Laurenson Bequest Grants

High-fibre high-protein bread in type 2 diabetes management: a randomised crossover trial

Principal investigator: Assoc Prof Andrew Reynolds, Department of Medicine, Faculty of Medicine, University of Otago (photo is of Andrew)

Bread is a staple food in Aotearoa, however most varieties do not provide many beneficial nutrients (e.g. fibre 3/100g, protein 8/100g). We have maximally-fortified a bread beyond anything available in the food supply (fibre 14/100g, protein 27/100g) to see if improving diet through a single fortified food can influence type 2 diabetes management. We will do this by having 30 adults with type 2 diabetes try both our fortified bread and a standard bread for periods of two-weeks. We will measure change in standard cardiometabolic risk factors as well as the move in novel markers of the blood metabolome, gut microbiota, and objective markers of food intakes from buccal cells.

Maternal diet and long-term effects on maternal and offspring health

Principal investigator: Assoc Prof Mike Garratt, Department of Anatomy, School of Biomedical Sciences, University of Otago

Co-investigators: Assoc Prof Tracy Perry, Division of Sciences, University of Otago ,Professor Sue Crengle, Ngāi Tahu Māori Health Research Unit, University of Otago, and Mr Cameron Young, Department of Anatomy, University of Otago

Gestational diabetes (GDM) is a metabolic disease spontaneously arising during pregnancy and affects approximately 7% of all pregnancies in New Zealand. Although GDM typically resolves after pregnancy, it has long-lasting impacts on the health of mother and child, increasing their risk of metabolic and cardiovascular disease in later life.

Maternal nutrition is a major factor influencing both the onset of GDM and its postpartum disease progression, although the effects of specific macronutrients (protein, carbohydrate, fat) have not been systematically assessed. This large-scale animal experiment will conclusively define the effect of specific macronutrient intake during pregnancy on the longterm health of mothers and their offspring.

Cannabidiol dry powder inhaler

Principal investigator: Assoc Prof Shyamal Das, School of Pharmacy, University of Otago

Cannabidiol (CBD) is an active constituent of cannabis, with potent biological properties but with no-psychoactive effects. Most exciting is that CBD could also treat inflammatory respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, which are common in New Zealand and worldwide. The therapeutic potential of CBD is limited when given orally. CBD can instead be delivered locally to the lungs via a dry powder inhaler to ensure sufficient concentration and effectiveness. This study will develop in vitro a dry powder inhaler containing CBD to treat local lung diseases such as asthma and COPD. This inhaler will also be useful for other systemic diseases.

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Diet and physical activity related health beliefs, knowledge and behaviour of South Asians with pharmacologically untreated hypercholesterolemia

Principal investigator: Dr Sherly Parackal, Centre for International Health, University of Otago

South Asians (SAs) have particularly high rates of Atherosclerotic Cardiovascular Diseases (ASCVD), such as coronary heart disease (CHD), stroke and peripheral arterial disease. NZ SAs are one of the three high risk groups for high blood cholesterol, a key risk factor of ASCVD, nevertheless targeted prevention measures are absent. Epidemiological investigations have identified a positive association between dietary saturated fats and the increased risk of ASCVD. Our recently completed (OMRF-funded) study indicates that most participants treated for high blood cholesterol were diagnosed at a young age and were disheartened for not being able to manage the disease via lifestyle changes. What is unknown is whether SAs with medically untreated high blood cholesterol have the knowledge to make lifestyle changes and if they have received culturally appropriate professional advice to enable this. The current study aims to address this gap in our knowledge to inform clinical practice and develop an ethnic-specific intervention.

Continuous glucose monitors (CGMs) as a novel tool for RED-S Funding

Principal investigator: Associate Professor Katherine Black, Department of Human Nutrition, University of Otago

Around half of our young active females are putting their health at serious risk, due to inappropriate diets. Yet there is no tool to identify the problems before dire health consequences occur. However, the relatively new technology of continuous glucose monitoring, originally developed for diabetics, could provide useful information before serious health problems develop. We will test the ability of continuous glucose monitors to detect differences between women with low energy and/or carbohydrate intake, and healthy women. If these monitors are accurate, clinicians and researchers working with active females will have a validated tool to facilitate health management amongst this vulnerable population.

