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Purpose Subcutaneous fentanyl injection is commonly prescribed to manage acute pain in older patients; however, there is a gap in the literature describing the pharmacokinetic parameters for this route of administration in this population. The aim of this study was to develop and evaluate a population pharmacokinetic model for subcutaneous fentanyl injection in older patients. Methods Twenty-one patients who received subcutaneous fentanyl injections (50 to 75 mu g) were recruited. Fentanyl concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. A base model was selected based on the Akaike information criterion. Age, sex, body weight, number of previous fentanyl doses, number of prescribed medications, creatinine clearance, Charlson Comorbidity Index, Identification of Seniors at Risk score and concurrent use of CYP3A4 inhibitors were covariates considered for inclusion. A p value of < 0.05 was considered statistically significant for inclusion of covariates in the final model by stepwise addition. The simulation performance of the model was assessed by visual predictive check. Results A one-compartment, first-order absorption with lag time and linear elimination model was the best to fit to the fentanyl concentration data. The absorption rate constant was 0.136 h(-1) (between subject variability (BSV), 46%), lag time 0.66 h (BSV 51%), apparent volume of distribution 6.28 L (BSV 30%), and apparent clearance 16.3 L.h(-1) (BSV 54%). The Charlson Comorbidity Index was the only covariate included in the final model, where a higher value of the index increased fentanyl exposure and C-max. Conclusion This is the first report of subcutaneous fentanyl population pharmacokinetic model to evaluate fentanyl pharmacokinetic in older patients. The between subject variability in clearance and subcutaneous absorption rate was relatively high, and some patients recorded high fentanyl concentrations in the context of their titration to effect. Refereed/Peer-reviewed

Background Opioids are commonly prescribed to managing chronic pain in older persons. However, these patients are often at risk of drug-opioid interactions due to polypharmacy. Objectives To identify the prevalence of opioid prescribing and drug-opioid interactions in poly-medicated older patients and factors associated with opioid prescribing. Setting Patients were included if they were admitted to the Royal Adelaide Hospital between September 2015 and August 2016, aged ≥ 75 years and took ≥ 5 medications at discharge. Methods After ethics approval, data of were retrospectively collected from case notes. The Charlson Comorbidity Index and Drug Burden Index were determined and opioids were classified as strong or weak. The association between opioid use and concurrent medications was computed using logistic regression and the results presented as odds ratios (OR) and 95% confidence intervals (95% CI), adjusted for age, sex, Charlson Comorbidity Index, number of prescribed medications and modified-Drug Burden Index. Main outcome measure Association between concurrent medications and opioid prescribing. Results 15,000 geriatric admissions were identified, of which 1192 were included. A total of 283 (23.7%) patients were prescribed opioids, with oxycodone accounting for 56% of these prescriptions. Opioid users were prescribed more medications (11.2 vs. 9.0, P

Although statins are effective in treating high cholesterol, adverse effects do occur with their use. Efficacy and tolerability vary among statins in different ethnic groups. Indigenous Australians have a high risk for cardiovascular and kidney diseases. Prescribing statins to Indigenous Australians with multi-morbidity requires different strategies to increase efficacy and reduce their toxicity. Previous studies have reported that Indigenous Australians are more susceptible to severe statin-induced myopathies. However, there is a lack of evidence in the underlying genetic factors in this population. This review aims to identify: inter-ethnic differences in the efficacy and safety of statins; major contributing factors accounting for any identified differences; and provide an overview of statin-induced adverse effects in Indigenous Australians Refereed/Peer-reviewed

Despite being one of the first-line treatments for osteoporosis, the bisphosphonate drug class exhibits an extremely low oral bioavailability (&lt, 1%) due to poor absorption from the gastrointestinal tract. To overcome this, and to explore the potential for sustained drug release, bioerodible poly(lactic acid) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) implants loaded with the bisphosphonate alendronate sodium (ALN) were prepared via hot-melt extrusion. The rate of drug release in vitro was modulated by tailoring the ratio of lactide to glycolide in the polymer and by altering the ALN-loading of the implants. All investigated implants exhibited sustained ALN release in vitro between 25 to 130 days, where implants of greater glycolide composition and higher ALN-loadings released ALN more rapidly. All PLGA implants demonstrated a sigmoidal release profile, characterised by an initial surface dissolution phase, followed by a period of zero-order drug diffusion, then relaxation or erosion of the polymer chains that caused accelerated release over the subsequent days. Contrastingly, the PLA implants demonstrated a logarithmic release profile, characterised by a gradual decrease in ALN release over time.

