it’s authorized for population-wide use. You don’t want a product that cures but kills at the same time.

It usually takes around 10-15 years and $1 billion in investment before a new drug reaches consumers. It’s expensive because there are a lot of failures and weeding out those failures are a necessary part of the process. Typically they start with 10,000 compounds of which only one will make it to the market – but someone has to pay for those 9,999 compounds that fail at different stages. That $1 billion is not just the cost of the one successful compound, it’s the cost of all the failures as well.

In recent years we’ve seen increasing interest in plant-based medicines, while at the same time nanotechnology has taken off. Does one field trump the other or can they peacefully co-exist?

They can coexist. Some people say nanotech has all the answers, others think plants have all the answers, but that’s simply not true. Nanotechnolgy is opening up opportunities that were not even possible a few years ago – one example is a project I’m working on with a company in Sydney to develop new anti-bacterials to fight resistant superbugs. Most of the promising compounds are insoluble, which are hard to use clinically, so we’re using nanotechnology to develop new formulations that are soluble and bioavailable.

Similarly, plant-based medicines have an enormous number of applications and opportunities. An example that comes to mind is Paclitaxel, one of the more common anti-cancer drugs; it's a semi-synthetic which comes from the bark of the Pacific Yew tree and it’s been used to treat lung, ovarian and breast cancer.

How important are university-based research programs – as compared to private companies – in the development of new medicines and the training of young scientists?

I think the difference is universities can afford to work on problems that don’t necessarily have a direct commercial tag attached to them. We still need money to do the work that we do, but thanks to funding from government bodies like the NHMRC it’s possible for us to focus on what’s really needed for humanity rather than what’s going to be of great commercial interest. So universities can afford to be more innovative and flexible in their approach to research.

That’s part of the reason I've chosen to stay in academia and collaborate with industry rather than working exclusively for one company. As well as enjoying working with students, I like the opportunity to work on creating solutions to the problems that really matter. The key to my research is industry and academics collaborating to find solutions that can reach people who need them.

You’ve worked in the US, India and New Zealand, making the move to the Sansom Institute for Health Research at UniSA in 2011. What attracted you here?

UniSA is a very exciting place to be – it’s very progressive and forward-looking. Its emphasis on establishing and supporting innovative research clusters has offered me opportunity to interact with leaders in fields like materials science and cancer biology.  

In Australia I have experienced openness, and a real encouragement of international collaboration. It's allowed me to bring in visiting students from Malaysia, Singapore and Brazil, as well as establishing a new partnership – the China Australia Health Science Centre – with Shandong University in China.

If science, money and policy were not barriers, what in your opinion would be the single medicines development breakthrough that would have the biggest positive impact upon human health?

I may be biased but I have to say new antibacterials to fight superbugs. Resistance to antibiotics is becoming a real problem and we’re now talking about going back to a pre-penicillin era where nothing will work to fight infection. I've recently been working to develop new antibacterial compounds for use in humans and animals as part of a collaboration with the Universities of Adelaide and Newcastle.

Infectious diseases have the greatest impact on the masses, particularly in developing countries, and I'm full of admiration for people like Bill and Melinda Gates who have put so much effort into supporting research into infectious diseases like AIDS, malaria, and tuberculosis; they've provided support to my group and so many other worthwhile projects around the world.

It's a challenging field. Pharmaceutical companies are not particularly interested in developing new medicines to treat infection because of smaller market opportunity, they are keen on developing drugs for cholesterol, diabetes etcetera. There hasn't been a new antibiotic released onto the market in the last 30 years and that's largely because there’s more money to be made in medicines that people have to keep taking long-term.

Finally, what are your predictions for the next big things in medicines development?

Some people talk about personalised medicine being the next big thing and while I'm keen to see how it emerges I’m sceptical because it's going to be very expensive to regulate and operate. Right now medicines are made for millions and when you start looking at it from an individual basis it’s going to be difficult.

Looking to the future, as well as fighting superbugs, I'm hoping we can develop better medicines and delivery systems for cancer. I've seen so many people affected – students, parents, colleagues – it's terribly distressing. The universities and research organizations are doing a lot, so I'm hopeful that if we keep up the momentum, we’ll be able to conquer cancer in the near future.

For more information on the Sansom Institute's research activities please visit our webpage

Research in actionFish oil tablets

Natural medicines to prevent chemo-induced bone defects

Developing more effective and safer medications to treat cancer is one of the highest priorities in health science today, with thousands of studies and trials being conducted around the world at any given time. However, the time lag between research discoveries and better medications reaching patients presents a dilemma for researchers keen to make a difference in the short and medium term. 

With this in mind, bone growth specialists from the Sansom Institute for Health Research have been exploring the potential of naturally-occurring substances including fish oil and genistein (an antioxidant sourced from soy beans) as supplements to offset the side effects of chemotherapy drugs.

The Sansom's Bone Growth and Repair Research Group started looking into natural substances as a way to counter the bone-damaging effects of chemotherapy drugs which, despite improving cancer survival rates, are also associated with bone growth impairments in young cancer patients and an increase in osteoporosis and bone fractures.

The results so far have been extremely encouraging and may open the door to beneficial treatments that will be straightforward to implement, according to group leader, Professor Cory Xian. "The beauty of this is that the substances we are looking at are natural and considered to be safe so they can be adopted relatively easier without too many safety or ethical concerns," Professor Xian says.

In research recently published in Plos One, the UniSA researchers investigated the use of fish oil and genistein supplements in rats to reduce the side effects of methotrexate (MTX), a commonly-used childhood cancer drug that is also used to treat breast cancer and rheumatoid arthritis.

While the beneficial properties of fish oil have been well-documented – including research showing Omega-3s’ capacity to limit bone mass loss in menopausal women – this is the first time researchers have tested fish oil’s effect upon bone health when taken in conjunction with chemotherapy drugs.

"The results showed multiple benefits from fish oil, genistein and combinations of the two, including the ability to preserve bone formation during chemotherapy; a reduction in the amount of bone degradation caused by MTX; and also limiting fat cell accumulation in bone marrow," Professor Xian says.

With all of these effects helping to maintain bone health, it's an important development in the quest to improve the health and quality of life of increasing numbers of cancer survivors.

This landmark research was funded by the NHMRC and the Channel 7 Children’s Research Foundation and conducted by PhD student Rethi Raghu Nadhanan, Yu-Wen Su, Dr Rosa Chung, Jayne Skinner, Professor Peter Howe, and Professor Xian. It was presented at the 8th Combined Meeting of Orthopaedic Research Societies in Venice in October 2013.

The next step, says Professor Xian, will be to investigate the effects of the natural supplements in conjunction with other chemotherapy drugs over a longer treatment period.

"This study was short-term and only looked at one drug," he says. "What we’re doing now is to see if the treatment can be used in an MTX longer term treatment model and a breast cancer combination chemotherapy model essentially to translate the research into a more clinically-relevant context. Then we can consider whether to initiate clinical trials."

"We’ve also collected samples from the intestines and have a PhD student, David Xu, looking at how supplements can reduce tissue damage in the gut caused by chemo," Professor Xian says. 

It’s all part of an important evolution in medical science that is seeing increasingly positive results from combining the use of synthetic and natural medicines to optimise patient wellbeing. "These days you cannot look at things in isolation," Professor Xian says. "Natural substances have enormous potential but it all comes down to the scientific evidence of knowing how they work and their effectiveness and safety in helping treating some conditions. There’s still a lot of work to be done and a lot to be discovered."

For more information on the Sansom Institute's research activities please visit our webpage

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