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Diet, activity, and medicine usage in South Asians at risk of cardiovascular disease

Principal investigator: Dr Sherly Parackal, Centre for International Health, University of Otago

Cardiovascular disease (CVD) is the most potent killer in New Zealand (NZ) with NZ South Asians (SA) being one of the three high risk groups. Nevertheless, targeted prevention measures for NZ SAs are glaringly negligible. Poor dietary habits and sedentary lifestyles are strongly associated with CVD as is poor medicine usage among SAs with diabetes, a risk factor for CVD. International research demonstrates the importance of first gaining an understanding of health beliefs, knowledge, and behaviours related to diet, physical activity, and medicine usage before designing ethnic-specific interventions to reduce CVD burden. We aim to gain this understanding for SAs in NZ, which is not known.

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Effects of empagliflozin in individuals with non-diabetic stage 4 chronic kidney disease

Principal investigator: Dr Luke Wilson, Department of Medicine, University of Otago

Sodium glucose 2 cotransporter inhibitors (SGLT2I) are recent medications that improve glucose control in individuals with type 2 diabetes. They also have a positive impact on the heart, blood vessels and kidneys not only in diabetics but non-diabetic individuals as well. This project will investigate the activity and the effect of empagliflozin (a SGLT2I) in individuals who do not have type 2 diabetes with advanced chronic kidney disease known as stage 4. Empagliflozin has not previously been studied at this level of impaired kidney function. We will look at its’ activity within the body and the body’s response to the drug; with a focus on analysing the cardiovascular and renal response.

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Liposomal drug therapy to treat bacterial infections

Principal investigator: Dr Daniel Pletzer, Department of Microbiology and Immunology, University of Otago

Antibiotic resistance is rising rapidly and there are relatively few novel compounds or strategies under development or entering the clinic. Our research will address these issues by investigating liposomes, small vesicles made from membrane lipids. Liposomes have traditionally been used as lipid-based drug delivery systems, but recently been shown to work as stand-alone drug therapy to neutralize toxins from pathogenic bacteria. In this project, we will assess the utility of liposomes to attack and disarm two important pathogens, Staphylococcus aureus and Acinetobacter baumannii. In New Zealand, both have emerged with limited antimicrobial treatment options and pose a significant threat to healthcare. The long-term goal of our research is to abrogate the adverse effects of antibiotics on the human body and prevent further development of antimicrobial resistance.

How do curcumin analogues alter microglial phenotype post stroke?

Principal investigator: Dr Ailsa L McGregor, School of Pharmacy, University of Otago

Curcumin, the active ingredient of the spice turmeric, has moved from alternative to mainstream medicine as a possible treatment for cancer and inflammatory bowel disease. It has been suggested that curcumin could also protect against inflammation following injury to the brain. Researchers at Otago have developed a series of agents that are more powerful than curcumin itself. We have shown these new agents can ‘switch off’ brain inflammation in an experimental model of stroke. This project will investigate exactly how these new compounds produce their anti-inflammatory effects and the length of time after stroke that they could be effective.

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Inhaled powder formulation for COVID-19

Principal investigator: Dr Shyamal Das, School of Pharmacy, University of Otago

Currently, there are no vaccines and proven approved treatment for COVID-19. The majority of therapeutic candidates that are in clinical studies do not show expected outcomes although they showed efficacy against SARS-CoV-2 in preclinical studies. One of the reasons is an insufficient amount of drugs in the lung, which is the primary site of COVID-19 infection. We are in the process of developing an inhaled delivery system for potential anti-COVID-19 drug(s) that will inhibit the entry and replication of the virus in the lung, ensuring an effective treatment at lower doses while reducing potential side effects.

