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Item Metadata only Adulterants and Contaminants in Psychotropic Herbal Medicines Detected with Mass Spectrometry and Next-Generation DNA Sequencing(Springer, 2018) Hoban, C.L.; Musgrave, I.F.; Coghlan, M.L.; Power, M.W.P.; Byard, R.W.; Nash, C.; Farrington, R.; Maker, G.; Crighton, E.; Trengove, R.; Bunce, M.Introduction: The role of herbal medicine in the treatment of common psychiatric disorders such as anxiety, depression and insomnia has become more established over the past decade. Some herbal preparations such as St John’s wort (Hypericum perforatum) have demonstrated clinical evidence but have also been included in recent reports of widespread adulteration and contamination. Herbal medicines sold in Australia are required to be listed on the Therapeutic Goods Administration’s (TGA) Australian Register of Therapeutic Goods (ARTG) and must comply with strict ingredient and manufacturing guidelines to assure quality and safety. Objective: The aim of this research was to assess whether pharmaceutical adulterants and contaminants were present in psychotropic herbal medicines available in Australia, as a measure of quality, and the effectiveness of regulation. Methods: A two-pronged approach combining next-generation DNA sequencing and small-molecule analysis techniques was undertaken to audit a subset of herbal medicines for the presence of prescription medications, illicit drugs, pesticides, herbicides, heavy metals and contaminant DNA. Small-molecule analysis included liquid chromatography with quadrupole time-of-flight mass spectrometer (LC-QTOF-MS) detection, liquid chromatography with UV/vis diode array (LC-UV) detection, gas chromatography with nitrogen–phosphorus and mass spectrometer detection (GC-NPD/MS) and heavy metal analysis using inductively coupled plasma with mass spectrometer (ICP-MS) detection. Results: In total, 49% (29 of 59) of the investigated herbal medicines had one or more materials not listed on their labels or ARTG registration, including Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES)-listed material (one medicine), heavy metals (12%) or components that could trigger food sensitivity, such as wheat (12%). In contrast to previous studies, no prescription pharmaceutical adulterants were detected, although 10% had undeclared caffeine. Twenty-four percent of herbal medicines had DNA from animal species, including mice and bats, indicating poor quality control. The surveyed herbal medicines included both traditional Chinese medicines (TCM) and Western herbals. Ninety-four percent of TCMs were contaminated or adulterated, compared with 37% of the Western herbals. Only two of the 59 samples contained the listed active ingredient(s) without additional adulterants and contaminants, or missing ingredients. Conclusions: The high levels of contamination found in this study suggests that closer surveillance of herbal medicines is needed in order to assure the required level of quality of herbal medicines available in Australia. The results suggest that the TGA’s low-/high-risk system for regulation coupled with post-market auditing is not keeping unapproved and/or unsafe herbal medicines from the market.Item Open Access In vitro and in vivo evaluation of diethyldithiocarbamate with copper ions and its liposomal formulation for the treatment of Staphylococcus aureus and Staphylococcus epidermidis biofilms(Elsevier BV, 2023) Kaul, L.; Abdo, A.I.; Coenye, T.; Swift, S.; Zannettino, A.; Süss, R.; Richter, K.Surgical site infections (SSIs) are mainly caused by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) biofilms. Biofilms are aggregates of bacteria embedded in a self-produced matrix that offers protection against antibiotics and promotes the spread of antibiotic-resistance in bacteria. Consequently, antibiotic treatment frequently fails, resulting in the need for alternative therapies. The present study describes the in vitro efficacy of the Cu(DDC)2 complex (2:1 M ratio of diethyldithiocarbamate (DDC−) and Cu2+) with additional Cu2+ against S. aureus and S. epidermidis biofilms in models mimicking SSIs and in vitro antibacterial activity of a liposomal Cu(DDC)2 + Cu2+ formulation. The in vitro activity on S. aureus and S. epidermidis biofilms grown on two hernia mesh materials and in a wound model was determined by