1,721,103 research outputs found
The Design and Evaluation of an Innovative Head Mounted Display Counselling Tool for Warfarin
No full textBackground Emergent and disruptive technologies such as augmented reality (AR) and head-mounted display (HMD) have not been explored in the context of pharmacy to date despite the potential benefits for the use of these technologies. Patient counselling could be potentially be modulated to better reflect their level of health literacy and the standardisation of the counselling given to each patient. Further benefits may also be seen with the continual education of pharmacists who use the HMD-AR warfarin counselling guide, as pharmacists have been found to favour interactive forms of continuing education. For this reason, a previously validated educational framework was used for the development of the HMD-AR warfarin counselling guide, the mobile augmented reality education (MARE) design framework. The acceptance of the HMD-AR warfarin counselling guide was gauged using the previously validated e-learning technology acceptance model (TAM). The use of TAM gives significant insight into participants perceived ease of use (PEU), perceived usefulness (PU) and their behavioural intention (BI) which correlate highly to actual use of technology being tested. Aims and Objectives: The aim of this study was to develop and test acceptance of a counselling tool for the drug warfarin using both HMD and AR (HMD-AR warfarin counselling guide). The objectives of this study were to (i) conduct background literature research prior to the developments of the HMD-AR warfarin counselling guide, followed by a (ii) pilot study with 7 Griffith University School of Pharmacy and Pharmacology academic staff. Use pilot study feedback to (iii) redevelop the HMD-AR warfarin counselling guide as well as the accompanying adapted TAM survey. Conduct a (iv) larger mixed method cohort study with a pre- and post-test with 40 Australian registered pharmacists. Methods: The HMD-AR warfarin counselling guide was developed in the same documented way as MARE framework. TAM was assessed in the post-test on a five-point Likert scale. The redeveloped HMD-AR warfarin counselling guide used in the larger cohort of 40 pharmacists to gauge acceptance of the redeveloped HMD-AR warfarin counselling guide. Descriptive statistics, two-tailed Spearman’s rank analysis, Wilcoxon signed rank test and qualitative analysis were then utilised. A pre-and post-test assessment was conducted on participants willingness to use technology and the usefulness of HMD-AR warfarin counselling guide. Results and Discussion: It was shown that even though overall each construct of TAM had an average positive result, this fluctuated. PEU was shown to be the best performing construct with an average score of 1.68 on a five-point Likert scale, while BI showed the lowest average score of 2.74. Spearman rank analysis showed the pre-test question regarding usefulness of the HMD-AR warfarin counselling guide was associated with the post-test statements for PU, AT, BI and SN. Wilcoxon signed rank analysis showed both the post-test additional question for usefulness of the HMD-AR warfarin counselling guide (p= 0.005) and willingness to use technology normally (p= 0.025) had declined compared to the same questions in the pre-test. Qualitative feedback was coded to form three major categories which were then split into two sub-categories each. This qualitative feedback showed a negative perception most participants towards the HMD-AR warfarin counselling guide, some praise was seen for the content and potential of the counselling guide itself however. This study was able to document the early acceptance of the HMD-AR warfarin counselling guide with the use of 40 recruited pharmacists. Expectations were higher prior to use of the HMD-AR but dropped after participants trialled the HMD-AR warfarin counselling guide. Perceptions regarding the HMD-AR technology incorporated into this device were more negative compared to the content and information of the counselling guide. This may have influenced the BI construct having a near neutral on average response from participants, this indicated a possible reluctance for actual use of the HMD-AR warfarin counselling guide in practice. This was
despite other constructs of TAM like PEU having a more positive average score indicating participants found the HMD-AR warfarin counselling guide easy to use. Conclusion: This study was successful in developing the HMD-AR warfarin counselling guide and testing for acceptance. Current technology available fell below expectations of usefulness for most participants. Future applications of this technology could mean the use of HMD-AR technology for other drugs. Further research would need to be conducted on a larger sample of participants from more diverse professional backgrounds in order further understand acceptance.Thesis (Masters)Master of Medical Research (MMedRes)School of Medical ScienceGriffith HealthFull Tex
Development of Innovative Chemical Tools for Studying O-GlcNAc Transferase Enzyme