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Prevalence of antibiotic-resistant bacteria on retail chicken in New Zealand

Principal investigator: Professor Sarah Hook, School of Pharmacy, University of Otago

Every year thousands of New Zealanders get gastrointestinal infections with diarrhoea and vomiting from eating improperly cooked chicken and/or handling uncooked chicken. This usually peaks over summer and there is some evidence to suggest this may be increasing. In some individuals these infections may need to be treated with antibiotics, however there is concern that some bacteria found in food such as chicken may now be resistant to the effects of common antibiotics. This project will survey the prevalence and antibiotic susceptibility/resistance of bacteria on fresh retail chicken in Aotearoa New Zealand. This data will be compared to historical research nationally and internationally and will provide important background information for further research in this area.

Pharmacological activation of the intrinsic regulator of heart metabolism for a healthy heart aging

Associate Professor Rajesh Katare, Physiology, University of Otago

Heart disease will result in 40% of all deaths in adults aged 75 and above, and rank as the leading cause. Aging impairs heart metabolism by reducing glucose transport. We have recently identified that reduced acetylcholine synthesis in aged heart muscle cells is associated with reduced glucose transport. In the current proposal, we aim to investigate if restoring acetylcholine bioavailability in the aged heart by preventing its breakdown improves recovery following a heart attack. Results from our study will provide knowledge for a novel treatment option for aging hearts by targeting acetylcholine bioavailability.

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Mycobacteria-responsive prodrugs to combat drug-resistant tuberculosis

Dr Allan Gamble (School of Pharmacy, University of Otago), Professor Gregory Cook (Department of Microbiology & Immunology, University of Otago) & Associate Professor Joel Tyndall (School of Pharmacy, University of Otago)

M tuberculosis is a bacterium that causes tuberculosis, a disease that infects more than 10 million people per year. Patients are treated with a mixture of drugs but as the bacteria mutates the drugs no longer work. To fight drug-resistant strains of M. tuberculosis, new drugs and drug delivery methods are needed. Two new classes of drugs have been shown to kill the bacteria, but clinical challenges exist. The drugs need to be in the bacteria at the exact same time, and one of the drugs in the combination is toxic to human cells. By attaching a linker we can convert the drugs into inactive forms (prodrugs), and trick the bacteria to activate each drug individually, killing itself and sparing human cells. Successful prodrug activation in this project will enable us to explore co-drugs, inactive forms of the drugs linked together for simultaneous delivery and bacteria-specific activation.

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Investigating the anti-inflammatory response of novel bioactive lipid vesicles to treat inflammation at the blood-brain barrier

Dr Shakila Rizwan, School of Pharmacy, University of Otago

Inflammation at the blood-brain barrier (BBB), a cellular barrier which safeguards the brain from the rest of the body, is an early hallmark of many neurodegenerative disorders. A group of fatty molecules known as NAEs promote neuroprotection and may slow down the progression of neurodegenerative disorders and thus have the potential to be transformative therapies. However, these molecules are challenging to formulate into a medicine and target to the BBB, which we have addressed with formulation science. This study will now investigate the anti-inflammatory properties of our new therapeutic formulation.

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Lithium-induced changes in renal tubular cell regulatory pathways

Professor Robert Walker (Department of Medicine, University of Otago), Dr Tania Slatter, Gregory Gimenez (Department of Pathology, University of Otago) & Professor Hans-Peter Marti (University of Bergen, Norway).

Lithium is an effective agent used to manage bipolar disorders. However, long-term lithium therapy can be associated with the development of chronic kidney disease. Our research group has been investigating how lithium induces kidney damage. Lithium induces changes in the specialised kidney cells responsible for handling salt and water. In addition, lithium is associated the slow development of fibrosis (scarring) in the kidney. We plan to explore the pathways that lead to the lithium-induced changes. Understanding these pathways could lead to new ways to treat and prevent chronic kidney disease.