colony forming unit (CFU) counting. Cu2+-liposomes and Cu(DDC)2-liposomes were prepared, and their antibacterial activity was assessed in vitro using the alamarBlue assay and CFU counting and in vivo using a Galleria mellonella infection model. The combination of 35 μM DDC− and 128 μM Cu2+ inhibited S. aureus and S. epidermidis biofilms on meshes and in a wound infection model. Cu(DDC)2-liposomes + free Cu2+ displayed similar antibiofilm activity to free Cu(DDC)2 + Cu2+, and significantly increased the survival of S. epidermidis-infected larvae. Whilst Cu(DDC)2 + Cu2+ showed substantial antibiofilm activity in vitro against clinically relevant biofilms, its application in mammalian in vivo models is limited by solubility. The liposomal Cu(DDC)2 + Cu2+ formulation showed antibiofilm activity in vitro and antibacterial activity and low toxicity in G. mellonella, making it a suitable water-soluble formulation for future application on infected wounds in animal trials.Item Metadata only Evaluation of Uptake of COVID-19 Temporary Allied Health Services for Residential Aged Care in Australia(Elsevier, 2023) Caughey, G.E.; Collier, L.; Cations, M.; Wesselingh, S.; Inacio, M.C.Item Metadata only Primary and Secondary Care Related Quality Indicators for Dementia Care Among Australian Aged Care Users: National Trends, Risk Factors, and Variation(IOS Press, 2022) Rahja, M.; Air, T.; Ahern, S.; Ward, S.A.; Caughey, G.E.; Sluggett, J.K.; Cations, M.; Lin, X.; Wallis, K.; Crotty, M.; Inacio, M.C.Background: Studies related to clinical quality indicators (CQIs) in dementia have focused on hospitalizations, medication management, and safety. Less attention has been paid to indicators related to primary and secondary care. Objective: To evaluate the incidence of primary and secondary care CQIs for Australians with dementia using governmentsubsidized aged care. The examined CQIs were: comprehensive medication reviews, 75+ health assessments, comprehensive geriatric assessments, chronic disease management plans, general practitioner (GP) mental health treatment plans, and psychiatrist attendances. Methods: Retrospective cohort study (2011–2016) of 255,458 individuals. National trend analyses estimated incidence rates and 95% confidence intervals (CI) using Poisson or negative binomial regression. Associations were assessed using backward stepwise multivariate Poisson or negative binomial regression model, as appropriate. Funnel plots examined geographic and permanent residential aged care (PRAC) facility variation. Results: CQI incidence increased in all CQIs but medication reviews. For the overall cohort, 75+ health assessments increased from 1.07/1000 person-days to 1.16/1000 person-days (adjusted incidence rate ratio (aIRR) = 1.03, 95%CI 1.02–1.03). Comprehensive geriatric assessments increased from 0.24 to 0.37/1000 person-days (aIRR = 1.12, 95%CI 1.10–1.14). GP mental health treatment plans increased from 0.04 to 0.07/1000 person-days (aIRR = 1.13, 95%CI 1.12–1.15). Psychiatric attendances increased from 0.09 to 0.11/1000 person-days (aIRR = 1.05, 95%CI 1.03–1.07). Being female, older, having fewer comorbidities, and living outside a major city were associated with lower likelihood of using the services. Large geographical and PRAC facility variation was observed (0–92%). Conclusion: Better use of primary and secondary care services to address needs of individuals with dementia is urgently needed.Item Open Access The Extracellular Molecular Chaperone Clusterin Inhibits Amyloid Fibril Formation and Suppresses Cytotoxicity Associated with Semen-Derived Enhancer of Virus Infection (SEVI)(MDPI AG, 2022) Elias, A.K.; Wilson, M.R.; Carver, J.A.; Musgrave, I.F.Clusterin is a glycoprotein present at high concentrations in many extracellular fluids, including semen. Its increased expression accompanies disorders associated with extracellular amyloid fibril accumulation such as Alzheimer’s disease. Clusterin is an extracellular molecular chaperone which prevents the misfolding and amorphous and amyloid fibrillar aggregation of a wide variety of unfolding proteins. In semen, amyloid fibrils formed from a 39-amino acid fragment of prostatic acid phosphatase, termed Semen-derived Enhancer of Virus Infection (SEVI), potentiate HIV infectivity. In this study, clusterin potently inhibited the in vitro formation of SEVI fibrils, along