In Vitro Evaluation of Vancomycin-Induced Toxicity in Human Primary Knee Chondrocytes.

Septic arthritis as a complication of orthopaedic joint surgery can have catastrophic outcomes for patients. To minimise infection risk associated with elective orthopaedics, topical vancomycin during surgery has become increasingly common. Evidence suggests that high concentrations of vancomycin, following direct application of the drug to the joint, are toxic towards various local cell types in the joint, including chondrocytes. However, the mechanism of this vancomycin tissue toxicity is yet to be determined. The aim of this study was to evaluate the toxicity of vancomycin on chondrocytes and the mechanisms of cell death involved. Human primary knee chondrocytes were exposed to vancomycin (1.25-10 mg/mL) for 24 h and their viability assessed using the resazurin reduction assay in vitro. Specific cell death mechanisms and their contributors, including reactive oxygen species (ROS) production and apoptosis, were measured. This study showed that high concentrations of vancomycin (5 and 10 mg/mL) were toxic towards human primary knee chondrocyte cells, while lower concentrations (1.25 and 2.5 mg/mL) were not. Cell death studies found that this occurred through an apoptotic pathway. This study provides additional support that vancomycin in high doses is toxic towards chondrocytes and preliminary evidence that this toxicity occurs via apoptotic cell death mechanisms.

Involvement of indoleamine 2, 3-dioxygenase (IDO) and brain-derived neurotrophic factor (BDNF) in the neuroprotective mechanisms of ferulic acid against depressive-like behaviour.

OBJECTIVE: Ferulic acid (FA) is a common food ingredient that is abundantly present in various routinely consumed food and beverages. Like many cinnamic acid derivatives, FA produces wide-ranging effects in a dose-dependent manner and various studies link FA consumption with reduced risk of depressive disorders. The aim of this study was to exploit the neuroprotective mechanisms of FA including indoleamine 2,3-dioxygenase (IDO), brain-derived neurotrophic factor (BDNF), and other pro-inflammatory cytokines by employing lipopolysaccharide (LPS)-induced depressive-like behaviour model. METHODS: C57BL/6J male mice were divided into 4 groups consisting of saline (SAL), LPS, FA and Imipramine (IMI). Animals were pretreated orally with FA (10 mg/kg) and IMI (10 mg/kg) for 21 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 21. RESULTS: LPS administration produced a biphasic change in the behaviour of the animals where the animals lost a significant weight and express high immobility time at 24 h. Proinflammatory cytokines including, TNF-α, IL-6, IL-1ß, and IFN-γ were significantly increased along with increased lipid peroxidation and reduced BDNF. Furthermore, the increased kynurenine to tryptophan ratio was indicative of elevated IDO activity. CONCLUSION: The results of this study emphasise that low dose of FA is effective in attenuating depressive-like behaviour by modulating IDO, BDNF and reducing neuroinflammation.

An education on pharmacologically active complementary and alternative medicine and its effects on cancer treatment: literature review.

PURPOSE: This literature review examines the provision of an education on pharmacologically active complementary and alternative medicines (CAMs), to people with cancer, their carers and oncology health professionals. METHODS: A search of the published literature between 2000 and 2020, in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, was conducted. The search retrieved 1121 studies, 1080 were excluded based on their title or abstract and 26 articles were excluded based on their text. One article was retrieved from the reference lists of the included articles and in total fifteen studies met the inclusion criteria. This review utilised Medical Education Research Quality Instrument (MERSQI) to evaluate the quality of the included studies. Four key outcomes were utilised for analysis and recommendations for future education and/or research were generated. The recommendations were graded according to the Strength of Recommendation Taxonomy (SORT). RESULTS: This review consistently found that people with cancer, their carers and oncology health professionals derived benefit from a pharmacologically active CAM education and recommends that this population receives one. Conversely, the review found many education formats utilised and no consensus on the most successful methods. CONCLUSION: Future research should examine who a CAM education should be delivered to, what type of delivery platform is most accessible and useful, and the features of the education that most increase CAM knowledge. The popularity of CAMs amongst people with cancer and the potential dangers associated with their use necessitates further research into how best to communicate CAMs to this population.

