Transdermal penetration of corticosteroids in the dog. Topical application of corticosteroids enhances drug concentration and effectiveness in the treatment of skin diseases. Most topical corticosteroid preparations have been developed for human use and are poorly efficacious or promote a high incidence of adverse effects in dogs. This project will characterize corticosteroid penetration through canine skin to permit the development of suitable topical formulations to more effectively control ....Transdermal penetration of corticosteroids in the dog. Topical application of corticosteroids enhances drug concentration and effectiveness in the treatment of skin diseases. Most topical corticosteroid preparations have been developed for human use and are poorly efficacious or promote a high incidence of adverse effects in dogs. This project will characterize corticosteroid penetration through canine skin to permit the development of suitable topical formulations to more effectively control skin diseases in the dog. Skin diseases are a significant problem in veterinary science and this project will not only provide an effective therapeutic option, but also reduce animal (and client) distress when suffering skin disease and/or adverse effects from traditional therapy.Read moreRead less
Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepress ....Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepressant drugs and to the design of drugs to prevent the effects of cocaine.Read moreRead less
Pharmacological modification of retinal and visual function and relation to control of refractive error. Myopia (short-sightedness) affects many hundreds of millions of people worldwide and can lead to blindness. Drug treatments that prevent myopia are being developed, however there is no efficient way of determining who is at risk of myopia or who will benefit from these treatments. This fundamental research project will determine the retinal and visual effects of pharmacologic agents that inhi ....Pharmacological modification of retinal and visual function and relation to control of refractive error. Myopia (short-sightedness) affects many hundreds of millions of people worldwide and can lead to blindness. Drug treatments that prevent myopia are being developed, however there is no efficient way of determining who is at risk of myopia or who will benefit from these treatments. This fundamental research project will determine the retinal and visual effects of pharmacologic agents that inhibit myopia, with the aim of determining an ocular measure that is related to myopia, which is altered by drugs that are known to slow myopia progression, and that could be used as an indication of an agent's likely effectiveness.Read moreRead less
Probing norepinephrine transporter (NET) structure-function. More selective drugs are needed to improve the treatment of a range of diseases including pain, depression and anxiety. This project will apply advanced molecular pharmacology approaches to better understand how the norepinephrine transporter functions and where small molecules and conotoxins bind to inhibit its activity.
Systematic evaluation of whether in vitro methods can predict in vivo opioid analgesic efficacy, safety and tolerability. It is estimated that chronic pain affects one in five individuals in the general community in Australia and worldwide, with prevalence rates correlated directly with advancing age. Chronic pain not only adversely affects the quality of life of individuals but it also places a large economic burden on our healthcare system. Development and validation of an in vitro method to ....Systematic evaluation of whether in vitro methods can predict in vivo opioid analgesic efficacy, safety and tolerability. It is estimated that chronic pain affects one in five individuals in the general community in Australia and worldwide, with prevalence rates correlated directly with advancing age. Chronic pain not only adversely affects the quality of life of individuals but it also places a large economic burden on our healthcare system. Development and validation of an in vitro method to successfully identify novel morphine-like strong analgesics with a reduced propensity for producing respiratory depression or constipation, has the potential to not only improve pain management for individuals and to reduce the economic burden of chronic pain on the Australian healthcare system, but it is also likely to produce direct economic benefits to our nation. Read moreRead less
Novel pharmacological agents to target stroke-induced brain injury. There is a looming stroke epidemic in Australia. 72% of Australian stroke sufferers are over the age of 65 and whereas in 1997 only 12% of Australians were in that age group, by 2030 that number will have increased to 23%. There is an urgent need for novel therapies. This project will aid the development of a novel anti-stroke therapy.
Treating Equine Laminitis. This project aims to explore the causes of equine laminitis, and to work with a newly-established Australian biopharma company to develop the world's first anti-laminitis medication. Equine laminitis is a painful, crippling disease of the foot, often necessitating euthanasia, and is the second-most common cause of death in domestic horses. In 2007, a landmark study identified insulin toxicity as a primary cause of laminitis, and subsequent research has identified over- ....Treating Equine Laminitis. This project aims to explore the causes of equine laminitis, and to work with a newly-established Australian biopharma company to develop the world's first anti-laminitis medication. Equine laminitis is a painful, crippling disease of the foot, often necessitating euthanasia, and is the second-most common cause of death in domestic horses. In 2007, a landmark study identified insulin toxicity as a primary cause of laminitis, and subsequent research has identified over-stimulation of the IGF-1 receptor as the most likely mechanism. This project aims to prove that mechanism and to develop an effective treatment.Read moreRead less
Examination Of The Molecular Pharmacology Of Anthracyclines Induced Via Their Interaction With Iron
Funder
National Health and Medical Research Council
Funding Amount
$618,401.00
Summary
Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and ....Anthracyclines are highly effective anti-cancer drugs, but their use is limited by toxic effects on the heart. This is thought to be due to these drugs directly binding iron (Fe). Indeed, we showed that anthracyclines induced marked changes in the way heart cells utilise Fe (DR1-3, 38; Mol. Pharmacol. 2002, 2003, 2004, 2005). We were the first to show that anthracyclines prevent Fe release from the criticial Fe storage protein ferritin. This prevents the use of Fe for vital processes eg. DNA and haem synthesis. Hence, this effect probably contributes to the cytotoxic activity of anthracyclines on the heart. We showed that novel drugs developed in my lab that bind Fe called chelators show high activity in animals (DR4) and prevent anthracycline-mediated Fe accumulation in ferritin. Importantly, Fe chelators have been shown to inhibit anthracycline-mediated cardiotoxicity. Indeed, the clinically used cardioprotective agent, ICRF-187, is actually an Fe chelator (5, DR6). However, ICRF-187 is not totally successful in terms of its cardioprotective effects and can cause myelosuppression (5, DR6). While the clinically used chelator, desferrioxamine (DFO), can prevent anthracycline-mediated cardiotoxicity, its poor membrane permeability limits its effectiveness. Our chelators are highly permeable and overcome the disadvantages of DFO (DR4). Thus, they are vital to examine for preventing anthracycline-mediated cardiotoxicity. In this proposal we will examine the changes in Fe metabolism induced by anthracyclines and test the hypothesis that novel Fe chelators may prevent the cardiotoxicity of these agents. We also aim to be the first to assess if preparation of anthracyclines which cannot bind iron prevents their cardiotoxicity. This will be done by preparing metal complexes of these drugs which prevent Fe-binding eg. anthracycline-zinc complexes. These studies are important for the development of less cardiotoxic forms of these very useful anti-tumour agents.Read moreRead less
A VAST potential for ion channel drug discovery. The purpose of this project is to bring innovation into the methods used for identifying and characterising novel carbohydrate-based compounds acting at ion channels. These molecules will have high potential to be developed as highly effective treatments for pain without the unpleasant side-effects associated with current treatments.
Efficacy profiling innovation in novel pain therapeutics discovery. The purpose of this project is to bring innovation into the methods used for selecting novel compounds with high potential for progression into development as highly effective pain-killers for improving the relief of chronic pain. This will result in new pain-killers that are highly effective without producing unpleasant side-effects.