Pathophysiology And Alternative Preventative Strategy For Breast Cancer Chemotherapy-induced Bone Loss
Funder
National Health and Medical Research Council
Funding Amount
$540,356.00
Summary
Combination cytotoxic chemotherapy is the current optimal approach for treating breast cancer in premenopausal women. However, long-term skeletal defects (osteoporosis and fractures) caused by the chemotherapy have become an increasingly serious problem due to its intensified use and improved patient survival rate. This project seeks to elucidate the mechanisms for chemotherapy-induced bone defects and to initiate development of a preventative treatment using natural bioactive micronutrients.
Measuring Adverse Events: Development Of A Patient-Centred Adverse Event Reporting Tool (PAET)
Funder
National Health and Medical Research Council
Funding Amount
$454,721.00
Summary
The decision to treat a patient depends on knowing whether the treatment does more good than harm. If it is likely that the treatment will work as well as or better than other treatments and will have minimal associated risks, then that treatment would be recommended unless unavailable or prohibited by cost. Given two equally effective treatments the one with fewer side effects and greater tolerability would be preferred by all. In the process of acquiring knowledge on treatment benefit and trea ....The decision to treat a patient depends on knowing whether the treatment does more good than harm. If it is likely that the treatment will work as well as or better than other treatments and will have minimal associated risks, then that treatment would be recommended unless unavailable or prohibited by cost. Given two equally effective treatments the one with fewer side effects and greater tolerability would be preferred by all. In the process of acquiring knowledge on treatment benefit and treatment harm we rely on evidence from clinical trials. However, the evaluation of benefit versus harm is not symmetric in this setting. Much more effort (e.g. study design, study power, standardisation of efficacy outcome measures) goes into the assessment of whether a treatment works and rather than its potential harm, as measured by adverse events. Adverse event ascertainment and reporting is poorly standardised . There is no standardised measurement process that elicits adverse event information. There is no standardised method for quantifying adverse event information into an index or profile scores equivalent to instruments developed to measure health status, quality of life and other benefits of treatment. Developing astandardised Patient-centred Adverse Event Questionnaire will benefit multiple stakeholders. For Patients: An easy to understand summary measure of treatment harm aids patient understanding of the benefit versus risk. For Doctors, allied health professionals: The Questionnaire includes drug profiles, to align a drug profile with an individual patient's clinical profile. This leads to better patient care. In health policy: All of the above has flow-on effects for policy. Better adverse event data will facilitate information and understanding generally of risks of treatments, risk-benefits of treatments, and cost-effectiveness of management strategies.Read moreRead less
Supraspinal Neural Adaptations In The Transition From Acute Injury To Chronic Pain And Disability
Funder
National Health and Medical Research Council
Funding Amount
$429,360.00
Summary
Although there have been significant clinical advances in the management of injury and the control of acute pain following tauma, many people still develop disabling conditions of chronic pain. Chronic pain and disability occurs even though the acute signs of trauma have subsided and injuries have healed. People with chronic pain conditions not only experience ongoing changes in sensation (ie., most commonly lowered thresholds for pain, touch evoked pain and spontaneous pain), they also endure a ....Although there have been significant clinical advances in the management of injury and the control of acute pain following tauma, many people still develop disabling conditions of chronic pain. Chronic pain and disability occurs even though the acute signs of trauma have subsided and injuries have healed. People with chronic pain conditions not only experience ongoing changes in sensation (ie., most commonly lowered thresholds for pain, touch evoked pain and spontaneous pain), they also endure a number of disabilities for example disrupted family and social relations, disturbed sleep, loss of appetite, weight changes, loss of sex drive, changes in menstrual cycle, the inability to cope with stressors, and often moderate to severe anxiety and depression. The proposed research aims to (i) identify changes in brain circuits which are responsible for producing these patterns of pain and disability following injury and (ii) attempts to selectively reverse some of these disabilities by reversing the brain changes. The results of this study will offer for the first time a rational basis for improving the outcomes of injury and pain management in the acute phase of trauma, by identifying and reversing the critical changes which predict the advent of the state state of chronic pain and disability.Read moreRead less
Clinical Pharmacology Of Methadone During Induction Onto Maintenance Treatment.
Funder
National Health and Medical Research Council
Funding Amount
$422,310.00
Summary
Heroin addiction can be very successfully treated by substituting heroin with methadone. The transition of stopping heroin and starting methadone is risky and can be associated with death. This application seeks to explore the mechanisms of the increased risk during this transition period so that appropriate management strategies might be instituted.