Remedial effects of caffeine against depressive-like behaviour in mice by modulation of neuroinflammation and BDNF.

Objective: Caffeine (CAF) is one of the most commonly consumed nutritional stimulant in beverages. Interestingly, CAF produces varied effects in a dose-dependent manner, and that makes it one of the most controversial nutritional ingredients. Various studies have linked CAF consumption and reduced risk of depressive disorders. The aim of this study was to investigate the effect of CAF on lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviour.Methods: C57BL/6J male mice were divided into four groups consisting of saline (SAL), LPS, CAF and Imipramine (IMI). Animals were pretreated orally with CAF (10 mg/kg) and IMI (10 mg/kg) for 14 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 14.Results: LPS produced a biphasic behavioural response with a significantly high immobility time and weight loss after 24 h. The brain cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) levels were remarkably high, along with increased lipid peroxidation and reduced Brain Derived Neurotrophic Factor (BDNF). These biochemical and behavioural changes were significantly alleviated by CAF and IMI chronic treatment.Conclusion: The results of this study implicate that mild-moderate consumption of CAF could impart anti-inflammatory properties under neuroinflammatory conditions by modulating the cytokine and neurotrophic mechanisms.

Putative involvement of sirtuin modulators in LPS-induced sickness behaviour in mice.

NAD+-dependent histone deacetylases (sirtuins 1-7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.

SIRT1 and SIRT2 modulators reduce LPS-induced inflammation in HAPI microglial cells and protect SH-SY5Y neuronal cells in vitro.

Neuroinflammation is associated with the development of depression. Deacetylases SIRT1 and SIRT2 are reported to exert neuroprotective effects in aging, neurogenesis, neurodegeneration and neuroinflammation. Therefore, this study aimed to investigate the effects of SIRT1 and SIRT2 modulators on LPS-induced neuroinflammation and neurodegeneration in vitro. To achieve this, HAPI rat microglial cells were pre-treated with the SIRT1 activator resveratrol (0.1-20 µM), the selective SIRT1 inhibitor EX527 (0.1; 1 µM), the dual SIRT1/SIRT2 inhibitor sirtinol (0.1-20 µM) and the SIRT2 inhibitor AGK2 (0.1; 1 µM), prior to exposure with LPS (5 ng/mL) for 20 h. The reference antidepressant drug fluoxetine and the nonsteroidal anti-inflammatory drug ibuprofen were also evaluated in the same paradigm, both at 1 µM. Resveratrol and sirtinol inhibited TNF-α production to a greater degree than either fluoxetine or ibuprofen. Resveratrol, sirtinol, EX527 and AGK2 significantly reduced PGE2 production by up to 100% in microglia. Then, the supernatant was transferred to treat SH-SY5Y cells for 24 h. In all cases, SIRT modulator pretreatment significantly protected undifferentiated SH-SY5Y human neuroblastoma cells from the insult of LPS-stimulated HAPI supernatant by up to 40%. Moreover, resveratrol and sirtinol also showed significantly better neuroprotection than fluoxetine or ibuprofen by up to 83 and 69%, respectively. In differentiated SH-SY5Y cells, only sirtinol (20, 10 µM) and AGK2 (0.1 µM) pretreatment protected the cells from LPS-stimulated HAPI supernatant. This study suggests that SIRT1 and SIRT2 modulators are effective in inhibiting LPS-stimulated production of TNF-α and PGE2 in HAPI microglial cells and protecting SH-SY5Y cells from inflammation. Thus, we provide proof of concept for further investigation of the therapeutic effect of SIRT1 and SIRT2 modulators and combination with current antidepressant medication as a treatment option.

Comparison of potential pharmacokinetic drug interactions in patients with atrial fibrillation and changing from warfarin to non-vitamin K oral anticoagulant therapy.