No full textO-GlcNAcylation can be defined as an addition of O-GlcNAc to the Serine/Threonine residue of proteins by the enzymatic activity of O-GlcNAc transferase (OGT) enzyme. O-GlcNAcylation is considered a dynamic and reversible process as another enzyme called O-GlcNAcase (OGA) undoes the action of OGT. OGT being one of the only two enzymes modulating O-GlcNAcylation, has a pivotal role in a wide range of biological processes such as cell signalling and communication, cell division and invasion, transcription and translation of factors/co-factors. The roles played by O-GlcNAcylation and OGT in the pathology of metabolic disorders such as cancer, diabetes and neurodegenerative diseases have been documented in detail over the last few decades. However, its exact molecular mechanism is poorly understood due to the lack of specific tools to perturb its functionality within the biological systems. Therefore, attempts have been made to construct specific chemical tools in the form of OGT inhibitors but the lack of potency and selectivity has slowed down their progress. In the current thesis, focus was set on the construction of novel, specific and potent inhibitors of the targeted OGT enzyme with a view to gain a better understanding of its active role. In addition, an attempt was made to investigate the impact of OGT inhibition on the cytotoxic effects exerted by the anticancer agents. Overall, the outcomes of this work further enhanced our understanding of the intricacies involved in the development of selective and potent OGT inhibitors. Chapter-1 presents the introduction of the OGT enzyme and helps to understand the significance of studying O-GlcNAcylation and the OGT enzyme in addition to outlining the major aims of the thesis. This chapter contains literature review paper specifically focusing on the role of O-GlcNAcylation and OGT enzyme in the stabilization of various oncogenic factors (manuscript-1) Chapter-2 describes the specific details on the materials and methodology used in chapter 3 to 5. Chapter-3 discusses the design and development of novel inhibitors targeting the OGT enzyme using bisubstrate analogues as a template. This strategy employed the identification of suitable donor and acceptor substrates where a flexible aliphatic linker was introduced to replace the negatively charged pyrophosphate group. This was based on the hypothesis that such exchange could improve the cell permeability of inhibitors. Uridine and GlcNAc were selected as donor substrate as UDP-GlcNAc is acting as a donor substrate for OGT enzyme for O-GlcNAcylation. The results demonstrated that one compound from the series, compound-17 (uridine-O-peptide conjugate, manuscript-2) could inhibit the human OGT enzyme with an IC50 value of 29.34 μM. In-silico prediction for physicochemical properties showed that compound-17 has higher value of Log P than previously reported bisubstrate inhibitors (i.e. Goblin-1 and Thiogoblin-1) which means theoretically compound-17 has better cell permeability.
Chapter-4 describes another series of bisubstrate inhibitors where uridine-mimetic scaffolds were selected as donor substrate. In this chapter, attempt was made to understand the impact of an exchange of modifiable amino acid (serine) with unmodifiable amino acid (alanine) as well as D-serine to evaluate chirality. One of the candidates from that series of compounds (compound-29, manuscript-3) was also found to have moderate inhibitory activity against OGT with an IC50 value of 134.40 μM. These preliminary findings laid a foundation for the better understanding of the nuances required within the basic scaffold of bisubstrate analogue inhibitors to achieve desired selectivity and potency.
Chapter-5 discusses the exploration of a combinatorial approach involving an OGT inhibitor (OSMI-1) with existing chemotherapeutic agents (doxorubicin and docetaxel). OGlcNAcylation and OGT are indispensable for the signal transduction and activation of various oncogenic factors that are thought to be responsible for the reduced sensitivity of prostate cancer cells towards these anticancer agents (manuscript-4). Investigation of concomitant treatment of doxorubicin with an OGT inhibitor demonstrated synergistic effects in terms of cell death in prostate cancer cells (manuscript-5).
Chapter-6 presents concluding remarks on the outcomes of the proposed work and future directions.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Pharmacy & Med SciGriffith HealthFull Tex
COX-2 selective inhibitors as an adjunct to radiotherapy
No full textBackground
Radiotherapy is a common treatment modality for many solid state cancers including prostate cancer (PCa). Unfortunately, up to 50% of patients that undergo radiotherapy for localised PCa will develop biochemical failure. Acute and delayed toxicities and tumour resistance are two key factors limiting the effectiveness of many cancer treatments, including radiotherapy. Toxicity rates in PCa patients that accompany radiotherapy are high with 80% of men experiencing some degree of urinary frequency, 40% bowel frequency and chronic impotence is usual.
Furthermore, tumour radioresistance is driven by a number factors with tumour hypoxia playing a key role. In addition to hypoxia driving tumourigenesis the lack of oxygen reduces the ability of ionizing radiation to produce reactive oxygen species (ROS) necessary to produce DNA damage that results in tumour death. Hypoxia also increases the expression of a number of genes including cyclooxygenase (COX) -2. COX-2 is an inducible enzyme that is upregulated in inflammation and carcinomas, making it a suitable target for new cancer treatment options.
COX-2 expression has been shown to be upregulated in a number of cancers including PCa and found to be involved in proliferation, invasion, apoptosis, host immune response and angiogenesis. Past research has also demonstrated that the major product of COX-2, prostaglandins (PG), provide radioprotection to cancer cells. As well as the ability of COX-2 to directly impact radiosensitivity, it has the ability to influence other cellular products that impact survival and apoptosis. One product that has been linked to COX-2 is the tumour suppressor p53. The p53 protein protects against genomic instability and the development of cancer by inducing cell cycle arrest and apoptosis. COX-2 expression has been shown to be induced by p53 and in turn results in inhibition of p53 mediated apoptosis. To our knowledge no studies have investigated the use of COX-2 inhibitors, at clinically relevant doses, as an adjunct to radiotherapy. In addition, while the direct mechanisms of COX-2 mediated radiosensitivity have been well investigated, research into the indirect mechanisms and also the effect of COX-2 inhibitors as radiosensitising agents in hypoxia is lacking.