Wholegrain structure and control of type 2 diabetes: randomised crossover trial

Dr Andrew Reynolds & Professor Jim Mann (Department Medicine, Dunedin School of Medicine)

We have considered the effects of wholegrain processing, specifically milling, on glycaemic control in free-living adults with type 2 diabetes with a randomised crossover trial of two interventions of two-weeks duration. Thirty one participants were provided wholegrain bread, oats, and brown rice that differed in their degree of processing. In one intervention these wholegrain foods were minimally processed, in the other intervention they were finely milled.

Participants consumed on average 5.5 serves of wholegrain foods a day and there was no difference in their reported energy intake. Blood glucose responses after meals and blood glucose variability during the day were significantly better when participants ate the minimally processed wholegrain foods when compared with those that were finely milled. These results indicate that dietary advice for those with type 2 diabetes should promote the consumption of minimally processed whole grains.

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Ketamine therapy for ‘neurotic’ disorders: is there a single mechanism?

Professor Paul Glue (Department of Psychological Medicine, Dunedin School of Medicine), Dr Shabah Shadli & Professor Neil McNaughton (Department of Psychology)

Neurotic disorders (anxiety and depression), are the most prevalent mental disorders in New Zealand, USA and Europe. Neurotic disorders have high chronicity, are highly disabling, have severe impact on societies, with suicidal ideation, suicide attempts and costs to public health. But, currently available medications are ineffective in almost 35 to 40% anxious/depressed patients; making them treatment resistant. Hope is raised by ketamine. We found that ketamine’s therapeutic effect in GAD and SAD cases where other treatments were ineffective correlated with decreased theta frequency rhythms in frontal brain activity. We will test if ketamine produce similar therapeutic changes in all neurotic disorders.

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Targeted nitric oxide donor drugs to cure breast cancer

Dr Gregory Giles, Professor Rhonda Rosengren & Dr Niroshini Giles (Department of Department of Pharmacology and Toxicology, School of Biomedical Sciences), Dr Carol Bussey (Department of Physiology, School of Biomedical Sciences)

Photodynamic therapy is a technique that uses light to activate a drug inside a tumour; the activated drug then proceeds to destroy the tumour from within. As the applied light can be selectively focused on the cancer, the drug only activates within the tumour environment. This causes localised anti-cancer action, whilst avoiding side effects in other areas of the body. We have recently developed a new lead compound for photodynamic therapy, tDodSNO, which has promising activity against cancer cells. We now propose to evaluate tDodSNO in animal and cell culture models of breast cancer, a disease which urgently needs new treatments as patients have a very poor prognosis.

A probiotic to improve ileal pouch health

Assoc Prof Mark Thompson Fawcett (Department of Surgical Sciences, Dunedin School of Medicine), Prof Gerald Tannock & Mr Blair Lawley (Department of Microbiology & Immunology, School of Biomedical Sciences)

Probiotics, or good bacteria, can improve health. Some patients with inflammatory bowel disease have their entire large bowel removed with surgery. To avoid a stoma bag, a pouch is made out of the end of the small bowel (ileum) and joined to the anus to make an ‘ileal’ pouch. Half of these patients develop an inflammatory condition in their pouch called pouchitis. After a decade of careful scientific investigation we have successfully produced a specific probiotic for pouchitis. A small pilot study has been successful and we now seek funding to do a larger national study to test the probiotic’s effectiveness properly.

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What are the dental consequences of vitamin D deficiency during pregnancy and infancy?

Dr Ben Wheeler (Department of Women’s & Children’s Health, Dunedin School of Medicine), Ms Deanna Beckett & Dr Carolina Loch (Department of Oral Sciences, Faculty of Dentistry), Dr Erin Mahoney (Department of Paediatrics, University of Otago Wellington) and Mr Andrew Gray (Department of Preventive & Social Medicine, Dunedin School of Medicine)

New Zealand children, particularly those living in the South Island, are at high risk of vitamin D deficiency . Deficiency during tooth development may result in developmental defects and dental decay . Data from a 2012 randomised controlled trial are available for 126 women and their infants, including vitamin D status at multiple time points during pregnancy and after delivery. The children from this study, now between five and seven years of age, will be losing their first baby tooth and gaining their first permanent molars. We aim to study potential childhood dental consequences of vitamin D deficiency during pregnancy and early life.