There are now anticoagulant choices with proposed advantages of non-vitamin K oral anticoagulants (NOACs) over warfarin being less routine monitoring and less drug interactions. Interacting medication can impact the efficacy and safety of anticoagulant therapy with management remaining clinically challenging. There have been limited studies comparing the potential for pharmacokinetic (PK) drug interactions between different anticoagulants. Therefore, the aim of this study was to compare potential PK interactions in patients with atrial fibrillation (AF) changing from warfarin to NOAC therapy. A retrospective analysis was conducted of patients with AF enrolled in a dedicated warfarin program but exiting this program to commence a NOAC. Patient data was collected, and concurrent medications were utilised to identify potential PK drug interactions with both warfarin and the chosen NOAC therapy. Patients were grouped according to the number of medications with potential PK interactions and comparisons made between groups. Of the 712 eligible patients who ceased warfarin to commence a NOAC, most commenced either apixaban (45.9%) or rivaroxaban (41.9%). When comparing warfarin to NOACs, there were significant differences in the proportion of patients taking no medication with potential PK drug interactions (46.9% vs 62.8%, p < 0.0001), and taking one (35.2% vs 28.5%, p = 0.0067) and two (14.5% vs 7.3%, p < 0.0001) potentially PK interacting medications. This study found when patients with AF were switched from warfarin to a NOAC, the potential for PK drug interactions significantly reduced but remained around 40%. Identifying and managing potential PK drug interactions with NOACs remains a priority to optimise clinical benefit of these anticoagulants.

Time to Stable Therapeutic Range on Initiation of Warfarin as an Indicator of Control.

OBJECTIVES: Warfarin remains widely used with a time in therapeutic range (TiTR) above 65% recommended for best outcomes. Patients not achieving or maintaining this warfarin control may be better suited to alternate anticoagulants. Despite this, there is limited data defining a suitable trial time in patients initiating warfarin therapy, therefore the aim of this study was to determine the mean time to stable therapeutic range (TtSTR). MATERIALS AND METHODS: Retrospective data was collected for patients with atrial fibrillation enrolled in a dedicated warfarin program at a private pathology practice within 7 days of warfarin initiation. TiTR at specified timepoints was calculated and median TtSTR determined as defined by TiTR ≥ 65% over three months. Comparisons were made of populations with TtSTR above or below the median. RESULTS: The 566 patients included in the study had a mean TiTR of 64.9±16.5% at month three and median TtSTR of six months. Patients with TtSTR≤6 months achieved a mean TiTR of 68.9±12.8% at month two and maintained a TiTR over 75% from month 3 to 24. Patients with a TtSTR>6 months obtained a TiTR of 66.4±10.6% at month nine and continued to achieve lower TiTR throughout the 24 months study period. CONCLUSIONS: A majority of patients can achieve a stable TiTR above 65% within six months so review at six to nine months is likely to be a good indicator of warfarin control and to determine if patients should continue warfarin or switch to alternate anticoagulant therapy.

The Impact of an Evidence-Based Education on Complementary and Alternative Medicine Usage in People with Cancer: Pilot Study.

Complementary and alternative medicine (CAM) usage amongst cancer patients is high globally and in Australia. CAM use in cancer care has the ability to increase chemotherapy toxicity or cause sub-therapy due to altered metabolism as well as increase a patient's bleeding risk. Furthering these risks, people with cancer are largely obtaining their CAM use information from non-evidence-based sources. This study aimed to determine whether the implementation of a CAM education influenced decision-making with regard to CAM usage amongst cancer patients. Twenty people with cancer were recruited for participation in this study. The aims of this study were achieved by surveying patients via questionnaire, both prior to and following receiving an evidence-based CAM education, in either or both written or audiovisual format. This exploratory study found, consistent with the literature, that the majority of participants were obtaining their CAM use information from non-evidenced-based sources. Additionally, it found that the participants wanted more CAM use information and that they demonstrated some altered decision-making after receiving evidenced-based information. On the post-educational questionnaire, the number of participants that stated that they would use CAMs decreased by almost 14%, and some participants made CAM use decisions in accordance with the information provided in the resources. Furthermore, a small increase in CAM knowledge was demonstrated, and it was reported that the resource had prompted them to look further into CAM information. Lastly, the participants in this study found the resource to be mostly useful and helpful and preferred the animated video to the written information.

The COX-2 inhibitor NS398 selectively sensitizes hypoxic HeLa cells to ionising radiation by mechanisms both dependent and independent of COX-2.