with dissociating them. Furthermore, clusterin reduced the toxicity of SEVI to pheochromocytoma-12 cells. In semen, clusterin may play an important role in preventing SEVI amyloid fibril formation, in dissociating SEVI fibrils and in mitigating their enhancement of HIV infection.Item Open Access Fc gamma receptor is not required for in vivo processing of radio- and drug-conjugates of the dead tumor cell-targeting monoclonal antibody, APOMAB®(Elsevier BV, 2022) Staudacher, A.H.; Liapis, V.; Wittwer, N.L.; Tieu, W.; Lam, H.C.; Leusen, J.; Brown, M.P.The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anti- cancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug con- jugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed. We found that, regardless of prior labeling with chDAB4, dead EL4 lymphoma or Lewis Lung (LL2) tumor cells were phagocytosed equally by wild-type or Fcγ knock-down macrophage cell lines. A similar result was seen with bone marrow-derived macrophages from wild-type, Fcγ knock-out (KO) and NOTAM mice that express Fcγ but lack immunoreceptor tyrosine-based activation motif (ITAM) signaling. Among EL4 tumor-bearing wild-type, Fcγ KO or NOTAM mice, no differences were observed in post-chemotherapy uptake of 89Zr-labeled chDAB4. Similarly, no differences were observed between LL2 tumor-bearing wild-type and Fcγ KO mice in post-chemotherapy uptake of 89Zr-chDAB4. Also, the post-chemotherapy activity of a chDAB4-antibody drug conjugate (ADC) directed against LL2 tumors did not differ among tumor-bearing wild-type, Fcγ KO and NOTAM mice, nor did the proportions and characteristics of the LL2 tumor immune cell infiltrates differ significantly among these mice. In conclusion, Fc-FcγR interactions are not essential for the diagnostic or therapeutic applications of chDAB4 conjugates because the tumor-associated macrophages, which engulf the chDAB4-labelled dead cells, respond to endogenous ‘eat me’ signals rather than depend on functional FcγR expression for phagocytosis.Item Open Access Review article: the future of microbiome-based therapeutics(Wiley, 2022) Gulliver, E.L.; Young, R.B.; Chonwerawong, M.; D'Adamo, G.L.; Thomason, T.; Widdop, J.T.; Rutten, E.L.; Rossetto Marcelino, V.; Bryant, R.V.; Costello, S.P.; O'Brien, C.L.; Hold, G.L.; Giles, E.M.; Forster, S.C.Background: From consumption of fermented foods and probiotics to emerging applications of faecal microbiota transplantation, the health benefit of manipulating the human microbiota has been exploited for millennia. Despite this history, recent technological advances are unlocking the capacity for targeted microbial manipulation as a novel therapeutic.Aim: This review summarises the current developments in microbiome- based medicines and provides insight into the next steps required for therapeutic development.Methods: Here we review current and emerging approaches and assess the capabilities and weaknesses of these technologies to provide safe and effective clinical inter-ventions. Key literature was identified through Pubmed searches with the following key words, ‘microbiome’, ‘microbiome biomarkers’, ‘probiotics’, ‘prebiotics’, ‘synbiotics’, ‘faecal microbiota transplant’, ‘live biotherapeutics’, ‘microbiome mimetics’ and ‘postbiotics’.Results: Improved understanding of the human microbiome and recent technological advances provide an opportunity to develop a new generation of therapies. These therapies will range from dietary interventions, prebiotic supplementations, single probiotic bacterial strains, human donor-derived faecal microbiota transplants, ra-tionally selected combinations of bacterial strains as live biotherapeutics, and the beneficial products or effects produced by bacterial strains, termed microbiome mimetics.Conclusions: Although methods to identify and refine these therapeutics are continually advancing, the rapid emergence of these new approaches necessitates accepted technological and ethical frameworks for measurement, testing, laboratory practices and clinical translation.Item Metadata only Expression of key apoptotic genes in hepatocellular carcinoma cell line treated with etoposide-loaded graphene oxide(Elsevier, 2020) Gholami, A.; Emadi, F.; Nazem, M.; Aghayi, R.; Khalvati, B.; Amini, A.; Ghasemi, Y.Etoposide (Et) is an antineoplastic agent used for cancer treatment as it promotes the