This study aims to demonstrate the ability of COX-2 inhibitors to improve treatment outcomes post-radiotherapy for PCa in human patients and also to investigate the mechanisms behind COX-2 inhibitor mediated radiosensitivity in normoxia and hypoxia.
Method
The ability of COX-2 to produce radiosensitisation in cancer cells was investigated in two ways in this research. Firstly, a retrospective human study investigated if the use of the COX-2 inhibitors meloxicam and celecoxib during radiotherapy improves treatment outcomes in PCa patients. Secondly, an in vitro model was developed that investigated the mechanisms behind COX-2 mediated radiosensitivity in human cancer cell lines.
The retrospective human study examined the patient database at Genesis Cancer Care to identify patients that received radiotherapy for primary treatment of localised PCa. Screening of the database then identified patients that had used meloxicam or celecoxib during radiotherapy treatment. Three treatment outcomes were measured; the percentage of patients that demonstrated biochemical relapse at 2 and 5 years post-treatment, the time to biochemical relapse and the prostate specific antigen (PSA) velocity of each group post-treatment.
The in vitro model used HeLa (cervical), PC3 (Prostate), MCF7 (breast) and MeWo (melanoma) cells to investigate, mechanistically, how structurally unrelated COX-2 inhibitors impact radiosensitivity in normoxia and hypoxia. This model utilised resazurin reduction to measure proliferation, siCOX-2 RNA to produce COX-2 knockdown cells and enzyme-linked immunosorbent assays (ELISAs) to measure p53 phosphorylation and prostaglandin E2 (PGE2) production.
Results
PSA velocity was found to be 0.197ng/mL/year (0.939) for the meloxicam group and 0.828 ng/mL/year (3.15) for the celecoxib group. The two treatment groups were found to have significantly lower (p<0.05) PSA velocities than the control group, 1.12 ng/mL/year (3.05). In addition, at the two year time point meloxicam was found to have no patients to have relapsed and the celecoxib and control groups had percentage relapse rates of 6.7% (n=4) and 8.6% (n=5). The percentage relapse at five years post-treatment was 18.9% (n=10), 18.3% (n=11) and 21.0% (n=31%) for the meloxicam, celecoxib and control groups respectively. Mean time to biochemical relapse was found to be 54.15 months (16.08) in the meloxicam group and 46.20 months (31.70) in the celecoxib group, in contrast the control group demonstrated a mean time to biochemical relapse of 35.53 months (20.21).
The in vitro model aimed to provide an insight to the mechanisms behind the results seen in the retrospective analysis. NS398 (10μM), a highly specific COX-2 inhibitor, selectively sensitised hypoxic HeLa (p<0.01) and MCF7 (p<0.05) cells to ioninsing radiation, however did not affect sensitisation in PC3 or MeWo cells. Celecoxib (20μM) and meloxicam (20μM) failed to produce radiosensitisation in any cell line in normoxia or hypoxia. Based on these findings further investigations were carried out in HeLa cells using NS398.
Investigations using COX-2 siRNA demonstrated that knockdown of the COX-2 enzyme did not produce radiosensitisation but resulted in the loss of radiosensitising ability of NS398. Furthermore, PGE2 release was significantly increased in response to hypoxia (p<0.05) and irradiation (p<0.001) and treatment with NS398 significantly (p<0.001) attenuated PGE2. Treatment with misoprostol, a prostaglandin analogue, significantly (p<0.01) increased cell survival in normoxic HeLa cells in response to ionising radiation, but had no effect on hypoxic HeLa cells.
The interaction between COX-2 and p53 was then explored. It was discovered that COX-2 knockdown HeLa cells had significantly (p<0.001) higher levels of p53 protein than wild-type HeLa cells. Furthermore, hypoxia was able to significantly (p<0.001) attenuate p53 phosphorylation at both 30 minutes and 4 hours post-irradiation and treatment of hypoxic HeLa cells with NS398 (10μM) resulted in a significant (p<0.01) increase in phosphorylated p53. The p53 inhibitor pifithrin-α did not effect the radiosensitivity of wild-type HeLa cells in either hypoxia or normoxia, however it significantly (p<0.01) increased cell survival in response to ionizing radiation in HeLa cells transfected with COX-2 siRNA.
Discussion
The findings from the retrospective analysis demonstrated that the use of the COX-2 inhibitors celecoxib and meloxicam may improve treatment outcomes in patients that receive radiation therapy for PCa. Importantly we were able to demonstrate that patients using these agents displayed a significantly lower PSA velocity than those who were not. Importantly, the PSA velocity was found to fall below the threshold of 0.35ng/mL, with PSA velocities that sit above this threshold having been found to have an approximate 5.3 to 10 fold increased risk of PCa. This retrospective analysis also found reduced biochemical relapse rates and reduced time to biochemical relapse in the celecoxib and meloxicam groups in comparison to the control.