It is widely accepted that the hypoxic nature of solid tumors contribute to their resistance to radiation therapy. There is increasing evidence that cyclooxygenase-2 (COX-2) contributes to increased resistance of tumors to radiation therapy. Several studies demonstrate that combination of COX-2 selective inhibitors with radiation therapy selectively enhances radio responsiveness of tumor cells. However, the majority of these studies utilised suprapharmacological concentrations under normoxic conditions only. Furthermore, the mechanism by which these agents act remain largely unclear. Therefore, the aim of this study was to determine the impact of COX-2 selective inhibitors on both normoxic and hypoxic radiosensitivity in vitro and the mechanisms underlying this. Because of the close, reciprocal relationship between COX-2 and p53 we investigated their contribution to radioresistance. To achieve this we exposed HeLa, MCF-7 and MeWo cells to the COX-2 selective inhibitor, NS398 (10µM). NS398 (10µM) selectively sensitized hypoxic HeLa and MCF-7 but not MeWo cells to ionising radiation (5 Gy). Furthermore, while knockdown of COX-2 with siRNA did not affect either normoxic radiosensitivity in HeLa cells, the radiosensitisation observed with NS398 was lost suggesting both COX-2 dependent and independent mechanisms. We also show that ionising radiation at 5 Gy results in phosphorylation of p53 at serine 15, a key phosphorylation site for p53-mediated apoptosis, and that hypoxia attenuates this phosphorylation. Attenuated phosphorylation of p53 under hypoxic conditions may therefore contribute to hypoxic radioresistance. We also show that NS398 selectively phosphorylates p53 under hypoxic conditions following irradiation at 5 Gy. p53 phosphorylation could be an underlying mechanism by which this agent and other COX-2 inhibitors sensitize tumors to radiation therapy.

The SAMe-TT2R2 score as an indicator of warfarin control for patients with deep vein thrombosis in Queensland, Australia.

Oral anticoagulation options for patients with venous thromboembolism (VTE) include vitamin K antagonists like warfarin. Good warfarin control is linked to outcomes of therapy, and the SAMe-TT2R2 model has been reported to predict control in atrial fibrillation patients with scores ≥ 2 linked to poor control. There has been limited and conflicting data in VTE populations, therefore this study aimed at determining the predictive ability of this model in Australian patients with deep vein thrombosis. Retrospective data of patients receiving warfarin care at a private pathology clinic in Queensland was collected. The time in therapeutic range (TTR) and SAMe-TT2R2 score was calculated for individual patients. Mean TTR and patients with TTR ≥ 65% were used for analysis and comparison across patients categorised as a score of 0-1 and ≥ 2. Of the 533 patients, the majority had a SAMe-TT2R2 score of 0-1. No significant difference was found in mean TTR between patients with a score of 0-1 and ≥ 2 but there was a significantly higher percentage of patients with a TTR ≥ 65% between groups (93.8% vs. 69.2%, p < 0.0001, respectively). The SAMe-TT2R2 score may assist in identifying patients with VTE likely to achieve good control (TTR ≥ 65%), but further investigation is required to determine the most suitable model for predicting warfarin control in this population.

Non-prescription medicines may contribute to non-adherence to prescription medicines in people living with chronic health conditions.

BACKGROUND: Non-adherence to prescribed medicines is linked to adverse health outcomes in people living with chronic health conditions (CHCs). Multiple factors are known to contribute to non-adherence to medicines including polypharmacy, demographic features and disease and health systems. Both non-prescription and prescription medicines contribute to polypharmacy; however, there is limited data on the influence of non-prescription medicines to non-adherence. AIM: Therefore, the aim of the study was to investigate the influence of non-prescription medicines to non-adherence in an Australian population. METHODS: Data from the 2016 National Survey of a random sample of Australian adult residents were utilised in this study to investigate factors associated with non-adherence. Descriptive statistics, χ2 , regression and generalised linear models were used to assess the relationships between variables of interest. Narrative response and comments were used to provide further insight. RESULTS: This study recruited 1217 participants to explore factors associated with non-adherence to medicines. Weak but statistically significant correlations were identified showing the number of CHCs, patient's age, number of prescription medicines, number of non-prescription medicines and total number of medicines associated with non-adherence. DISCUSSION: The findings suggest that people living with CHCs and taking multiple medicines, including non-prescription medicines, are likely to be non-adherent to prescription medicines. This study shows the possible involvement of non-prescription medicines in contributing to non-adherence in an Australian population and suggests that future studies with a broader demographic are warranted.