Drug combination testing in an in vivo model of anaplastic lymphoma kinase (ALK) mutated lung cancer

Dr John Ashton (Department of Pharmacology & Toxicology)

Lung cancer is responsible for more deaths than any other cancer in New Zealand. It has recently been discovered that the anaplastic lymphoma kinase (ALK) receptor is overexpressed in 2-5% of lung cancer patients. While inhibiting this protein improves survival, resistance usually develops, within a year, frequently because of the overexpression of other proteins, such as IGF1-R. We seek to develop a model of metastatic lung cancer in order to test a novel combination strategy to prevent the development of resistance to ALK inhibitors. This will aid in the development of more effective treatment strategies for lung cancer patients.

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Platinum (II) “click” antimicrobials: new weapons for fighting resistant microbes

Assoc Prof James Crowley (Department of Chemistry), Dr Heather Brooks (Department of Microbiology & Immunology) and Dr Gregory Giles (Department of Pharmacology & Toxicology)

Resistance of microbes to currently used antimicrobial drugs represents a major threat to human health. We propose to synthesise a small family of platinum(ll) “click” complexes and examine their antimicrobial activity against a range of resistant bacteria. Additionally the mode of action and cytotoxicity of these “click” metal complexes will be characterised. The resulting new class of metallo-antimicrobials could lead to antibacterial agents that display novel modes of action.

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Ribose-cysteine supplementation: translating from animals into humans

Prof Sally McCormick (Department of Biochemistry) & Prof Samir Samman (Department of Human Nutrition)

Cardiovascular disease (CVD) is responsible for over 30% of deaths in New Zealand per year. Statin drugs reduce CVD death rates by reducing levels of low density lipoprotein cholesterol (LDL-C). However, statins alone do not adequately reduce CVD mortality, and cause side-effects in some individuals that preclude their use. Ribose-cysteine is a promising antioxidant compound that shows both antioxidant and LDL-C lowering properties in animals. We hypothesise that ribose-cysteine has the potential to protect individuals at risk of CVD. We propose to perform the first ribose-cysteine supplementation trial in humans to evaluate its effects.

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Developing a novel therapeutic to protect hypertrophic hearts in acute ischaemic surgery

Assoc Prof Ivan Sammut, Dr Joanne Harrison & Dr Morgayn Read (Department of Pharmacology & Toxicology)

Over 800,000 surgical interventions requiring cardiac bypass are conducted globally each year. Whilst for the majority, the outcome is favourable, the procedure can inevitably result in damage to the heart through ischaemia-reperfusion injury. This exacerbates the patient’s condition and ultimately affects mortality. We have developed novel low-dose carbon monoxide releasing compounds that can prophylactically protect hearts from ischaemia-reperfusion injury. While this is a valuable finding, we wish to confirm that the same protection can be obtained in diseased hearts typically seen in bypass patients. We will trial our lead compound in a model of ischaemia-reperfusion conducted in enlarged hearts resulting from chronic hypertension. Ultimately this intervention will be developed as an adjunct therapeutic for use in cardiac surgery.

Pulmonary delivery of kanamycin dry powder for treating tuberculosis

Dr Jack Dummer, Dr Ben Brockway (Department of Medicine, Dunedin School of Medicine), Dr Shyamal Das (School of Pharmacy) & Prof Philip Hill (Department of Preventive & Social Medicine, Dunedin School of Medicine)

Tuberculosis (TB), caused by Mycobacterium tuberculosis , is a disease mainly of the lungs. Rifampicin, a first-line anti-TB medicine, is given orally for 6 months, and only a small fraction of the dose goes to the lung. Direct delivery of rifampicin to the lungs by inhalation can achieve high levels in the lung and in blood to kill M. tuberculosis more effectively throughout the body. In this project, we will produce rifampicin dry powder for inhalation in a GMP site and conduct a clinical study in healthy human participants to confirm safety and determine the optimal dose for inhalation. This will enable design of clinical studies combining inhaled and oral rifampicin in TB patients, aiming to shorten the duration of treatment.