The in vitro model was able to demonstrate the ability of COX-2 inhibitors to increase radiosensitivity, however this effect was not demonstrated by all COX-2 inhibitors or all cell lines. This finding suggested that this effect may be drug and cell line specific. Furthermore, COX-2 was found to be necessary for NS398 induced radiosensitivity but knockdown of COX-2 alone did not affect radiosensitivity. Based on these findings it was suggested that COX-2 inhibitor mediated radiosensitivity occurs through both direct and indirect COX-2 mechanisms. We also demonstrated the relationship between COX-2 and p53, with COX-2 knockdown cells demonstrating increased p53 expression. Furthermore, the inhibition of COX-2 by NS398 resulted in increased p53 phosphorylation.
Results from both the retrospective and in vitro studies provide evidence that further study into the role of COX-2 inhibitors as an adjunct treatment option in radiotherapy is warranted. Further studies, including large prospective human studies, are needed to confirm these findings. These large studies should collect tumour biopsies to allow for histological investigations. The research provides further evidence to the potential for COX-2 inhibitors to be used as an adjunct to radiotherapy in cancer.Thesis (Masters)Master of Medical Research (MMedRes)School of Medical ScienceGriffith HealthFull Tex
The role of serotonin in human corticospinal-motoneuronal function
No full textSerotonin (5-HT) has strong effects on motor function; whereby converging lines of evidence indicate that 5-HT modulates spinal motoneuron excitability to regulate motor output. In the nervous system, 5-HT neurons form monosynaptic connections with motoneurons, and animal studies indicate that 5-HT release onto motoneurons varies in proportion to the intensity of motor activity. In this regard, strong motor activity causes large 5-HT release that activates excitatory somato-dendritic 5-HT2 receptors, which tends to facilitate motoneuron gain. Yet, 5-HT release to motoneurons also contribute to central fatigue via an inhibitory mechanism. Excessive 5-HT release during fatiguing motor behaviours can reduce motoneuron excitability by activating inhibitory 5-HT receptors located at the motoneuronal axon initial segment. To date, there are limited human studies that have examined serotonergic effects on motor function. Therefore, the purpose of this thesis was to explore how human corticospinal-motoneuronal function is modulated by 5-HT activity and to translate serotonergic mechanisms from animal models and in vitro studies to human neurophysiology experiments. Using double-blind, placebo-controlled, crossover designs, all studies in this thesis assessed the effects of serotonergic drugs on isometric muscle contractions and muscle responses to stimulation of the motor cortex, cervicomedullary junction or peripheral nerves in healthy participants. In Study 1, to examine the contribution of 5-HT to submaximal fatigue, the selective 5-HT reuptake inhibitor (SSRI) paroxetine was administered to increase 5-HT availability in synapses. After paroxetine administration, Study 1 assessed the ability of participants to generate maximal elbow flexions that were intermittently performed during a prolonged low-intensity elbow flexion, and it was found that paroxetine did not affect maximal contractions or voluntary activation (i.e., measures of central fatigue), but increased fatigue perceptions and shortened the transcranial magnetic stimulation (TMS) silent period recorded in the fatigued biceps brachii. For Study 2 and 3, the 5-HT2 antagonist cyproheptadine was administered to attenuate the facilitatory effects of 5-HT at motoneurons. Study 2 assessed how 5-HT2 antagonism affected muscle responses to TMS of the motor cortex, whereby the strength of elbow flexion was fixed and the intensity of TMS was manipulated, or the strength of elbow flexion was manipulated and the intensity of TMS was fixed. For the fixed-intensity elbow flexions, 5-HT2 antagonism reduced the amplitude of biceps motor evoked potentials (MEPs) across a spectrum of TMS intensities, but reductions in MEP amplitude with cyproheptadine were largest with high-intensity TMS. In the same study, during elbow flexions of different strengths, it was found that 5-HT2 antagonism reduced maximal contraction torque and lengthened the TMS silent period only during maximal effort contractions. Lastly, Study 3 assessed the effects of 5-HT2 antagonism on biceps cervicomedullary motor evoked potentials (CMEPs) and F-waves in the abductor digiti minimi (ADM). In Study 3, cyproheptadine reduced the amplitude and persistence of ADM F-waves but did not affect the amplitude of biceps CMEPs from corticospinal axon stimulation. Study 3 also found that 5-HT2 antagonism reduced maximal elbow flexion strength, which replicated findings from Study 2. Overall, this thesis presents novel human evidence that serotonergic effects at motoneurons depend on the intensity of motor activity. In addition to 5-HT effects at motoneurons, some findings indicate that 5-HT modulates motor cortical function and/or the activity of other supraspinal networks indirectly involved in voluntary movement.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Health Sci & Soc WrkGriffith HealthFull Tex
Comparison of Warfarin and Non-vitamin K Oral Anti-Coagulants in Non-Valvular Atrial Fibrillation in South-East Queensland
No full textBackground: Atrial Fibrillation (AF) is a cardiac rhythm disorder that can result in stroke and heart failure. Treatment to prevent the incidence of ischemic stroke involves initiating patients on an Oral Anticoagulant (OAC.). Warfarin which is a vitamin K antagonist has long been the only OAC available, but now other options include dabigatran which is a direct thrombin inhibitor, and rivaroxaban and apixaban which are factor Xa inhibitors. These OACs can cause adverse drug reactions, including bleeding complications which cause fears associated with prescribing of OAC. When the OAC options became available in Australia, a government review of anticoagulant usage highlighted key points such as the underuse of anticoagulants in patients with a high risk of stroke and the concerns regarding the safety of anticoagulants. Therefore, investigating the introduction of Non-Vitamin K Oral Anticoagulants (NOAC) and the use of warfarin will assist in addressing the concerns raised by the government-commissioned review of anticoagulant therapy in AF.