Anticoagulant Initiation During Hospital Admissions for Atrial Fibrillation in South-East Queensland, Australia.

BACKGROUND: Anticoagulation reduces stroke risk in patients with atrial fibrillation (AF) but under-prescribing in eligible patients has been commonly reported. Introduction of the direct acting oral anticoagulants (DOACs) was considered to potentially improve prescribing due to increased anticoagulant options. At the time of release to the Australian market, there were limited studies investigating anticoagulant usage during hospitalisations for AF. Therefore, the aim of this study was to investigate prescribing of oral anticoagulants during hospitalisation admissions for AF during the time of DOAC introduction to the Australian market. METHOD: A retrospective study was conducted of admissions to a tertiary Queensland hospital during 1 July 2012 to 10 June 2015. Patients were categorised according to oral anticoagulant therapy on both hospital admission and discharge. Changes to therapy and patient factors associated with prescribing were analysed. RESULTS: A total of 1,911 patients were included with 3,396 admissions during the study period. There was a significant increase in the number of patients initiated on anticoagulant therapy during their first admission with higher rates of initiation of DOACs compared to warfarin. Ischaemic heart disease and high bleed risk were significantly associated with reduced prescribing of anticoagulant therapy on first and second admission respectively, while patients with a history of stroke or transient ischaemic attack were significantly more likely to receive therapy. CONCLUSION: The introduction of the DOACs to the Australian market increased initiation of anticoagulants to hospitalised patients with AF across all stroke risk categories. The availability of greater anticoagulant options has increased initiation of therapy but there remains potential to further optimise anticoagulant prescribing by targeting therapy according to guidelines and patient factors.

Yes to Recreational Drugs and Complementary Medicines But No to Life-Saving Medications: Beliefs Underpinning Treatment Decisions Among PLHIV.

Despite the life-preserving benefits of antiretroviral therapy (ART), some people living with HIV (PLHIV) delay, decline or diverge from recommended treatment while paradoxically being willing to use potentially dangerous substances, such as recreational drugs (RD) and complementary medicines (CM). During 2016 and 2017, interviews were conducted with 40 PLHIV, in Australia to understand drivers underpinning treatment decisions. While many believed ART to be effective, they expressed concerns about long-term effects, frustration over perceived lack of autonomy in treatment decisions and financial, emotional and physical burdens of HIV care. In contrast, they ascribed a sense of self-control over the use of RD and CM, along with multiple professed benefits. The perceived burden of ART emerged as a motivator for deviating from recommended treatment, while positive views towards RD and CM appear to justify use. This study may serve as guidance for the development of future strategies to address barriers to treatment uptake and adherence and subsequently health outcomes for PLHIV in Australia and elsewhere.

Proton pump inhibitors co-prescribed with warfarin reduce warfarin control as measured by time in therapeutic range.

INTRODUCTION: Warfarin is an oral anticoagulant that requires ongoing monitoring with time in therapeutic range (TTR), a common measure of the quality of warfarin control and likelihood of adverse events including bleeds. Numerous factors can influence these warfarin outcomes including drug interactions. Proton pump inhibitors (PPIs) have been reported to interact with warfarin but there remain conflicting reports with regard to the impact on bleeds and limited data on TTR. Therefore, the aim of this study was to determine the effect of PPIs on warfarin control using TTR and bleeds as endpoints. METHODS: Retrospective data were collected for patients managed by a warfarin management clinic in Queensland. Data collected included current medications, reported bleeds and INR results to calculate TTR. Patients were grouped as taking PPIs or not taking PPIs. Analysis of TTR and bleeds occurred for these groups both before and after exclusions of other medication reported to interact with warfarin. RESULTS: Of the 4494 included patients, almost half (44.5%) were taking PPIs with esomeprazole most commonly (34.8%) prescribed. Patients taking PPIs had significantly reduced TTR compared with patients not taking PPIs both before (78.5 ± 9.7% vs 81.7 ± 10.2%, P < 0.0001) and after (84.4 ± 5.1% vs 89.4 ± 8.0%, P < 0.0001) excluding all other interacting medications with warfarin. Patients taking PPIs also had significantly higher incidence of minor bleeds compared with patients not taking PPIs (32.4% vs 26.1%, P = 0.0487). DISCUSSION: Patients taking PPIs with warfarin had significantly lower TTRs and higher incidence of minor bleeds. This combination warrants additional caution and monitoring with warfarin control as measured by TTR potentially affected.