apoptosis of cancer cells. One of the important concerns about Et is the poor water solubility and bioavailability which lowers its cytotoxicity for pharmaceutical applications. Here, Et was loaded on a new carrier, made of carboxylated graphene oxide (GO-COOH), to improve the cytotoxicity of Et on hepatocellular carcinoma (Hep-G2) cells without any destruction on the apoptosis pathway of Et. SEM, TEM, UV–Vis, FT-IR, DLS and Raman were utilized as the characterization techniques. The cytotoxicity of Et on Hep-G2 cells was probed by MTT before and after loading on GO-COOH as well as the flow cytometry. Real-time PCR was used to find the expression of apoptotic genes in Hep-G2 cells treated with free Et and Et-loaded GO-COOH (Et-GO-COOH). From MTT results, IC50s of Et and Et- GO-COOH were measured as 6 ± 1.73 and 4 ± 0.11 μg/mL, respectively. Real-time PCR results revealed that both Et-GO-COOH and Et caused toxicity through induction of the expression of same seven apoptotic genes. However, Et-GO-COOH acted more efficiently than Et to induce apoptosis in Hep-G2 cells. The findings verified that GO-COOH improved the cytotoxicity effect of Et with no impact on the Et apoptosis pathway.Item Metadata only The Requirements of Developing Countries' Health Systems Facing with COVID-19: A Case Study of Iran(Oxford University Press (OUP), 2020) Ghanbarzadegan, A.; Bastani, P.; Emadi, F.; Mohammmadpour, M.; Pourmohammadi, K.; Javanmardi, S.; World Congress on Public Health (12 Oct 2020 - 17 Oct 2020 : virtual online)Abstract not availableItem Open Access Functionalized Graphene Oxide with Chitosan for Protein Nanocarriers to Protect against Enzymatic Cleavage and Retain Collagenase Activity(Nature Publishing Group, 2017) Emadi, F.; Amini, A.; Gholami, A.; Ghasemi, Y.Proteins have short half-life because of enzymatic cleavage. Here, a new protein nanocarrier made of graphene oxide (GO) + Chitosan (CS) is proposed to successfully prevent proteolysis in protein and simultaneously retain its activity. Bovine serum albumin (BSA) and collagenase were loaded on GO and GO-CS to explore the stability and activity of proteins. SEM, AFM, TEM, DSC, UV-Vis, FT-IR, RBS, Raman, SDS-PAGE and zymography were utilized as characterization techniques. The protecting role of GO and GO-CS against enzymatic cleavage was probed by protease digestion analysis on BSA, where the protease solution was introduced to GO-BSA and GO-CS-BSA at 37 °C for 0.5-1-3-6 hours. Characterizations showed the successful synthesis of few layers of GO and the coverage by CS. According to gelatin zymographic analysis, the loaded collagenase on GO and GO-CS lysed the gelatin and created non-staining bands which confirmed the activity of loaded collagenase. SDS-PAGE analysis revealed no significant change in the intact protein in the GO-BSA and GO-CS-BSA solution after 30-minute and 1-hour exposure to protease; however, free BSA was completely digested after 1 hour. After 6 hours, intact proteins were detected in GO-BSA and GO-CS-BSA solutions, while no intact protein was detected in the free BSA solution.Item Open Access Functionalization of Graphene Oxide Nanosheets Can Reduce Their Cytotoxicity to Dental Pulp Stem Cells(Hindawi Publishing Corporation, 2020) Gholami, A.; Emadi, F.; Amini, A.; Shokripour, M.; Chashmpoosh, M.; Omidifar, N.Background. The dental pulp is a heterogeneous soft tissue that supplies nutrients and acts as a biosensor to identify pathogenic stimuli. Regeneration of the dental pulp is one of the desirable topics for researchers. Graphene oxide nanosheets (nGOs) help overexpression of the genes related to odontogenic differentiation of stem cells from dental pulps and increases attachment and proliferation of dental pulp stem cells. Despite its benefits, nGO may be considered as a threat to the environment and human health. Therefore, the purpose of this study was to evaluate the biocompatibility potential of graphene oxide (nGO), chitosan functionalized graphene oxide (nGO-CS), and carboxylated graphene (nGO-COOH) when exposed to human dental pulp stem cells (hDPSCs). Material and Methods. Some different aspects of biocompatibility of nGO, nGO-CS, and nGO-COOH were synthesized, and several intracellular effects induced by different concentrations of graphene-based nanosheets, including cell viability, intracellular oxidative damages, and