Aim: This study aims to compare the prescribing of warfarin and the introduction of NOACs in patients with Non-Valvular Atrial Fibrillation (NVAF) in Southeast Queensland.
Method: This retrospective cohort study was conducted in a hospital located in Southeast Queensland, Australia, using hospital records from patients admitted from 2012 to 2015. Data was extracted for all adult patients (aged ≥18 years) with an admission of AF and prescribed an OAC from 1 July 2012 to 10 June 2015. Data collection included patient details such as age, gender, comorbidities, and primary diagnosis together with admission details such as length of stay in hospital and discharge status. Data analysis included calculating CHA2DS2 (Congestive heart failure, Hypertension, Age>75, Diabetes, prior Stroke/transient ischaemic attack) and CHA2DS2VA (Congestive heart failure, Hypertension, Age>75, Diabetes, prior Stroke/transient ischaemic attack, Vascular disease, Age 65-74 years, Sex category of female) scores to find the risk of stroke and HASBLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history, Labile INR, Elderly>65years, Drugs/alcohol) scores to show the risk of bleeds, comparison of OAC usage from 2012 to 2015, logistic regression analysis for further data analysis.
Results: Data extraction found 10636 admissions for AF. These admissions were further screened according to the inclusion and exclusion criteria, leaving 3396 admissions by 1911 patients for further analysis. There were 834 (54.4%) patients on nil OAC therapy during the first admission with a CHA₂DS₂-VA score of ≥2, which significantly decreased (p < 0.001) to 285 (18.6%) patients discharged on nil OAC therapy. There were 745 patients on nil OAC during the first admission and 450 (42.1%) patients were discharged on NOAC therapy, while 295 (27.6%) patients were discharged on warfarin therapy. A total of 68 patients admitted on an OAC were ceased from OAC therapy upon discharge for various reasons. This study found 27 patients had changed therapies from warfarin to NOAC or NOAC to warfarin due to numerous reasons. Furthermore, this study found the risk of bleeding, stroke episode, and ischaemic heart disease to significantly affect the prescribing of OACs. In addition, age regarding the high risk of falls and kidney function influenced the prescribing of OAC.
Conclusion: The findings from this study highlighted the under prescribing of OAC upon patient admission. However, upon discharge and subsequent patient admissions, there was an increased prescribing of OAC, especially for patients with a high risk of stroke. Therefore, this study established that the total prescribing and initiation of OAC had increased overall after the introduction of NOACs, with rivaroxaban being more commonly prescribed than warfarin. Further investigations into the usage of OAC highlighted the fears associated with prescribing of OAC especially the risk of bleeding, which significantly affected the prescribing of OAC in regards to ceasing and changing OAC therapies. In addition, the outcomes of OAC therapy investigated, found admissions to hospital due to bleeding, stroke, and death for patients initiated and established on OACs.Thesis (Masters)Master of Medical Research (MMedRes)School of Medical ScienceGriffith HealthFull Tex
The Contribution of Central Cholinergic Pathways to Motor Control and Cognitive Function
No full textAcetylcholine acts as a neuromodulator in the central nervous system as it plays an important role in the control of motor and cognitive functions. However, little is known about how motor control and cognition is affected by targeted pharmacological interventions that alter central cholinergic neurotransmission. As such, this Thesis investigated the effects of over-the-counter medications with varying degrees of central
anticholinergic activity on oculomotor function (smooth pursuit and saccadic eye movement), ocular responses (pupil diameter and blink rate) and cognition (attention network test) in healthy young adults.
All experiments were double-blind, placebo controlled, human, four-way cross-over trials. Physiological responses were obtained from each subject pre-ingestion as well as 0.5 h and 2 h post-ingestion of promethazine hydrochloride (strong centrally acting anticholinergic), hyoscine hydrobromide (moderate centrally acting anticholinergic), hyoscine butylbromide (anticholinergic devoid of central properties), and a placebo.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of PharmacyGriffith HealthFull Tex
Predictors of Warfarin Control in Patients with Atrial Fibrillation in South-East Queensland and Singapore
No full textBackground
Warfarin is an oral anticoagulant widely prescribed for several thromboembolic indications
including stroke associated with atrial fibrillation (AF). Warfarin control is influenced by a
number of genetic and environmental factors which, combined with a narrow therapeutic
index, results in a need for close monitoring using the International Normalised Ratio (INR).
Maintaining INR values within the therapeutic range can reduce adverse effects such as
bleeding and stroke, with time in therapeutic range (TTR) commonly used as a measure of
the quality of anticoagulation with warfarin. Increased TTR directly correlates to the
efficacy and safety of warfarin and improved patient outcomes.
