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
Heritability And Biological Consequences Of Human Variation In Mitotic Recombination
Funder
National Health and Medical Research Council
Funding Amount
$130,906.00
Summary
Cells in our bodies constantly sustain damage to their genetic material (genes) most of which is efficiently repaired. Some is not and accumulated damage to genes in a cell can start a cancer. There are several repair mechanisms that cells possess which have evolved since the earliest life-forms. One repair mechanism homologous recombination repair will, as a minor by-product of its activity, produce an event called mitotic recombination (MR). MR causes a loss of diversity of genes and this can ....Cells in our bodies constantly sustain damage to their genetic material (genes) most of which is efficiently repaired. Some is not and accumulated damage to genes in a cell can start a cancer. There are several repair mechanisms that cells possess which have evolved since the earliest life-forms. One repair mechanism homologous recombination repair will, as a minor by-product of its activity, produce an event called mitotic recombination (MR). MR causes a loss of diversity of genes and this can contribute to cancer rather than prevent it. We have shown that the rate at which MR occurs varies very widely in humans. In this project we will devise a simple method for measuring MR, use identical and non identical twins to find if the rate of MR is inherited and finally see whether the rate of MR is associated with risk of cancer, as we expect.Read moreRead less
The Roles Of Lipoprotein Multigene Families In Pathogenesis Of Mycoplasma Pneumoniae
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Mycoplasma pneumoniae is one of the most common causes of community acquired pneumonia. Although it can usually be successfully treated with antibiotics, it can result in more severe diseases and can be difficult to diagnose accurately. It has been identified as a target for vaccine development, but this has been hampered by the limited understanding we have of how it causes disease. The attempts at vaccination that have been made have resulted in vaccines which induced more severe, rather than ....Mycoplasma pneumoniae is one of the most common causes of community acquired pneumonia. Although it can usually be successfully treated with antibiotics, it can result in more severe diseases and can be difficult to diagnose accurately. It has been identified as a target for vaccine development, but this has been hampered by the limited understanding we have of how it causes disease. The attempts at vaccination that have been made have resulted in vaccines which induced more severe, rather than less severe, disease. Investigations of several other related bacteria have shown that they are able to vary their surface proteins and thus may evade the immune system, permitting them to cause more prolonged disease. Better understanding how this occurs, and what this enables the bacteria to do, may assist in developing improved vaccine strategies. This project aims to investigate the six gene families in Mycoplasma pneumoniae which are known to encode surface proteins and establish how and why the bacteria switch from one gene to another during infection. In addition the capacity of bacteria expressing different versions of the six surface proteins to adhere to different tissues will be investigated. Once this is known, these mechanisms may be able to be specifically disrupted to prevent a strain of Mycoplasma pneumoniae from being able to establish prolonged infections. Such a strain might be a useful basis for an effective vaccine.Read moreRead less