various factors such as LDH, GSH, SOD, MDA, and MMP, were studied on hDPSCs. Results. According to results, IC50 was determined as 232.01, 467.81, and ≥1000 μg/mL for nGO, nGO-CS, and nGOCOOH, respectively. These results demonstrated the lower toxicity and higher cytocompatibility of nGO-CS and nGO-COOH compared to nGO. nGO-COOH not only has any adverse effect on the cell membrane and mitochondrial activity but also shows slight antioxidant activity at some concentrations. Conclusion. The findings help design safe and cytocompatible nGO derivatives for biomedical applications in dental fields.Item Open Access Defining and unpacking the core concepts of pharmacology education(Wiley, 2021) Santiago, M.; Davis, E.A.; Hinton, T.; Angelo, T.A.; Shield, A.; Babey, A.M.; Kemp-Harper, B.; Maynard, G.; Al-Sallami, H.S.; Musgrave, I.F.; Fernandes, L.B.; Ngo, S.N.T.; Christopoulos, A.; White, P.J.Pharmacology education currently lacks a research-based consensus on which core concepts all graduates should know and understand, as well as a valid and reliable means to assess core conceptual learning. The Core Concepts in Pharmacology Expert Group (CC-PEG) from Australia and New Zealand recently identified a set of core concepts of pharmacology education as a first step toward developing a concept inventory—a valid and reliable tool to assess learner attainment of concepts. In the current study, CC-PEG used established methodologies to define each concept and then unpack its key components. Expert working groups of three to seven educators were formed to unpack concepts within specific conceptual groupings: what the body does to the drug (pharmacokinetics); what the drug does to the body (pharmacodynamics); and system integration and modification of drug–response. First, a one-sentence definition was developed for each core concept. Next, sub-concepts were established for each core concept. These twenty core concepts, along with their respective definitions and sub-concepts, can provide pharmacology educators with a resource to guide the development of new curricula and the evaluation of existing curricula. The unpacking and articulation of these core concepts will also inform the development of a pharmacology concept inventory. We anticipate that these resources will advance further collaboration across the international pharmacology education community to improve curricula, teaching, assessment, and learning.Item Metadata only Cost-utility analysis of factor VIII diet therapies prepared using blood plasma vs. recombinant technique for patients with hemophilia A(Springer Nature, 2020) Lotfi, F.; Talebianpour, H.; Keshavarz, K.; Emadi, F.; Bordbar, M.R.; Bastani, P.Background: Hemophilia is known as one of the most common coagulation disorders whose treatment costs are particularly high in developing countries, and about 90% of them are related to factor VIII (FVIII) and direct medical costs (DMCs). Thus, the present study aimed to analyze cost-utility of two FVIII diet therapies prepared using blood plasma and recombinant technique. Methods: This study was an economic evaluation fulfilled through a cost-utility approach. To this end, a total number of 120 patients were randomly selected using Krejcie & Morgan’s Table and then received blood plasma and recombinant FVIII. The decision tree structure was also utilized to estimate economic and clinical outcomes. Moreover, costs were reviewed from societal perspective. Quality-adjusted life year (QALY) was subsequently determined as the measure of effectiveness (MOE). Besides, one-way (univariate) sensitivity analysis was performed to quantify uncertainty effects of the study parameters. The information was ultimately analyzed using the TreeAge Pro 2011 and the Microsoft Office Excel 2010 software. Results: The results revealed that the recombinant diet therapy had higher costs and effectiveness compared with blood-plasma-derived FVIII, so that the mean costs of these two diet therapies were equal to 37,624 and 20,349 purchasing power parity (PPP) $ with utility scores of 0.78 and 0.62; respectively. Since the incremental cost-effectiveness ratio (ICER) for the recombinant medications was over three times of the threshold level, it was considered as overwhelming because of its high cost in spite of its better effectiveness. Moreover, the results of one-way (univariate) sensitivity analysis demonstrated the highest sensitivity to the utility in patients who had been injected with blood-plasma-derived FVIII and had been successfully treated. Conclusion: The study results revealed that FVIII prepared using blood plasma for hemophilia A patients had higher cost-effectiveness compared with that made using recombinant technique.Item Metadata only A Comprehensive Insight Towards Pharmaceutical Aspects of Graphene Nanosheets(Bentham Science Publishers Ltd., 2020) Emadi, F.; Emadi, A.; Gholami, A.Graphene Derivatives (GDs) have captured the interest and imagination of pharmaceutical scientists. This review exclusively provides pharmacokinetics and pharmacodynamics information with a particular focus on biopharmaceuticals. GDs can be used as multipurpose pharmaceutical delivery systems due to their ultra-high surface area, flexibility, and fast mobility of charge carriers. Improved effects, targeted delivery to tissues, controlled release profiles, visualization of biodistribution and clearance, and overcoming drug resistance are examples of the benefits of GDs. This review focuses on the application of GDs for the delivery of biopharmaceuticals. Also, the pharmacokinetic properties and the advantage of using GDs in pharmaceutics will be reviewed to achieve a comprehensive understanding about the GDs in pharmaceutical sciences.Item Metadata only CDK12: a potential therapeutic target in cancer(Elsevier, 2020) Emadi, F.; Teo, T.; Rahaman, M.H.; Wang, S.Cyclin-dependent kinase (CDK) 12 engages in diversified biological functions, from transcription, post-transcriptional modification, cell cycle, and translation to cellular proliferation. Moreover, it regulates the expression of cancer-related genes involved in DNA damage response (DDR) and replication, which are responsible for maintaining genomic stability. CDK12 emerges as an oncogene or tumor suppressor in different cellular contexts, where its dysregulation results in tumorigenesis. Current CDK12 inhibitors are nonselective, which impedes the process of pharmacological target validation and drug development. Herein, we discuss the latest understanding of the biological roles of CDK12 in cancers and provide molecular analyses of CDK12 inhibitors to guide the rational design of selective inhibitors.Item Open Access Identifying the core concepts of pharmacology education(Wiley Open Access, 2021) Ngo, S.; White, P.J.; Davis, E.A.; Santiago, M.; Angelo, T.; Shield, A.; Babey, A.-M.; Kemp-Harper, B.; Maynard, G.; Al-Sallami, H.S.; Musgrave, I.F.; Fernandes, L.B.; Hinton,, T.Pharmacology education currently lacks an agreed knowledge curriculum. Evidence from physics and biology education indicates that core concepts are useful and effective structures around which such a curriculum can be designed to facilitate student learning. Building on previous work, we developed a novel, criterion-based method to identify the core concepts of pharmacology education. Five novel criteria were developed, based on a literature search, to separate core concepts in pharmacology from topics and facts. Core concepts were agreed to be big ideas, enduring, difficult, applicable across contexts, and useful to solve problems. An exploratory survey of 33 pharmacology educators from Australia and New Zealand produced 109 terms, which were reduced to a working list of 26 concepts during an online workshop. Next, an expert group of 12 educators refined the working list to 19 concepts, by applying the five criteria and consolidating synonyms, and added three additional concepts that emerged during discussions. A confirmatory survey of a larger group resulted in 17 core concepts of pharmacology education. This list may be useful for educators to evaluate existing curricula, design new curricula, and to inform the development of a concept inventory to test attainment of the core concepts in pharmacology.Item Open Access Examining the cost and impact of dosing fees among clients in opioid agonist treatment: results from a cross-sectional survey of Australian treatment clients(Wiley, 2022) Zahra, E.; Chen, R.; Nielsen, S.; Tran, A.D.; Santo, T.; Degenhardt, L.; Farrell, M.; Byrne, J.; Ali, R.; Larance, B.Introduction: Opioid agonist treatment (OAT) clients frequently bear costs associated with their treatment, including dosing fees. This study aimed to