Possible involvement of metformin in downregulation of neuroinflammation and associated behavioural changes in mice.

Metformin (MET), a biguanide oral hypoglycaemic agent, recently has been shown to be effective in various conditions other than type-2 diabetes including cancer, stroke, weight reduction, and polycystic ovarian syndrome, to name a few. MET has also possessed antioxidant and antiinflammatory properties by activation of AMPK . This study was aimed at evaluating the effects of MET on lipopolysaccharide (LPS)-induced systemic and neuroinflammation, oxidative stress, and behavioural changes. The study consisted of six groups, where three selected doses of MET (100, 200, and 300 mg/kg) were employed in male Swiss albino mice, with one group of imipramine (IMI), saline, and LPS each. Systemic inflammation was induced by injecting LPS (1.5 mg/kg) by intraperitoneal route. A battery of behavioural tests including open field, forced swim, and tail suspension tests were employed to assess the impact of systemic inflammation on exploratory behaviour and learned helplessness. LPS induced significant immobility with profound symptoms of sickness behaviour. Furthermore, LPS led to significant increase in serum and brain proinflammatory cytokines TNF-α and IL-6; and also increased lipid peroxidation with reduced glutathione levels. Pretreatment of the animals with 100 and 200 mg/kg of MET significantly reduced both systemic and central inflammatory markers along with protecting against LPS-induced oxidative stress. The higher dose, 300 mg/kg of MET was not effective against most of LPS-induced biochemical changes. Our preliminary results from this study suggest the antiinflammatory and neuroprotective effects of MET in LPS-induced model of sickness behaviour and neuroinflammation.

Warfarin control in patients transitioning to warfarin after non-vitamin K oral anticoagulant (NOAC) therapy.

Warfarin has long been the most widely prescribed oral anticoagulant. Introduction of non-vitamin K oral anticoagulants (NOACs) has provided anticoagulant options but also presented the potential challenge of transitioning between agents. Changes from NOACs to warfarin are particularly problematic with delays to therapeutic effect and limited real-world data regarding the impact on warfarin control. The aim of this study was to investigate the frequency of switching anticoagulants and the effect on warfarin control. Retrospective data was collected for patients at a warfarin program in Queensland Australia who had exited the program for NOACs plus those who had reverted to warfarin. Data included documented reasons for change and International Normalised Ratio (INR) results with time in therapeutic range (TTR) calculated as a measure of warfarin control. Over 5 years, a total of 3036 patients ceased warfarin to commence a NOAC but 142 (4.7%) reverted to warfarin. Majority of patients (60.6%) reverted to warfarin within 6 months of trialling NOACs with a median of 6 days to therapeutic INR. There was no significant difference in warfarin control before changing to NOACs and after reverting to warfarin (mean TTR 75%) but significantly more frequent testing and lower doses were required to achieve this control. Transitions from warfarin to NOACs results in almost a week to therapeutic effect and warfarin therapy may be further complicated by a need for increased frequency of testing. Further studies are required to refine transition strategies particularly from warfarin to NOAC and minimise potential risks to patients.

Dedicated warfarin care programme results in superior warfarin control in Queensland, Australia.

BACKGROUND: Warfarin is used to prevent stroke in patients with atrial fibrillation (AF). Ongoing monitoring of International normalised ratio (INR) and time in therapeutic range (TTR) commonly used to assess the quality of warfarin management are required. Anticoagulant clinics have demonstrated improved TTRs, particularly in countries with poorer control in primary care settings. Reported TTR in Australia has been relatively high; so, it is unknown if benefit would be seen from dedicated warfarin clinics in Australia. The aim of this study was to compare the level of warfarin control in patients managed by their general practitioner (GP) and a warfarin care programme (WCP) by Sullivan Nicolaides Pathology. METHOD: Retrospective data were collected for AF patients enrolled in the warfarin care programme at WCP, and included patients with INR tests available while managed by their GP. INR tests were used to calculate TTR and frequency of testing for the time managed by GP and WCP, with mean data used for analysis and comparison. RESULTS: The eligible 200 warfarin patients had a TTR of 69% with GP management and 82% with WCP management (<.0001). Significant differences were also found between GP and WCP management in the percentage of tests in range, total number of tests and frequency of testing. WCP had a reduced time to repeat test at extremes of INR results. CONCLUSION: Australian warfarin control was good when managed by either GP or WCP, but WCP management increased TTR by 13%. Dedicated warfarin programmes can improve warfarin control and optimise therapy for patients.

