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
Understanding The Mechanisms Used By G-protein Coupled Receptors To Regulate Insulin-independent Glucose Transport
Funder
National Health and Medical Research Council
Funding Amount
$105,590.00
Summary
In type 2 diabetes, stimulation of glucose transport in fat cells and skeletal muscle by insulin is impaired. As a result there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G-protein coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose transport for potential as treatments.
Targeted Cancer Chemotherapy: The Potential Of L-Nucleoside Prodrugs
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
The aim of this project to develop novel anti-cancer agents. We plan to use an unusual sugar (an L-nucleoside) that is not normally found in the body. This unusual sugar has the property of being taken up by tumour cells but not normal cells. We will use this unusual sugar to transport a toxic compound inside tumour cells so that the tumour cells are killed. In this way, we will preferentially kill tumour cells but leave normal cells unaffected. Hence we will produce an anti-cancer agent that is ....The aim of this project to develop novel anti-cancer agents. We plan to use an unusual sugar (an L-nucleoside) that is not normally found in the body. This unusual sugar has the property of being taken up by tumour cells but not normal cells. We will use this unusual sugar to transport a toxic compound inside tumour cells so that the tumour cells are killed. In this way, we will preferentially kill tumour cells but leave normal cells unaffected. Hence we will produce an anti-cancer agent that is highly effective at killing tumour cells but has few side-effects because it does not enter normal cells. Experimentally we will synthesise compounds where the L-nucleoside is attached to a toxic agent, fluorouridine or cisplatin analogues. We will then assess the ability of these novel compounds to kill tumour cells grown in the laboratory as well as tumours growing in mice. Additionally we will attempt to determine the mechanism of action of these drugs by investigating the following: the transport properties of the drugs; how and where these drugs damage DNA; the effect of the gene, p53, which can act to stop tumour growth. The ultimate aim of this project is to develop a novel class of anti-tumour agent based on L-nucleosides. These L-nucleoside analogues are expected to be more efficient at killing tumour cells but have fewer side effects.Read moreRead less