Many patients with AF are either ineffectively managed with warfarin or not candidates for
warfarin therapy. This led to the development of alternate non-vitamin K oral
anticoagulants (NOACs) which were compared to warfarin in patients with AF through large
randomised controlled trials. Meta-analyses of these trials demonstrated the NOACs to be
either non-inferior or slightly superior to warfarin in terms of stroke and associated with a
lower risk of intracranial haemorrhage. However, sub-analyses of these trials highlighted
concerns regarding the mean warfarin TTR in these trials and the differences in TTR
according to geographical location and management systems. Variation in warfarin TTR
impacts the clinical outcomes of warfarin therapy including the comparative outcomes with
NOACs. The choice between anticoagulants requires consideration of likely warfarin control
which may be influenced by patient demographics and clinical characteristics together with
health care management systems. In Australia, this prompted the Australian Government
to commission a review of anticoagulant therapies in AF. This review identified a need for national guidelines for AF and therapeutic management algorithms for individual
anticoagulants including warfarin. However, this review also identified a barrier to
producing these management algorithms was the lack of information regarding the quality
of warfarin management in Australia and factors which may influence TTR including patient
variables and management systems.
Aims
The overall aim of this study was to determine predictors of warfarin control in patients
with AF in South-East Queensland and Singapore. Singapore was chosen as a comparator
site in the Asia-Pacific region to assist with applicability of results across the multi-cultural
population of Australia given potential factors influencing warfarin TTR include patient
demographics, ethnicity and management systems. Specific objectives of the study were to:
(1) establish the prescribing of warfarin in AF since the introduction of the NOACs (2)
determine the quality of warfarin control in Queensland achieved by different warfarin
management systems; (3) identify factors influencing warfarin TTR in patients with AF in
Queensland as compared to Singapore; and (4) establish the efficacy of risk models
recommended in AF guidelines to predict warfarin control.
Methods
Ethics approval was granted (PHM/09/14HREC,2015/863 and 2015/2435). A retrospective
observational study was conducted of patients receiving warfarin for AF at two study sites,
Sullivan Nicolaides Pathology (SNP) in Queensland and the National Heart Centre Singapore
(NHCS). PBS data was utilised to establish prescribing rates of oral anticoagulants since the introduction of the NOACs, Data was collected as of 30 September 2014 at SNP and between 1 January and 30 June
2014 at the NHCS. Data collected was INR test results, together with patient demographics
such as age, gender, co-morbidities and concurrent medications. Warfarin control for
individuals was determined by calculation of percentage of INR tests within target range and
TTR via a linear interpolation method. Patients were excluded if TTR could not be
calculated, that is less than two INR tests, or if less than thirty days of treatment. Patient
data categorised patients according to specific factors, including gender, age, concurrent comorbidities
and medication, bleed an stroke risk scores, and a predictor score for warfarin
control. Mean patient data was used for analysis and comparison between groups with
analysis of specific factors on TTR conducted using chi-squared, Tukey-Kramer, or a one-way
analysis of variance tests via nonparametric methods including Kruskal-Wallis test and
Dunn’s multiple comparisons test with GraphPad Instat Version 3. Significance was defined
at p<0.05(*), p<0.01(**), p<0.001(***), and p<0.0001(****).
Results
Warfarin prescribing decreased since introduction of the NOACs but it remains widely
prescribed with almost 1.5 million units prescribed in Australia (2017/8 financial year), of
which 250,478 units were prescribed in Queensland. In Queensland, the number of patients
with AF managed by SNP decreased from 10,806 patients in July 2012 to 5524 patients in
July 2017. During this time, 3036 patients exited the warfarin program to commence NOAC
therapy but almost 5% (n=141) reverted to warfarin. In these patients, no significant
difference in mean TTR was found before or after NOAC treatment but significantly more frequent testing and lower doses were required to obtain this level of control.
In Queensland, warfarin control in patients with AF was above recommended minimum
targets of 65% with a mean TTR of 68.5±16.2% by general practitioner (GP) and 81.5±9.1%
by SNP with significant differences (p < 0.0001) in frequency of testing between
management systems. Warfarin control in Singapore was significantly lower than
Queensland (mean TTR 82.3±15.6% vs 57.6±34.2%, p < 0.0001). There were significant
differences (p < 0.0001) in mean frequency of testing between Queensland and Singapore
(16.9 vs 29.3 days). Patients with chronic kidney disease in both Queensland and Singapore
had significantly lower TTR (77.2±16.8%, p<0.01 and 50.9±32.9%, p<0.05 respectively). Age
less than 60 years (p<0.05) in Queensland and use of a platelet inhibitor in Singapore (p <
0.01) also significantly reduced TTR. After excluding interacting drugs with warfarin, a
significantly reduced TTR (p<0.05) was found in Queensland for patients taking concurrent
non-steroidal inflammatory drugs (NSAIDs) and aspirin In Singapore, a predictor score
could identify poor warfarin control as patients with a score > 2 had significantly lower TTR
than other patients (55.8±34.1% vs 63.2±34.1%, p<0.001).
