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
NATIONAL TRENDS IN SUICIDE BY AGE, GENDER, GEOGRAPHY, SOCIO-ECONOMIC AND MIGRANT STATUS AND MENTAL HEALTH
Funder
National Health and Medical Research Council
Funding Amount
$148,690.00
Summary
Suicide in Australia has become an increasingly important public health problem, chiefly because of increasing rates in some population sub-groups, and to a lesser extent because declines in other external causes of death have increased the prominence of suicide. Since the 1970s suicide rates have increased in young males and have eclipsed motor vehicle accidents as the dominant cause of death in this group. Suicide in the young produces a significant impact on years of life lost from premature ....Suicide in Australia has become an increasingly important public health problem, chiefly because of increasing rates in some population sub-groups, and to a lesser extent because declines in other external causes of death have increased the prominence of suicide. Since the 1970s suicide rates have increased in young males and have eclipsed motor vehicle accidents as the dominant cause of death in this group. Suicide in the young produces a significant impact on years of life lost from premature mortality. Suicide rates have been shown to vary by socio-economic status, ethnicity, area of residence, age and sex. In NSW for example, suicide rates in young males have been found to have increased by 50% in urban areas, and by 5-6 times in isolated rural areas. Another study has shown suicide rates to vary by country-of-birth which in turn has an effect on its relationship with socio-economic status. However, not all studies have replicated findings in NSW. In Queensland, for example, it has been shown that male youth suicide rates in rural areas have not substantially exceeded those in urban areas. There have been very few studies at the national level of variations in suicide in Australia. Most studies of Australian suicide to date have been confined to state-level analyses or to very limited nation-level analyses. An additional spur to a whole-nation approach to suicide has been the nation-wide Australian Bureau of Statistics Mental Health and Wellbeing Profile of Adults and a similar mental health survey of youth. Thus for the first time it will be possible to relate population prevalence of self-reported mental illness to suicide rates. In short, the current proposal addresses the two major gaps in Australia in population suicide research: examining suicide at the national level with regard to geographic location, immigrant and socio-economic status; and correlating surveyed prevalence of mental illness with suicide rates.Read moreRead less
Melanoma is the 4th most common cancer diagnosed in Australia. Advanced melanoma frequently spreads to other organs and can acquire resistance to anti-melanoma treatments, making it fundamentally incurable. I am focused on investigating the mechanisms underlying melanoma disease progression. I will achieve this by comparing the biological nature of melanoma cells at different stages of disease and therapy-resistance to identify new targets for the more effective treatment of patients with melano ....Melanoma is the 4th most common cancer diagnosed in Australia. Advanced melanoma frequently spreads to other organs and can acquire resistance to anti-melanoma treatments, making it fundamentally incurable. I am focused on investigating the mechanisms underlying melanoma disease progression. I will achieve this by comparing the biological nature of melanoma cells at different stages of disease and therapy-resistance to identify new targets for the more effective treatment of patients with melanoma.Read moreRead less
Synthetic DNA Standards For Clinical Genome Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$870,005.00
Summary
Genome sequencing can diagnose a wide range of mutations that cause human disease. However, errors during sequencing and analysis can lead to incorrect diagnosis. We propose to develop synthetic representations of genetic mutations that are then added to a patient’s DNA sample and act as internal controls throughout the clinical sequencing workflow. These controls improve the accuracy and reliability of mutation detection, resulting in improved diagnosis and better-informed patient care.
Diagnosis Of Inherited Genetic Disorders Using DNA Reference Standards
Funder
National Health and Medical Research Council
Funding Amount
$690,820.00
Summary
Whole genome sequencing can diagnose mutations that cause inherited disease, however, errors during sequencing and analysis can result in incorrect diagnosis. We propose to develop synthetic DNA standards that mirror important disease-associated mutations. These DNA standards are then added directly of a patient DNA sample and act as internal controls during sequencing and analysis to provide more accurate and reliable diagnosis.