Prazosin but Not Tamsulosin Sensitises PC-3 and LNCaP Prostate Cancer Cells to Docetaxel.

BACKGROUND/AIMS: Docetaxel is currently the first-line chemotherapeutic agent available for the treatment of patients with advanced prostate cancer (PCa). While docetaxel has been shown to modestly improve survival times for patients; they also experience significant docetaxel-induced toxicities. If treatment failure occurs, there are currently limited alternatives that show survival benefits for patients and therefore there is an urgent need for adjunct therapies. Some quinazoline-based alpha1-adrenoceptor (ADR) antagonists have previously been shown to have cytotoxic actions in PCa cells, but there is no research into their effects on docetaxel-induced toxicity. Therefore, the aim of this study was to determine if the quinazoline ADR, prazosin influenced the sensitivity of PCa cells to docetaxel in vitro. We hypothesised that prazosin, but not tamsulosin, in combination with docetaxel would possess synergistic cytotoxic actions on PC-3 and LNCaP PCa cells. METHODS: PC-3 and -LNCaP cells were pre-treated (1 h) with prazosin (30 µmol/L) or tamsulosin (30 µmol/L), followed by docetaxel (12.5-100 µmol/L) for 24 h. Docetaxel-induced toxicity was measured in terms of changes in cell proliferation, autophagy, apoptosis and the production of reactive oxygen species (ROS). RESULTS: Prazosin sensitised both cell lines (PC-3 and LNCaP) to docetaxel-induced toxicity. This effect appears to be mediated by autophagy and may also involve apoptosis. These sensitising effects of prazosin appear to be largely independent of ROS production. In contrast, tamsulosin did not affect docetaxel-induced toxicity. CONCLUSION: We have shown for the first time that prazosin increases docetaxel-induced toxicity in PC-3 and LNCaP cells. Prazosin may therefore offer a viable treatment option in combination with docetaxel in metastatic PCa.

Interplay between adenosine receptor antagonist and cyclooxygenase inhibitor in haloperidol-induced extrapyramidal effects in mice.

Antipsychotic drugs are the mainstay of psychotic disorders. The 'typical' antipsychotic agents are commonly employed for the positive symptoms of schizophrenia, though at an expense of extrapyramidal side effects (EPS). In the present study, we employed haloperidol (HP)-induced catalepsy model in mice to evaluate the role of adenosine receptor antagonist and cyclooxygenase (COX) enzyme inhibitor in the amelioration of EPS. HP produced a full blown catalepsy, akinesia and a significant impairment in locomotion and antioxidant status. Pre-treatment with COX inhibitor; naproxen (NPx) and adenosine receptor antagonist; caffeine (CAF), showed a significant impact on HP-induced cataleptic symptoms. Adenosine exerts pivotal control on dopaminergic receptors and is also involved in receptor internalization and recycling. On the other hand, prostaglandins (PGs) are implicated as neuro-inflammatory molecules released due to microglial activation in both Parkinson's disease (PD) and antipsychotics-induced EPS. The involvement of these neuroeffector molecules has led to the possibility of use of CAF and COX inhibitors as therapeutic approaches to reduce the EPS burden of antipsychotic drugs. Both these pathways seem to be interlinked to each other, where adenosine modulates the formation of PGs through transcriptional modulation of COXs. We observed an additive effect with combined treatment of NPx and CAF against HP-induced movement disorder. These effects lead us to propose that neuromodulatory pathways of dopaminergic circuitry need to be explored for further understanding and utilizing the full therapeutic potential of antipsychotic agents.