Introduction: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method. Aims: To develop a liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices. Methods: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM). Results: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84–124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83–122%. Conclusion: A LC–MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS. Refereed/Peer-reviewed

Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam&ndash, polyvinyl acetate&ndash, polyethylene glycol copolymer (Soluplus&reg, ) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr&reg, ) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index &lt, 0.2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 &plusmn, 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation.

Background:The effect of cruciferous vegetable intake on breast cancer survival is controversial at present. Glucosinolates are the naturally occurring constituents found across the cruciferous vegetables. Isothiocyanates are produced from the hydrolysis of glucosinolates and this reaction is catalysed by the plant-derived enzyme myrosinase. The main isothiocyanates (ITCs) from cruciferous vegetables are sulforaphane, benzyl ITC, and phenethyl ITC, which had been intensively investigated over the last decade for their antibreast cancer effects.Objective:The aim of this article is to systematically review the evidence from all types of studies, which examined the protective effect of cruciferous vegetables and/or their isothiocyanate constituents on breast cancer.Methods:A systematic review was conducted in Pubmed, EMBASE, and the Cochrane Library from inception to 27 April 2020. Peerreviewed studies of all types (in vitro studies, animal studies, and human studies) were selected.Results:The systematic literature search identified 16 human studies, 4 animal studies, and 65 in vitro studies. The effect of cruciferous vegetables and/or their ITCs intake on breast cancer survival was found to be controversial and varied greatly across human studies. Most of these trials were observational studies conducted in specific regions, mainly in the US and China. Substantial evidence from in vitro and animal studies was obtained, which strongly supported the protective effect of sulforaphane and other ITCs against breast cancer. Evidence from in vitro studies showed that sulforaphane and other ITCs reduced cancer cell viability and proliferation via multiple mechanisms and pathways. Isothiocyanates inhibited cell cycle, angiogenesis and epithelial mesenchymal transition, as well as induced apoptosis and altered the expression of phase II carcinogen detoxifying enzymes. These are the essential pathways that promote the growth and metastasis of breast cancer. Noticeably, benzyl ITC showed a significant inhibitory effect on breast cancer stem cells, a new dimension of chemo-resistance in breast cancer treatment. Sulforaphane and other ITCs displayed anti-breast cancer effects at variable range of concentrations and benzyl isothiocyanate appeared to have a relatively lower inhibitory concentration IC50. The mechanisms underlying the cancer protective effect of sulforaphane and other ITCs have also been highlighted in this article.Conclusion:Current preclinical evidence strongly supports the role of sulforaphane and other ITCs as potential therapeutic agents for breast cancer, either as adjunct therapy or combined therapy with current anti-breast cancer drugs, with sulforaphane appeared to display the greatest potential.

Aims: To examine the physical, chemical and microbiological stability characteristics of an extemporaneously compounded carbimazole 2 mg/mL oral suspension. Methods and Results: To determine the chemical stability of carbimazole in oral suspension, an analytical method was developed with high‐performance liquid chromatography (HPLC) that achieved a good resolution of the analysis. The physical and chemical stability studies of the drug were conducted at four different storage conditions: 4°C, 25°C, 4°C in‐use (to simulate a patient daily use condition), and 7 days at 4°C and 3 days at 25°C (to simulate a condition in which a patient does not return the medication back into the refrigerator after use). The microbiological test was performed on the “4°C in‐use” storage condition. The preparations were found to be physically and microbiologically stable since there were no significant changes in colour, odour, dispersion and microbial contamination tests. Regarding chemical stability, samples stored at 4°C and 25°C maintained more than 90% drug recovery limit for up to 3 weeks and 3 days, respectively. There were no significant changes in pH value for up to 6 weeks. Conclusion: A shelf life of up to 19 days at 4°C, based on the 95% lower confidence interval (CI) of the data obtained, and 2 days at room temperature can be recommended for carbimazole oral suspension. Refereed/Peer-reviewed

Background: Pain is common in older patients and management guidelines rarely consider the effect of multiple comorbidities and concurrent medications on analgesic selection. Objectives: The objectives of this study were to identify the prevalence and pattern of analgesic prescribing and associated factors in older patients with polypharmacy. Methods: Older patients (aged ≥ 75 years) admitted to the Royal Adelaide Hospital between September 2015 and August 2016 and with polypharmacy were included and their comorbidities and medications prescribed at discharge were recorded. Drug Burden Index and Charlson Comorbidity Index were calculated. The number of medications that increased the risk of orthostatic hypotension were recorded. Logistic regression was used to compute the association between analgesic use and participant characteristics, and results were presented as odds ratios and 95% confidence intervals, adjusted for age, sex, Charlson Comorbidity Index, Drug Burden Index and orthostatic hypotension. Results: Over 15,000 admissions were identified, of which 1192 patients were included, 824 (69%) of whom were prescribed an analgesic medication. Paracetamol (used by 89% of analgesic users), opioids (34%) and adjuvants (17%) were used more frequently than non-steroidal anti-inflammatory drugs (8%). Analgesic users had a higher Drug Burden Index, were prescribed more medications and were less likely to be male compared with non-users. Charlson Comorbidity Index across the cohort was high (7.3 ± 1.9) but there was no difference between analgesic users and non-users, but analgesic users were more likely to have a documented diagnosis of osteoarthritis, osteoporosis and falls. Opioid use was associated with the Drug Burden Index, while adjuvant use was associated with orthostatic hypotension. Opioid use was associated with having a diagnosis of osteoporosis and falls. Conclusions: In our cohort of poly-medicated elderly patients, prescription of analgesic medications was common, and these patients are likely to have an increased rate of adverse drug reactions and falls compared with those who were not prescribed analgesic medications. Refereed/Peer-reviewed

Purpose Results of a study to determine the stability of an extemporaneously compounded minoxidil oral suspension under various temperature and stress conditions are reported. Methods Commercially available minoxidil tablets (10 mg) were crushed to a fine powder, and predetermined amounts of 2 suspending vehicles were added to produce a 1-mg/mL suspension, which was stored in glass bottles at room temperature (25 ± 2 °C) or in a refrigerator (4 ± 2 °C). To simulate daily patient use, 5 days weekly 1 bottle of the suspension was removed from refrigerated storage and shaken and 0.5 mL of the contents discarded. At each specified time point, samples were analyzed in duplicate ( n = 6 for each test condition) using a validated high-performance liquid chromatography method. Samples were visually observed and their pH measured at each time point. Microbiological studies were performed on day 0 and at week 24. Results The mean percentage of initial minoxidil concentration remaining in all refrigerated samples exceeded 90% throughout the 24-week study, with no change in appearance, pH, microbial activity, odor, or redispersibility. During storage at room temperature, the suspension exhibited a color change at week 4, with slight sedimentation after 6 weeks, although minoxidil recovery exceeded 90% for 10 weeks. Conclusion An extemporaneously compounded minoxidil oral suspension was stable for 24 weeks when stored in a refrigerator. This suspension can be used for up to 3 weeks when stored at room temperature.