explore the financial and social impact of dosing fees upon clients. Methods: Cross-sectional survey of people who use opioids regularly (N = 402) between December 2017 and March 2018, conducted in Australia. Dosing fees were calculated and expressed as percentage of income, by OAT type. Consequences and strategies for difficulties making payments were examined as proportions. Results: A total of N = 360 participants had ever been in OAT and N = 245 participants currently engaged in OAT reported data on dosing fees, of them 53% (n = 129) reported paying dosing fees. Compared to clients with high levels of dosing supervision, those with moderate or low levels of supervision were more likely to pay dosing fees. The median 28-day dosing fee was AUD$110 (interquartile range AUD$80); median 28-day income was AUD$1520 (interquartile range AUD$700). For those who paid dosing fees, the fee comprised <10% of total monthly income for 70% of participants; however, 23% of participants paid fees comprising 10% to <20%, and 7% of participants paid fees comprising 20% or more of monthly income. Among those that had ever been in OAT, 72% experienced difficulties in paying treatment costs; 36% left treatment earlier than intended and 25% had been excluded due to payment difficulties. Discussion and Conclusions: Negative consequences of treatment costs to clients, particularly dosing fees, are evident. These costs impact treatment access and retention that may negatively impact clients' physical health, mental health and social wellbeing.Item Metadata only Recent developments in relaxin mimetics as therapeutics for cardiovascular diseases(Elsevier, 2019) Leo, C.H.; Jelinic, M.; Ng, H.H.; Parry, L.J.; Tare, M.Cardiovascular disease is the most common cause of mortality worldwide, accounting for almost 50% of all deaths globally. Vascular endothelial dysfunction and fibrosis are critical in the pathophysiology of cardiovascular disease. Relaxin, an insulinlike peptide, is known to have beneficial actions in the cardiovascular system through its vasoprotective and antifibrotic effects. However, relaxin has several limitations of peptide-based drugs such as poor oral bioavailability, laborious, and expensive to synthesize. This review will focus on recent developments in relaxin mimetics, their pharmacology, associated signalling mechanisms, and their therapeutic potential for the management and treatment of cardiovascular disease.Item Metadata only Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms(International Association for the Study of Pain; Ovid, 2015) Griggs, R.B.; Donahue, R.R.; Morgenweck, J.; Grace, P.M.; Sutton, A.; Watkins, L.R.; Taylor, B.K.Repeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARγ is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal (i.t.) injection of pioglitazone, a PPARγ agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid antihyperalgesic actions of PPARγ activation, we administered pioglitazone to rats with spared nerve injury and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 minutes of injection, consistent with a nongenomic mechanism. Systemic or i.t. administration of GW9662, a PPARγ antagonist, inhibited the antihyperalgesic actions of intraperitoneal or i.t. pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further address the contribution of nongenomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When coadministered intrathecally, anisomycin did not change pioglitazone antihyperalgesia at an early 7.5-minute time point, further supporting a rapid nongenomic mechanism. At later time points, anisomycin reduced pioglitazone antihyperalgesia, suggesting delayed recruitment of genomic mechanisms. Pioglitazone reduction of spared nerve injury-induced increases in GFAP expression occurred more rapidly than expected, within 60 minutes. We are the first to show that activation of spinal PPARγ rapidly reduces neuropathic pain independent of canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation and through both genomic and nongenomic PPARγ mechanisms.Item Metadata only Opioid-induced central immune signaling: implications for opioid analgesia(Wiley, 2015) Grace, P.M.; Maier, S.F.; Watkins, L.R.Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by Toll-like receptor 4, purinergic, ceramide, and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted.