Assessment Of Hypoxia And Hepatic Metabolism In Cirrhotic Rats Using NMR
Funder
National Health and Medical Research Council
Funding Amount
$355,341.00
Summary
Liver function and hepatic drug metabolism are impaired in patients with cirrhosis but there is currently no adequate explanation to account for this. As a direct consequence, there is no useful therapy beyond liver transplantation. We propose studies aimed at confirming a hypothesis on the mechanisms underlying the development of cirrhosis. From this mechanistic hypothesis, a testable therapeutic hypothesis has been derived. Our primary mechanistic hypothesis is that cirrhosis is associated wit ....Liver function and hepatic drug metabolism are impaired in patients with cirrhosis but there is currently no adequate explanation to account for this. As a direct consequence, there is no useful therapy beyond liver transplantation. We propose studies aimed at confirming a hypothesis on the mechanisms underlying the development of cirrhosis. From this mechanistic hypothesis, a testable therapeutic hypothesis has been derived. Our primary mechanistic hypothesis is that cirrhosis is associated with reduced oxygen delivery from the blood supply into the liver due to a process known as capillarisation (i.e., The Oxygen Limitation Theory). It is proposed that this reduced oxygen availability leads to impairment of liver function. The major aim of this research project is to confirm or refute the presence of intracellular hypoxia (i.e., decreased oxygen in cells) using nuclear magnetic resonance (NMR) techniques and cirrhotic rats. The nature of any metabolic disturbances or changes in cellular components resulting from intracellular hypoxia will then be characterised. The project will also aim to confirm the impairment of oxygen-dependent drug metabolism in cirrhosis by using NMR to measure the degradation or elimination of a fluorinated drug. Our hypothesis for therapy is that intracellular hypoxia may be reversed, and global liver function improved, by oxygen supplementation and-or an increase in hepatic arterial flow by using oral hepatic arterial vasodilators. Vasodilators exert their action by direct relaxation of blood vessels or by blocking the action of vasoconstrictors. Vasodilators that act solely on the hepatic artery and their influence upon blood pressure will be studied using treated rat livers so that such vasodilators can be tested for their ability to modify liver function in cirrhotic rats in vivo. The ultimate goal will be to carry these observations into studies in normal healthy volunteers and cirrhotic patients in the future.Read moreRead less
Acute Stroke: Imaging The Ischaemic Penumbra With Perfusion CT
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
The burden of stroke is large. Clot-dissolving medication (thrombolysis) may dramatically improve the outcome of many patients with severe stroke by unblocking the affected brain artery. However, very few patients receive this medication, as the current approval is restricted to treatment within 3 hours of stroke onset. The major aim of thrombolysis is to rescue brain tissue with reduced blood flow (the ischaemic penumbra) from becoming irreversibly damaged (infarcted). The penumbra progressivel ....The burden of stroke is large. Clot-dissolving medication (thrombolysis) may dramatically improve the outcome of many patients with severe stroke by unblocking the affected brain artery. However, very few patients receive this medication, as the current approval is restricted to treatment within 3 hours of stroke onset. The major aim of thrombolysis is to rescue brain tissue with reduced blood flow (the ischaemic penumbra) from becoming irreversibly damaged (infarcted). The penumbra progressively becomes infarcted over the next 48 hours if blood flow is not restored by the blood clot in the brain artery being dissolved. Penumbral brain tissue cannot be identified with clinical assessment or standard CT scanning. New generation CT scanners are capable of assessing brain blood flow. Perfusion CT imaging (CTP) is well tolerated and time-efficient, and can be integrated into the brain CT scanning process performed on all stroke patients. Preliminary evidence suggests that CTP can distinguish between tissue that represents the ischaemic penumbra, and tissue that is already permanently injured. This project aims to validate the use of CTP in imaging the ischaemic penumbra. This will be based on testing the accuracy of CTP tissue signatures of the penumbra in predicting clinical outcome and final stroke size. This is the only national collaborative study planned worldwide for this relatively new but increasingly accessible imaging technique. The ability to rapidly identify under-perfused but still viable brain with CTP would add new and exciting management options to the routine emergency assessment of stroke patients. The results of this unique study could have a significant impact on the management of acute stroke worldwide. If validated, it is anticipated that CTP would be widely used to improve patient selection for stroke thrombolysis, especially in safely extending the time window so that a greater number of patients can be treated with better outcomes.Read moreRead less