This article reviews the major physiological and physicochemical principles of the effect of food and gastrointestinal (GI) pH on the absorption and bioavailability of oral drugs, and the various absorption models that are used to describe/predict oral drug absorption. The rate and extent of oral drug absorption is determined by a complex interaction between a drug's physicochemical properties, GI physiologic factors, and the nature of the formulation administered. GI pH is an important factor that can markedly affect oral drug absorption and bioavailability as it may have significant influence on drug dissolution & solubility, drug release, drug stability, and intestinal permeability. Different regions of the GI tract have different drug absorptive properties. Thus, the transit time in each GI region and its variability between subjects may contribute to the variability in the rate and/or extent of drug absorption. Food-drug interactions can result in delayed, decreased, increased, and sometimes un-altered drug absorption. Food effects on oral absorption can be achieved by direct and indirect mechanisms. Various models have been proposed to describe oral absorption ranging from empirical models to the more sophisticated “mechanism-based” models. Through understanding of the physicochemical and physiological rate-limiting factors affecting oral absorption, modellers can implement simplified population-based modelling approaches that are less complex than whole-body physiologically-based models but still capture the essential elements in a physiological way and hence will be more suited for population modelling of large clinical data sets. It will also help formulation scientists to better predict formulation performance and to develop formulations that maximize oral bioavailability. Refereed/Peer-reviewed

Background: Problems with achieving the continuum of medicines management are long-standing. Audits are valuable in improving medication management and the quality and safety of healthcare systems. Aim: To evaluate the accuracy and timeliness of electronic discharge summaries (EDS) provided to patients and their primary care providers at discharge. This was a forerunner to the study hospital’s National Accreditation Examination and for routine safety and quality evaluation. Methods: This study was a retrospective audit using an adaptation of the NSW indicator 5.3, ‘Percentage of discharge summaries that include medication therapy changes and explanations for changes’ (National quality use of medicines indicators for Australian Hospitals. ACSQHC, Sydney, NSW, 2014). The additions to the NSW tool included: assessing the completion and timeliness of delivery to primary health care providers, and the accuracy of the information. Results: In patients leaving hospital, 75% had a hospital EDS completed, with 46% completed within the recommended 48 h from discharge. For an EDS to be delivered, a primary healthcare provider must be nominated by the patient. This occurred in 53% of our sample. Accuracy of information on what medicines patients should use post-discharge was also assessed. It indicated 46% accuracy, with the majority of erro rs being omissions of required medicines. None of the EDSs included documented reasons for changes to medicines, in the provided table, to the primary healthcare provider. In patients on a short-term therapy, such as antibiotics, 71% of EDSs had documented a plan for short-term therapies to be completed in the community. Conclusion: The lack of information on the primary care provider recorded in the patient’s clinical system and discharge summaries, limited the timely transfer of essential information on post-discharge medicine management to the patient’s primary care provider. Work has commenced on an educational program to improve data entry of the patient’s primary care provider when they are admitted, and plans to improve compliance with the EDS policy. Results: In patients leaving hospital, 75% had a hospital EDS completed, with 46% completed within the recommended 48 h from discharge. For an EDS to be delivered, a primary healthcare provider must be nominated by the patient. This occurred in 53% of our sample. Accuracy of information on what medicines patients should use post-discharge was also assessed. It indicated 46% accuracy, with the majority of erro rs being omissions of required medicines. None of the EDSs included documented reasons for changes to medicines, in the provided table, to the primary healthcare provider. In patients on a short-term therapy, such as antibiotics, 71% of EDSs had documented a plan for short-term therapies to be completed in the community. Conclusion: The lack of information on the primary care provider recorded in the patient’s clinical system and discharge summaries, limited the timely transfer of essential information on post-discharge medicine management to the patient’s primary care provider. Work has commenced on an educational program to improve data entry of the patient’s primary care provider when they are admitted, and plans to improve compliance with the EDS policy. Conclusion: The lack of information on the primary care provider recorded in the patient’s clinical system and discharge summaries, limited the timely transfer of essential information on post-discharge medicine management to the patient’s primary care provider. Work has commenced on an educational program to improve data entry of the patient’s primary care provider when they are admitted, and plans to improve compliance with the EDS policy. Refereed/Peer-reviewed

