Comprehensive Assessment Of Novel Artemisinin-based Combination Regimens For Treatment Of Malaria In Papua New Guinea
Funder
National Health and Medical Research Council
Funding Amount
$529,500.00
Summary
Malaria is one of the most important causes of death and disease in Australia's closest neighbour, Papua New Guinea (PNG). The cornerstone of strategies to tackle malaria is the provision of prompt and effective drug treatment for those at risk. Unfortunately older drugs are becoming ineffective due to development of resistance and most newer drugs are too expensive for poor countries. As in sub-Saharan Africa, a looming public health disaster awaits the imminent loss of effectiveness of afforda ....Malaria is one of the most important causes of death and disease in Australia's closest neighbour, Papua New Guinea (PNG). The cornerstone of strategies to tackle malaria is the provision of prompt and effective drug treatment for those at risk. Unfortunately older drugs are becoming ineffective due to development of resistance and most newer drugs are too expensive for poor countries. As in sub-Saharan Africa, a looming public health disaster awaits the imminent loss of effectiveness of affordable antimalarials in PNG. There are however some new drugs that may be highly effective and relatively cheap but require further evaluation before they can be deployed. The new artemisinin drugs from China are cheap, safe and effective. However they must be combined with a second drug to ensure cure and to prevent the development of resistance, a stragegy known as artemisinin combination therapy (ACT). The World Health Organisation has endorsed ACT but finding a suitable 2nd drug to combine with the artemisinin drug has been challenging. Our group has pioneered research into the drug piperaquine, which we believe may be the best affordable drug to combine with artemisinin drugs. Piperaquine was first synthesised in the 1960's and was shown to be effective in Chinese studies in the 1970's, but little is known of its blood levels, metabolism and interactions with other drugs in humans. We plan to carry out laboratory studies, studies in healthy volunteers, and field studies in PNG children with malaria that should provide detailed information about piperaquine and its potential role in ACT for malaria. This will help us to develop better dosing formulations and to maximise the effectiveness of this treatment. Development and registration of a piperaquine-containing ACT would consititute a new and potent weapon in the fight against malaria in PNG and other tropical countries.Read moreRead less
Potential Anti-tumour Agents: Iron Chelators Of The Pyridoxal Isonicotinoyl Hydrazone Class
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
Iron (Fe) is essential for proliferation. Generally, cancer cells have a high Fe requirement due to their rapid rate of proliferation making them very susceptible to iron chelators which deplete cells of Fe. The potential of this therapy has been confirmed by the entrance of the chelator, Triapine (Vion Pharmaceuticals), into clinical trials. Further, a wide variety of studies including clinical trials have shown that the clinically used Fe chelator, desferrioxamine (DFO), can have potent anti-t ....Iron (Fe) is essential for proliferation. Generally, cancer cells have a high Fe requirement due to their rapid rate of proliferation making them very susceptible to iron chelators which deplete cells of Fe. The potential of this therapy has been confirmed by the entrance of the chelator, Triapine (Vion Pharmaceuticals), into clinical trials. Further, a wide variety of studies including clinical trials have shown that the clinically used Fe chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial (Cancer Res 1990;50:4929), a marked decrease in tumour burden was observed while there was no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers serious problems, including that it requires long infusions and does not readily permeate cells. Considering this, during the current NHMRC grant, we developed a novel group of chelators that show far greater activity than DFO and Triapine at inhibiting cancer growth in vitro and in vivo (Richardson BLOOD 2004;104:1450). These studies have been published in high quality journals such as BLOOD and Clin Cancer Res (Richardson 1995, 1997, 1999, 2001, 2002, 2004a,b,c) Recently, a potent metastasis suppressor gene, known as differentiation related gene-1 (Drg-1), has been identified. Up-regulation of this molecule plays an important role in inhibiting the growth of primary cancers and their metastatic spread. Importantly, we have recently shown that our new chelators markedly up-regulate the expression of Drg-1 in cancer cells and at the same time markedly and selectively inhibit the growth of these cells (Richardson BLOOD 2004;104:2967). Our hypothesis is the marked increase in Drg-1 expression after treatment with chelators could inhibit cancer cell growth and metastasis. Studies in this NHMRC grant renewal will lead to the development of new therapies and a greater understanding of cancer metastasis and biology.Read moreRead less
Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in ....Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in tumour burden was observed while there were no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers from serious problems, including that it requires long infusions and does not readily penetrate cells. Further, in some cancer patients, DFO has shown little activity. Considering these results, we have developed a new group of chelators that show far greater activity than DFO at inhibiting cancer cell growth. These studies have been published in high quality journals such as BLOOD (Richardson et al. 1995, 1997, 1999) and form the basis for the current study. In this study we will examine how these iron-binding drugs work to inhibit the growth of cancer cells compared to their normal counterparts. These studies are important for the rational design of even more effective chelators. Recent studies in my lab have shown that our new chelators have far greater activity than a drug currently used to treat leukemia, known as hydroxyurea (HU). Our studies also show that the chelators act by a variety of mechanisms, explaining their greater activity than HU. Furthermore, we have shown that these chelators show significant anti-tumour activity in mice. The potential of this form of therapy has been confirmed by the entrance of the chelator, Triapine, into clinical trials (Vion Pharmaceuticals, USA). Our chelators are more effective than Triapine, thus, the present project is crucial for developing novel anti-tumour therapies.Read moreRead less
Targeting Protease Activated Receptor 2 In Immunometabolism And Obesity
Funder
National Health and Medical Research Council
Funding Amount
$720,760.00
Summary
New approaches to prevent and treat obesity and metabolic diseases are National Health Priorities. Obesity is now recognised as an inflammatory disease. This project seeks new biomedical information to verify a new hypothesis that a protein (PAR2) on the surface of fat cells and immune cells is associated with the development of obesity and metabolic disorders.