Role Of An Endogenously Synthesised Sterol In Regulating Cholesterol Removal From The Macrophage
Funder
National Health and Medical Research Council
Funding Amount
$276,000.00
Summary
Heart disease remains the greatest killer of Australians and involves accumulation of cholesterol in the artery wall. Cholesterol accumulates in a specific cell-type called the macrophage (literally means ' big-eater'). Once macrophages accumulate cholesterol, they become bloated cholesterol-filled foam cells. The early and persistent appearance of foam cells in diseased artery suggests that foam cells are active participants in the development of heart disease. Prevention or reversal of their f ....Heart disease remains the greatest killer of Australians and involves accumulation of cholesterol in the artery wall. Cholesterol accumulates in a specific cell-type called the macrophage (literally means ' big-eater'). Once macrophages accumulate cholesterol, they become bloated cholesterol-filled foam cells. The early and persistent appearance of foam cells in diseased artery suggests that foam cells are active participants in the development of heart disease. Prevention or reversal of their formation is therfore an attractive target for new therapies to treat heart disease. In this proposal, we address specific questions which will increase our understanding of how best to prevent or reverse foam cell formation. This work may indicate new therapeutic possibilities for combating heart disease.Read moreRead less
Effect Of Liver Pathophysiology On Hepatic Pharmacokinetics
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
The liver is the main organ in the body for the metabolism and biliary excretion of natural and foreign solutes. Various liver diseases such as cirrhosis, alcoholic liver disease, diet and drug induced fatty livers can affect the uptake and metabolism of drugs and their suitability- dosing needs. Some liver diseases such as fatty livers are very common but how rapidly drugs are metabolised in these patients is not well described. The work is important as it may help us better design new drugs an ....The liver is the main organ in the body for the metabolism and biliary excretion of natural and foreign solutes. Various liver diseases such as cirrhosis, alcoholic liver disease, diet and drug induced fatty livers can affect the uptake and metabolism of drugs and their suitability- dosing needs. Some liver diseases such as fatty livers are very common but how rapidly drugs are metabolised in these patients is not well described. The work is important as it may help us better design new drugs and better choose which drugs to give and, if so, in what doses. In addition, many liver diseases require a biopsy for a definite diagnosis of the likely function of the liver. Estimation of liver function is particularly important in estimating whether there will be sufficient reserve on resection of a cancer or deciding if a liver transplant is needed. The liver is also a very complex organ which can trap or breakdown solutes by a range of different systems. Also of importance is how those diseases affect drug disposition in the liver given that an altered hepatic drug disposition may affect systemic response to the drugs and their metabolites. This work seeks to answer these questions.Read moreRead less
Regulation Of Human Arylamine N-acetyltransferase Transcription, Translation And Protein Stability
Funder
National Health and Medical Research Council
Funding Amount
$470,958.00
Summary
Individuals respond very differently to many drugs and other chemicals in the diet and workplace. This variation can be a significant complication in treating patients and in attempting to determine risk with exposure to toxins. Genetic differences between individuals are a common reason for this variation. However, many enzymes and other proteins in humans are controlled by environmental factors that can either increase their activity or inhibit it. In this study, we will investigate how the ac ....Individuals respond very differently to many drugs and other chemicals in the diet and workplace. This variation can be a significant complication in treating patients and in attempting to determine risk with exposure to toxins. Genetic differences between individuals are a common reason for this variation. However, many enzymes and other proteins in humans are controlled by environmental factors that can either increase their activity or inhibit it. In this study, we will investigate how the activity of an important family of enzymes (the acetyltransferases) varies between individuals as a result of environmental factors. We will look at the genes for each of the enzymes and learn about this control mechanism. We will also look careful at the structure of the proteins and determine how this may change when challenged with external stimuli. The expected outcome will be a better understanding of these important enzymes that are involved in the metabolism of many drugs, and also provide a means of determining how different individuals may respond to foreign chemicals and drugs that use these enzymes in the body for metabolism.Read moreRead less
Pathogenesis Of Antiretroviral Induced Sub-cutaneous Fat Wasting
Funder
National Health and Medical Research Council
Funding Amount
$331,650.00
Summary
The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successful ....The use of potent antiretroviral therapy has resulted in great clinical and survival benefit in patients with HIV infection and has in most cases, outweighed the risk of short term side effects. However, not that survival of patients with AIDS has considerably improved the long-term complications of chronic therapy have become a critical issue. Lipodystrophy syndrome(s) is the name given to a set of changes to blood lipids, glucose levels and body habitus and typically occurs in those successfully treated with anti-HIV therapy. The facial and body habitus changes are common, progressive and are frequently disfiguring. Aside from the psychological and social effects of such changes, many patiens are not able to retain their anonymity as HIV infected individuals. In addition, changes to blood lipids may lead to atherosclerosis. Already there have been several case reports of premature coronary disease in young HIV infected patients. It is increasingly difficult for patients to remain strictly adherent to chronic therapy because of all these concerns. There is an urgent need to understand the exact biological cause(s) of lipodystrophy syndrome(s) in HIV infected patients in order to help identify which of our currently available antiretroviral therapies will offer the long term clinical and survival benefit of strong viral suppression without increasing risk of vascular disease. Based on results of our previous studies on lipodystrophy syndrome, we have proposed that lipodystrophy may be the result of antiviral drugs depleting the DNA content of mitochondria within fat cells. We propose to examine sequential fat biopsy specimens from HIV infected volunteers to determine whether antiretroviral therapy has had adverse effects on mitochondrial DNA content and-or function.Read moreRead less
The Role Of The Osteoblast In Mediating Glucocorticoid-Induced Metabolic Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$825,254.00
Summary
Glucocorticoids (GC) exceed most other drugs in terms of numbers of patients treated and indications. Preventing or attenuating the deleterious effects of GC on fuel metabolism is therefore of great clinical significance. Our studies will create new knowledge regarding the mechanisms of GC-induced diabetes and osteoporosis, and will contribute to the development of new approaches that are essential to tackle the pressing medical problem of GC-induced disease.