The current models for colorectal cancer (CRC) are essentially linear in nature with a sequential progression from adenoma through to carcinoma. However, these views of CRC development do not explain the full body of published knowledge and tend to discount environmental influences. This paper proposes that CRC is a cellular response to prolonged exposure to cytotoxic agents (e.g., free ammonia) as key events within a sustained high-risk colonic luminal environment. This environment is low in substrate for the colonocytes (short chain fatty acids, SCFA) and consequently of higher pH with higher levels of free ammonia and decreased mucosal oxygen supply as a result of lower visceral blood flow. All of these lead to greater and prolonged exposure of the colonic epithelium to a cytotoxic agent with diminished aerobic energy availability. Normal colonocytes faced with this unfavourable environment can transform into CRC cells for survival through epigenetic reprogramming to express genes which increase mobility to allow migration and proliferation. Recent data with high protein diets confirm that genetic damage can be increased, consistent with greater CRC risk. However, this damage can be reversed by increasing SCFA supply by feeding fermentable fibre as resistant starch or arabinoxylan. High protein, low carbohydrate diets have been shown to alter the colonic environment with lower butyrate levels and apparently greater mucosal exposure to ammonia, consistent with our hypothesis. Evidence is drawn from in vivo and in vitro genomic and biochemical studies to frame experiments to test this proposition. Refereed/Peer-reviewed

The Journal of Pharmacy Practice and Research has enjoyed an excellent reputation for publishing articles in a wide range of areas of pharmacy practice. Under ‘Aims and Scope’ within the Author Guidelines, it is stated that the ‘Journal strives to promote excellence in medicines management for better health outcomes through leading edge practice and research’. The Journal seeks to publish high-quality research and reviews about innovations in medication management, advances in clinical and specialty practice, and developments in therapeutics and pharmaceutical science research that inform and develop practice. Refereed/Peer-reviewed

Azoxymethane (AOM) is a methylating agent capable of inducing mutations in DNA by forming adducts with DNA bases. It has been used to understand the mechanisms involved in colon carcinogenesis. Of the adducts formed in response to AOM, O6-methyl-2'-deoxy-guanosine (O6-mdGua) is the most mutagenic. Based on studies in rodents of the abundance and persistence of DNA adducts in various tissues after treatment with alkylating agents, previous results suggest, as a generalization, that the longer O6-mdGua adducts remain unrepaired in the cells of a tissue, the greater the risk for tumorigenesis. To test this hypothesis, we have built on these studies, expanding the number of tissues in which O6-mdGua abundance and persistence were examined and correlating these data with tumour distribution and abundance in rats maintained for 26 weeks after the treatment with AOM. Our study revealed firstly the existence of groups of tissues that developed relatively large amounts (proximal and distal colon, proximal small intestine (SI), liver and kidney) and relatively low levels (stomach, distal SI, bladder, spleen, blood and lung) of O6-mdGua after AOM exposure. Secondly, while all tissues showed an increase in adduct levels at 6 h after mutagen treatment and most showed a significant drop in adduct levels between 6 h and 48 h (stomach, proximal and distal SI, liver, spleen, blood and lung), one group of tissues displayed O6-mdGua levels that did not decrease at 48 h (proximal and distal colon, kidney and bladder). Predictably, the colon displayed tumours 26 weeks after treatment. Interestingly, however, the proximal SI also displayed significant tumour formation at that time. Our findings demonstrate (1) a direct association between exposure to O6-mdGua and tumours of the distal colon and (2) a dissociation of the relationship between adduct clearance and tumorigenesis in the SI. This diversity of response in the gastrointestinal tract warrants further analysis. Refereed/Peer-reviewed