Discussion and conclusion
Warfarin requires regular monitoring to maintain INR levels within range and minimum
targets of 65% TTR are recommended to optimise benefits from warfarin therapy. This
study demonstrated that warfarin is well controlled in Queensland with TTR levels above
this minimum by both GP and dedicated warfarin management systems but, in contrast,
Singapore has poor control. Frequency of INR testing strongly contributed to warfarin
control with increased warfarin monitoring leading to improved control in Queensland
compared to Singapore but also by the dedicated warfarin management system compared to GP management in Queensland.
In this study, patient factors which consistently influenced warfarin TTR in both Queensland
and Singapore were chronic kidney disease and the concurrent administration of NSAIDs
and aspirin, whilst age < 60 years also influenced TTR in Queensland. Based on these
factors, prescribing guidelines have been proposed which highlight these subsets of patients
as being at risk of poor warfarin control and who may benefit from the additional
intervention of a dedicated warfarin management system to optimise control. In addition, a
risk model combining these factors into the mnemonic WARFARIN (Warfarin management
program available, AF valvular, Renal Function normal, Age > 60 years, Race = Caucasian,
Intolerance to NOAC, NSAIDs or aspirin not concurrently used) has been proposed as a
method of identifying patients likely to obtain good warfarin control and best suited to
warfarin therapy.
In conclusion, despite the introduction of the NOACs, warfarin remains widely prescribed
and is currently the only anticoagulant option available for patients with valvular AF.
Dedicated warfarin management programs can improve warfarin control and use of
proposed algorithms or guidelines can identify subsets of patients at risk of reduced control
who may benefit from additional intervention to improve warfarin TTR. This addresses
recommendations from an Australian government report and may help optimise anticoagulant therapy for patients with AF.Thesis (PhD Doctorate)Doctor of Philosophy (PhD)School of Pharmacy and PharmacGriffith HealthFull Tex
Pharmacy Staff Perceptions on Complementary Framework and Advanced Scope for Hospital Pharmacy Support Staff
No full textPharmacy assistants and technicians, as pharmacy support staff, play an important role in hospital pharmacy departments by alleviating pharmacists’ time to concentrate on more clinically oriented tasks. Whilst organisations such as the Society of Hospital Pharmacists Australia (SHPA) have recognised the need to further integrate pharmacy assistants and technicians into more advanced roles, such as medication reconciliation, there is currently limited research on the availability of training and consistency in service delivery provided by these support staff in Australian hospital settings. As a result, hospitals/organisations around the country have implemented individualised in-house training suited to their respective needs and environment.
In order for pharmacy support staff to be equipped to perform advanced roles, training frameworks and support from pharmacists are required. The aim of this study was to explore and compare the perceptions of roles and available training frameworks that support career advancement for pharmacy support staff, amongst pharmacists and support staff, in the hospital sector. A literature review was completed to inform international comparisons of roles, training frameworks and benefits of support staff advancement within the pharmacy profession. Semi-structured interviews were conducted with personnel from both private and public hospitals to explore key issues identified in the literature. A total of 25 participants consisting of ten pharmacists and 15 pharmacy support staff were recruited from a private (n=13) and a public (n=12) hospital in South East Queensland. Interviews were conducted either face-to-face or via telephone between October 2017 to August 2018 across both sites, with a mean duration of 39.85 minutes (range: of 20.08 to 60.04 minutes). All interviews were audio-recorded, transcribed verbatim, and quality checked by a second researcher prior to data analysis using the qualitative software NVivo® 11. The general inductive approach was used for thematic data analysis, which allowed for the emergence of new themes and sub-themes within the research topic.
Findings from this research confirmed that the core duties of pharmacy support staff were dispensing and inventory management in both hospital settings, with greater clinical task involvement sought by participants. Tasks such as assisting with medication history taking, collating pathological results, research involvement, and discharge facilitation were considered as technical tasks within a clinical setting. Most participants supported the career advancement of pharmacy support staff irrespective of their own professional role, and believed that with appropriate training, this could include technical tasks in a clinical setting and administrative roles currently performed by pharmacists. Professional autonomy, time, and monetary incentives were commonly reported by participants as motivators, with lack of organisational support and course availability reported as common barriers for pharmacy support staff career progression. With some participants having international knowledge and experiences, emerging themes such as pharmacy technician registration and the need for governing bodies such as universities and registration boards were also expressed. Other emerging themes included the perception of hierarchy from inside and outside of the pharmacy profession by selected participants.
This study also identified inconsistencies in the application of role titles used across both sites with pharmacy assistant and pharmacy technician used interchangeably, and differences in role expectations. For example, tasks such as supply of inpatient medication performed across both hospital environments had diverse processes with different levels of pharmacist involvement. As a result, this study highlighted the need for greater consistency in the definition and application of pharmacy support staff titles and roles. Additionally, participants revealed the need for governing bodies to streamline roles and training frameworks similar to the accreditation and registration processes seen internationally, as means of ensuring and maintaining the quality of service provided to stakeholders.
