Identification Of Cardiac Sarcoplasmic Reticulum Targets For Cardiotoxic Drugs
Funder
National Health and Medical Research Council
Funding Amount
$265,986.00
Summary
Anthracyclines are drugs which are used successfully in chemotherapy. Unfortunately, these drugs can lead to serious heart problems which sometimes result in death, and the mechanisms behind this remain elusive. Finding the specific targets of these drugs and how these drugs affect heart contraction may lead to designing drug cocktails which protect the heart from side effects.
Effects Of Ageing On Hepatic Drug Clearance And Mechanisms Of Drug Induced Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
With increasing age, there is increase in disease, for which medications may provide benefit, and an increase in the risk of adverse drug reactions, even after considering the increase in medication use by older people. We will investigate how the liver clears drugs from the blood in old age. This will guide dosing of medications for older people. We will also study how drugs injure the liver in old age and test interventions to prevent this toxicity.
Human Arylamine N-acetyltransferase Regulation And Function - Effect Of Genetic Poymorphisms.
Funder
National Health and Medical Research Council
Funding Amount
$421,980.00
Summary
How we handle chemicals that enter our bodies depends on a series of enzymes that are responsible for breaking down the chemicals and eliminating them. The activity of many of these enzymes varies between individuals so our responses to chemicals and drugs is different for each individual. Some of the enzymes vary because of inherited mutations, but others vary because of the diets we eat and the environment in which we live. This project will investigate a major enzyme called acetlytransferase ....How we handle chemicals that enter our bodies depends on a series of enzymes that are responsible for breaking down the chemicals and eliminating them. The activity of many of these enzymes varies between individuals so our responses to chemicals and drugs is different for each individual. Some of the enzymes vary because of inherited mutations, but others vary because of the diets we eat and the environment in which we live. This project will investigate a major enzyme called acetlytransferase that has been implicated as a risk factor in diseases such as cancer, asthma, liver cirrhossis and adverse drug reactions. We plan to look at the enzyme in cells and determine what environmental factors contribute to its variation between individuals, and how this impacts on the genetic mutations that have been found in its gene. From these studies, we will have a much better undersanding of how different people metabolise foreign chemicals, and should be able to predict those most at risk of certain diseases.Read moreRead less
Unravelling The Mechanism Of MHC Class-I Associated Drug Hypersensitivities
Funder
National Health and Medical Research Council
Funding Amount
$566,308.00
Summary
Some drugs cause adverse reactions that are life threatening. We think these reactions are mediated by killer T cells as they are genetically controlled by immune response genes that normally guide immunity to microbes. We will study immune reactions to the drug abacavir, used to treat HIV (AIDS); allopurinol used to prevent gout and carbamazepine, used to treat epilepsy. The study may also help devise better treatments for patients who experience severe forms of these reactions.
Clozapine Toxicity: Role Of Pharmacogenetic Variation In CYP Enzymes And Bioactivation Mechanisms In Patient Neutrophils
Funder
National Health and Medical Research Council
Funding Amount
$336,000.00
Summary
The treatment of mental disorders such as schizophrenia involves the administration of potent drug combinations to patients. Some individuals, however, do not respond to commonly-used antipsychotic drugs and their condition only improves with a unique drug called clozapine. The major problem with clozapine is its toxicity toward blood cells, heart and other organs. All people who receive clozapine must be monitored closely, especially in the first 3-4 months after starting therapy. Several new d ....The treatment of mental disorders such as schizophrenia involves the administration of potent drug combinations to patients. Some individuals, however, do not respond to commonly-used antipsychotic drugs and their condition only improves with a unique drug called clozapine. The major problem with clozapine is its toxicity toward blood cells, heart and other organs. All people who receive clozapine must be monitored closely, especially in the first 3-4 months after starting therapy. Several new drugs have been suggested to be safer versions of clozapine but these are all ineffective. Clozapine is the only agent that is effective in people who do not respond to the other drugs used to treat schizophrenia. Thus, clozapine toxicity, which necessitates discontinuation of the drug, is a devastating outcome because there is no alternative treatment that is available. Another significant problem with clozapine is that its rate of removal from the body is slowed down by many other drugs that are used concurrently. The problems with clozapine occur in some but not all individuals. This suggests that the patient's genetic makeup and their exposure to drugs and environmental agents determine the incidence of toxicity. The present project looks at how clozapine is removed from the body and how it is converted into a toxic product that damages cells. These processes will be examined, with emphasis on differences between individual patients, and strategies to protect cells from damage from the toxic derivative will be tested. Corresponding studies will be done in patients who are receiving clozapine as treatment for psychoses. We will be able to compare experimental and clinical findings in order to identify those patients who appear to be at risk. This will be possible before the toxic effects occur and will help us to identify subjects in whom the drug should only be used with great care. We may also devise strategies that will minimise the incidence of toxicity.Read moreRead less
Many products are applied to the skin to prevent skin cancer or to treat skin diseases. This project seeks to better understand how we can make such products more affective, safer and appropriate for conditions such as psoriasis. One major component of the grant is concerned with the evaluation of nanotechnology products applied to the skin.
Inactivation Of HERG Potassium Channels: Dynamic Changes In The Outer Pore Structure
Funder
National Health and Medical Research Council
Funding Amount
$422,716.00
Summary
Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic me ....Sudden cardiac death, due to disturbances in the normal electrical activity of the heart, is one of the leading causes of death in Australia and its incidence is increasing. Tackling the problem of cardiac arrhythmias is therefore one of the major challenges for cardiology in the 21st century. Two factors are greatly limiting progress in this area, the inability to predict who is most at risk and a paucity of treatment options. To address these problems, we need to better understand the basic mechanisms underlying arrhythmias. The rhythm of the heart beat is controlled by electrical signals mediated by the flow of ions through specialised proteins called ion channels. Of the channels that contribute to cardiac electrical activity, potassium ion channels encoded by the Human ether-a-go-go-related gene (HERG) have been of particular interest for three reasons. Firstly, mutations in HERG are the cause of one third of cases of congenital long QT syndrome, an inherited cause of sudden cardiac death. Secondly, HERG is the molecular target for the vast majority of drugs that cause drug-induced long QT syndrome, the commonest cause of drug-induced arrhythmias and cardiac death. Thirdly, HERG channels have very unusual biophysical properties, which has led to the suggestion that they may act as an endogenous anti-arrhythmic agent . Accordingly, the major objective of the proposed research program is to understand the molecular and structural basis of the unusual properties of HERG channels. We will use a combination of molecular and electrical techiques in conjunction with computer modeling to probe the micoscopic motions in the channel that underly the unusual biophyscial properties of these channels. This work will facilitate a better understanding of how clinically identified mutations in HERG contribute to the increased risk of cardiac arrhythmias. More generally, it will improve our understanding of how cardiac ion channels maintain the normal rhythm of the heart.Read moreRead less