We have conducted a review of relevant literature, purchased chemicals and developed powders suitable for inhalation by spray drying method. The spray-dried powders were characterised for physical properties such as particle size, surface morphology, moisture content, glass transition temperature and crystallinity and identified a formulation which provides high deep-lung delivery capacity as determined by an in vitro test. Now we are working on the first aim of the project i.e., characterising the surface of the particles to understand the mechanism of increased aerosolisation. We are investigating the composition of the spray-dried powders using several techniques: X-ray fluorescence, Energy dispersive X-ray Scanning Electron microscopy, Raman spectroscopy and X-ray Photo Electron Microscopy. In addition, we are conducting preliminary experiments for the second aim of the project: determining dissolution, alveolar macrophage uptake and cytotoxicity of the powders.

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Ghrelin dilates human mammary arteries; implications in heart failure

Dr Daryl Schwenke, Dr Regis Lamberts & Dr Pete Jones (Department of Physiology)

We have previously shown that the hormone ghrelin improves heart function following a myocardial infarction, although the underlying mechanisms remain unclear. Evidence has emerged which suggests that ghrelin may directly dilate arteries to improve blood flow. Accordingly, we aimed to assess whether ghrelin could dilate isolated human mammary arteries and potentially identify that the mechanism by which ghrelin ameliorates damage to the heart following acute myocardial infarction is by way of improving coronary blood flow. We are currently utilising the technique of vessel myography to assess the functional integrity of an isolated artery, based on dilatory or constrictor responses to select vasoactive modulators; in particular, the response to ghrelin. Following on from the functional measurements, we will utilise the technique of fluorescence myography to identify whether the mechanism underpinning ghrelin’s vasoactive properties is linked to disruption of the intracellular calcium-signaling pathway, since calcium signaling is vital for vascular smooth muscle contraction and, thus, vessel function.

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The impact of intensive care unit (ICU)-based sustained low efficiency hemodiafiltration on the pharmacokinetics of meropenem and tazocin

Professor Rob Walker, Dr Mat Bailey & Dr Craig Carr (Department of Medicine) & Associate Professor Natalie Medlicott & Dr Dan Wright (School of Pharmacy)

Powerful antibiotics such as meropenem and piperacillin/tazobactam (Tazocin) are required to treat severe infections in patients in the intensive care unit (ICU). Many of these patients develop acute kidney injury (AKI) and will require renal replacement therapy with sustained low efficiency dialysis (SLED) plus haemodiafiltration (HOF).

SLED-HOF is very effective in removing substances from the blood stream in the acutely unwell patient and it is therefore probable that antibiotics will also be removed. This may result in subtherapeutic antibiotic concentrations and failure to adequately treat the life-threatening infection and possible death of the patient. By measuring how these antibiotics are removed by SLED-HOF, we aim to develop an appropriate dosing regimen to maintain appropriate therapeutic concentrations of the antibiotics for patients requiring SLED-HOF treatment.

There was initially an issue related to a Crown law ruling related to observational studies in the intensive care setting. As a consequence the study was modified to undertake the drug clearance studies in stable haemodialysis patients who, instead of their usual dialysis session, would undertake a standard SLED-HDF as used in the ICU for 4 hours. This required a second ethics approval (duly obtained). The study is currently underway with 2 subjects out of 6 having completed both a session investigating meropenem clearance and a session investigating Tazosin clearance. As per the protocol, a total of 6 individuals will be studied. We expect to have the studies completed by the end of August and analyses completed by December 2016.