This exploratory study provides valuable insight into the thoughts and motivation of pharmacy support staff and pharmacists that can inform the evolution of support staff career pathways. By documenting the accounts and views of pharmacists and pharmacy support staff in two different hospital environments, this study has added to existing research by being one of the first studies to obtain insight into the lived experience of pharmacy staff within the Australian hospital environment. This study has also identified potential areas for further research in the field of pharmacy support staff education and professional practice.Thesis (Masters)Master of Medical Research (MMedRes)School of Medical ScienceGriffith HealthFull Tex
Effects of Melatonin on Chemotherapy-Induced Neuroinflammation and Neurodegeneration
No full textCytotoxic chemotherapy leads to debilitating neurological side-effects, such as fatigue, cognitive impairment, and peripheral neuropathy. Certain chemotherapy agents and/or classes have been linked to a higher incidence of neurological side effects. There have been numerous biological pathways suggested as potential routes of chemotherapy-induced neurotoxicity, with inflammation being the most widely proposed cause. Although there is a great deal of studies investigating how chemotherapy-induced inflammation leads to neurological abnormalities, the exact causal mechanisms remain largely unknown. In addition to this, currently there are no therapies to prevent or treat the neurological side-effects caused by chemotherapy. Melatonin has been extensively researched as a neuroprotective agent for the treatment/prevention of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. Melatonin has potent antioxidant, anti-inflammatory and anti-apoptotic benefits that make it an attractive potential therapeutic candidate for attenuating chemotherapy-induced neuroinflammation and neurodegeneration. However, it has not been studied for such a purpose previously. This study aimed to determine melatonin's effect on chemotherapy-induced neuroinflammation and neurodegeneration in vitro, which we achieved through our three objectives. [...]Thesis (Masters)Master of Medical Research (MMedRes)School of Pharmacy & Med SciGriffith HealthFull Tex
Determination of a recommended trial period for atrial fibrillation (AF) patients commencing warfarin therapy in Australia.
No full textBackground: Over the past five decades, warfarin, an anticoagulant drug, has been used in patients with Atrial Fibrillation (AF) for the prevention of embolic stroke. Many guidelines suggest that AF patients who have had warfarin treatment initiated, should also be supervised to provide optimised quality control of the warfarin by monitoring the Time in Therapeutic Range (TiTR). If patients achieve a high TiTR, warfarin treatment is appropriate and should not be switched to Novel Oral Anticoagulant drugs (NOACs). Moreover, the guideline from the Thrombosis and Haemostasis society of Australia and New Zealand (THANZ) suggests that AF patients who have had TiTR > 65% for over a three months period are stable on warfarin treatment and should not be switched from warfarin to NOACs drug treatment. However, international guidelines do not indicate what the suitable duration for observing the quality of warfarin control should be and there is no study about the duration of warfarin trials in patients with AF. Aim: This research aimed to address the Time to Stable Therapeutic Range (TtSTR) and determined the factors that affected this. In addition, this research also aimed to assist in the screening for patients’ suitability for warfarin treatment and patients who might not achieve good quality control from warfarin. Furthermore, this research aimed to provides a suitable duration recommendation for a warfarin trial, which has not previously been provided. This was to ensure that the actual TiTR observed at the time of decision making is a true reflection of the potential TiTR that a patient is likely to achieve. Method: Retrospective data were collected between November 2007 and October 2014 from Sullivan Nicolaides Pathology, Queensland. International Normalised Ratio (INR) measurements were collected and used to calculate the individual TiTR at different specific time points: 1, 2, 3, 4, 5, 6, 9, 12, 18 and 24 months by using Rosendaal's linear
interpolation algorithm. The TiTR results at different specific time points were assessed in order to discover the Time to Stable Therapeutic Range (TtSTR). Patients were divided into two groups according to low or high (≤ median of TtSTR or ˃ median of TtSTR, respectively) TtSTR. The independent t test was used to compare the mean TiTR between these two groups at each time point. Moreover, this study investigated the factors which were associated with higher TtSTR by using a multivariate logistic regression analysis.
Results: The median of the TtSTR of the eligible 566 AF patients was six months, and almost 57% of patients had TtSTR ≤ 6 months. Only two factors, namely IRSAD (Index of Socioeconomic Advantage and Disadvantage) rank 9 and carbamazepine, had a significant relationship with TtSTR > 6 months. Patients who were concurrently treated with carbamazepine during the first six months of warfarin treatment had 15 times the risk of TtSTR > 6 months when compared to patients who were not treated with carbamazepine. On the other hand, patients with IRSAD rank 9 had a decreased risk of TtSTR > 6 months (OR = 0.392, p = 0.022) when compared with patients with IRSAD rank 1.
Conclusion: The results of this study indicate that the patients who achieve TtSTR within 6 months could maintain good warfarin control (TiTR ≥ 65%) in the next 18 months. Moreover, it could be suggested that a six month period is the minimum duration of a warfarin trial and a 12 month period might be the maximum duration for Australian patients with AF. However, the factors that associated with TtSTR cannot be indicated due to the limitation of this study.Thesis (Masters)Master of Medical Research (MMedRes)School of Medical ScienceGriffith HealthFull Tex
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