Small Molecule Modulators Of Complement In Metabolism And Obesity
Funder
National Health and Medical Research Council
Funding Amount
$682,820.00
Summary
We have discovered that certain inflammatory proteins in the blood that are produced in the immune response to infection are involved in regulating the storage and burn off of fat in adipose tissue in the abdomen. These proteins bind to the surfaces of both fat and immune cells. We will study the effects of new drugs that compete with these blood proteins for the surfaces of these cells, since our experiments indicate that such drugs can potentially prevent and reverse fat deposition in rats fed ....We have discovered that certain inflammatory proteins in the blood that are produced in the immune response to infection are involved in regulating the storage and burn off of fat in adipose tissue in the abdomen. These proteins bind to the surfaces of both fat and immune cells. We will study the effects of new drugs that compete with these blood proteins for the surfaces of these cells, since our experiments indicate that such drugs can potentially prevent and reverse fat deposition in rats fed a high-fat, high-carbohydrate, diet.Read moreRead less
I am a pharmacologist-cell biologist-molecular biologist and chemist examining the metabolism of iron in normal and neoplastic cells and the development of iron chelators for the treatment of a variety of diseases e.g., ?-thalassaemia and cancer.
Molecular Regulators Of Adaptive Immunity To Overwhelming Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$786,898.00
Summary
Diseases caused by overwhelming viral infections, such as COVID-19, are associated with widespread impairments in immunity and constitute a major burden to human health. We have discovered that the molecule c-Myb is essential for the maintenance of immunity during chronic infection. In order to lay the foundations for novel and innovative anti-viral therapies, this project will dissect the molecular pathways regulated by c-Myb that maintain immunity during severe or chronic infection.
INTER-ETHNIC DIFFERENCES IN TOLERANCE OF ANTI-CANCER DRUGS
Funder
National Health and Medical Research Council
Funding Amount
$345,894.00
Summary
In 2 previous studies we have shown that Asian cancer patients experience more side-effects than their Caucasian counterparts when treated with the same dose and schedule of treatment. This does not appear to be related to any difference in size. We wish to explain this difference as it may avoid Asian patients receiving overdoses of treatment. Possible causes include dietary and nutritional differences
Tropisetron: Molecular Mechanisms Of Action At The 5-HT3 Receptor And The Glycine Receptor
Funder
National Health and Medical Research Council
Funding Amount
$371,800.00
Summary
Tropisetron and related drugs are used clinically to combat chemotherapy-induced nausea and vomiting. These drugs are termed '5-HT3 antagonists' because they block the activity of 5-HT3 receptor ion channels, which are found in parts of the brain that control the vomit reflex. Tropisetron also has potent effects on the glycine receptor chloride channel, which inhibits the nervous system. Depending on the concentration used, tropisetron can either increase or decrease the activity of the glycine ....Tropisetron and related drugs are used clinically to combat chemotherapy-induced nausea and vomiting. These drugs are termed '5-HT3 antagonists' because they block the activity of 5-HT3 receptor ion channels, which are found in parts of the brain that control the vomit reflex. Tropisetron also has potent effects on the glycine receptor chloride channel, which inhibits the nervous system. Depending on the concentration used, tropisetron can either increase or decrease the activity of the glycine receptor. If a drug can be found to selectively increase glycine receptor activity, it may be useful as an analgesic. In this project, we aim to understand the molecular mechanisms by which tropisetron interacts with the 5-HT3 receptor and the glycine receptor. This may help to identify novel analgesic drugs and more selective anti-emetic drugs.Read moreRead less
Microbiological And Immunological Determinants Of Prolonged Illness Following Q Fever.
Funder
National Health and Medical Research Council
Funding Amount
$362,036.00
Summary
Q fever is a severe, sometimes life-threatening infection acquired by individuals who work with livestock, particularly abattoir workers. At least 10% of individuals who develop Q fever experience prolonged ill-health in the form of weeks or months of debilitating fatigue, profuse night sweats, headaches, as well as muscle and joint pains. This poorly understood persistent illness is associated with substantial disability and loss of income. This research is based upon an established cohort stud ....Q fever is a severe, sometimes life-threatening infection acquired by individuals who work with livestock, particularly abattoir workers. At least 10% of individuals who develop Q fever experience prolonged ill-health in the form of weeks or months of debilitating fatigue, profuse night sweats, headaches, as well as muscle and joint pains. This poorly understood persistent illness is associated with substantial disability and loss of income. This research is based upon an established cohort study in which subjects with acute, documented Q fever are recruited shortly after the onset of symptoms and followed at regular intervals through to recovery or persistent symptoms. The aim of this research is to determine whether abnormal persistence of the causative organsim of Q fever, Coxiella burnetii, underlies the continued symptoms in those who do not recover promptly from the acute illness. Furthermore, the research is examining the host defense response against the organism via the production of cytokines or immunological hormones, to determine whether these proteins mediate the ongoing symptoms. If confirmed, these hypotheses would lead the way to diagnostic markers for the disorder and a rational treatment strategy.Read moreRead less