Aim: The aims of this study were to prepare and evaluate chitosan-polyacrylic acid complex (CS-PAA) as polymeric osmogents for swellable micro/nanoporous osmotic pump propranolol tablets. Methods: The complexes were characterized and evaluated for their swelling characteristics. The selected complexes were incorporated into the core propranolol tablets as polymeric osmogents. The core tablets were formulated, compressed as monolithic and two-layered tablets, and finally coated with cellulose acetate containing PEG 400 and PVP K30 as plasticizers and pore formers, respectively. As a final point, the drug release was determined. Results: A direct correlation was found between the CS content in the complex and the maximum swelling force and swelling ratio of the complex mixture. In vitro drug release revealed that the percent drug release increased with the amount of osmogent in the two-layered tablets. Drug release could be prolonged up to 12?h and conformed to the USP 31 criteria. In contrast, percent release decreased with the increasing amount of complexes in monolithic tablets. It was postulated that two opposing mechanisms were involved. Following water uptake, the complexes of polymers swelled and pushed the drug out of the tablets, and the drug bound to the polymer network and remained in the tablets. Conclusions: The results indicated that the complex of CS-PAA at optimal proportion and amount was a promising polymeric osmogent for a zero-order controlled release from two-layered swellable micro/nanoporous osmotic pump tablets. Refereed/Peer-reviewed

Background Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, ibudilast attenuates glial activation and is able to reduce neuropathic pain and markers of substance dependence. We therefore hypothesized ibudilast would reduce headache burden and opioid analgesic requirements in patients with opioid overuse headache. Objective To determine if treatment with ibudilast provides a greater reduction in headache index than placebo in MOH patients consuming opioids. Methods Participants with MOH who were using opioids were randomized via computer-generated code to ibudilast 40 mg or placebo twice daily for 8 weeks in a double-blind, parallel groups study. Before randomization participants completed a 4-week baseline headache diary. During treatment, headache diary data collection continued and participants attended 4 study visits during which quantitative sensory testing was performed. Blood samples for immune biomarker analyses were collected before and after treatment in a subgroup of participants. Results Thirty-four participants were randomized, 13 of 15 randomized to ibudilast and 17 of 19 randomized to placebo completed treatment. Ibudilast was generally well-tolerated with mild, transient nausea reported as the most common adverse event (66.7% vs 10.5% in placebo group). Results are shown as mean (SD). At the end of treatment no differences in the primary outcome average daily headache index (placebo 62 [44] vs ibudilast 77 [72] groups, difference −15, CI −65 to 35 h × numerical rating scale), or secondary outcomes headache frequency (placebo 23 [8.1] vs ibudilast 24.5 [6.2], difference −1.5, CI −7.7 to 4.8 days/month) and opioid intake (placebo 20.6 [43] vs ibudilast 19 [24.3], difference 1.6, CI −31.5 to 34.8 mg morphine equivalent) were observed between placebo and ibudilast groups. Conclusions Using the current dosing regimen, ibudilast does not improve headache or reduce opioid use in patients with MOH without mandated opioid withdrawal. However, it would be of interest to determine in future trials if ibudilast is able to improve ease of withdrawal during a forced opioid down-titration when incorporated into an MOH detoxification program.

Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4 ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3–9.1), 2.2-fold increase in flare (95% CI 1.9–2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1–2.5) following 50 lg intradermal capsaicin injected into the forearm 3.5 h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics. Refereed/Peer-reviewed

Background Accurate and timely medication information at the point of discharge is essential for continuity of care. There are scarce data on the clinical significance if poor quality medicines information is passed to the next episode of care. This study aimed to compare the number and clinical significance of medication errors and omission in discharge medicines information, and the timeliness of delivery of this information to community-based health practitioners, between the existing Hospital Discharge Summary (HDS) and a pharmacist prepared Medicines Information Transfer Fax (MITF). Method The study used a sample of 80 hospital patients who were at high risk of medication misadventure, and who had a MITF completed in the study period June – October 2009 at a tertiary referral hospital. The medicines information in participating patients’ MITFs was validated against their Discharge Prescriptions (DP). Medicines information in each patient’s HDS was then compared with their validated MITF. An expert clinical panel reviewed identified medication errors and omissions to determine their clinical significance. The time between patient discharge and the dispatching of the MITF and the HDS to each patient’s community-based practitioners was calculated from hospital records. Results DPs for 77 of the 80 patients were available for comparison with their MITFs. Medicines information in 71 (92%) of the MITFs matched that of the DP. Comparison of the HDS against the MITF revealed that no HDS was prepared for 16 (21%) patients. Of the remaining 61 patients; 33 (54%), had required medications omitted and 38 (62%) had medication errors in their HDS. The Clinical Panel rated the significance of errors or omissions for 70 patients (16 with no HDS prepared and 54 who’s HDS was inconsistent with the validated MITF). In 17 patients the error or omission was rated as insignificant to minor; 23 minor to moderate; 24 moderate to major and 6 major to catastrophic. 28 (35%) patients had their HDS dispatched to their community-based practitioners within 48 hours post discharge compared to 80 (100%) of MITFs. Conclusion The MITF is an effective approach for the timely delivery of accurate discharge medicines information to community-based practitioners responsible for the patient’s ongoing care.

Introduction Patients with chronic headache who consume large amounts of analgesics are often encountered in clinical practice. Excessive intake of analgesics is now considered to be a cause, rather than simply a consequence, of frequent headaches, and as such the diagnosis “medication-overuse headache” (MOH) has been formulated. Despite the prevalence and clinical impact of MOH, the pathophysiology behind this disorder remains unclear and specific mechanism-based treatment options are lacking. Discussion Although most acute headache treatments have been alleged to cause MOH, here we conclude from the literature that opioids are a particularly problematic drug class consistently associated with worsening headache. MOH may not be a single entity, as each class of drug implicated may cause MOH via a different mechanism. Recent evidence indicates that chronic opioid administration may exacerbate pain in the long term by activating toll-like receptor-4 on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Thus, from the available evidence it seems opioid-overuse headache is a phenomenon similar to opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitisation, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation. Conclusion Treatment strategies directed at inhibiting glial activation may be of benefit alongside medication withdrawal in the management of MOH.

Butyrate and its analogues have long been investigated as potential chemotherapeutic agents. Our previous structure-activity relationship studies of butyrate analogues revealed that 4-benzoylbutyrate had comparable in vitro effects to butyrate when used to treat HT29 and HCT116 colorectal cancer cell lines. The aim of this study was to identify potential mechanisms associated with the antitumorigenic effects of 4-benzoylbutyrate. In this study, butyrate, 3-hydroxybutyrate and 4-benzoylbutyrate were also investigated for their effects on histone deacetylase (HDAC) activity and histone H4 acetylation in HT29 and HCT116 cells. The biological effects of these analogues on HT29 cells were further investigated using quantitative proteomics to determine the proteins potentially involved in their apoptotic and antiproliferative effects. Because 3-hydroxybutyrate had minimal to no effect on apoptosis, proliferation or HDAC activity, this analogue was used to identify differentially expressed proteins that were potentially specific to the apoptotic effects of butyrate and/or 4-benzoylbutyrate. Butyrate treatment inhibited HDAC activity and induced H4 acetylation. 4-Benzoylbutyrate inhibited HDAC activity but failed to enhance H4 acetylation. Proteomic analysis revealed 20 proteins whose levels were similarly altered by both butyrate and 4-benzoylbutyrate. Proteins that showed common patterns of differential regulation in the presence of either butyrate or 4-benzoylbutyrate included c-Myc transcriptional targets, proteins involved in ER homeostasis, signal transduction pathways and cell energy metabolism. Although an additional 23 proteins were altered by 4-benzoylbutyrate uniquely, further work is required to understand the mechanisms involved in its apoptotic effects. Refereed/Peer-reviewed

BackgroundPatients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes.AimThis study compared the effects of pregabalin (300 mg) and the tetracycline antibiotic and glial attenuator minocycline (400 mg) on capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia in patients with unilateral sciatica on both their affected and unaffected leg.Methods/resultsEighteen patients with unilateral sciatica completed this randomised, double-blind, placebo-controlled, three-way cross-over study. Participants received a 10 µg dose of capsaicin into the middle section of their calf on both their affected and unaffected leg, separated by an interval of 75 min. Capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were recorded pre-injection and at 5, 20, 40, 60 and 90 min post-injection. Minocycline tended to reduce pre-capsaicin injection values of hyperalgesia in the affected leg by 28% (95% CI 0% to 56%). The area under the effect time curves for capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were not affected by either treatment compared to placebo. Significant limb differences were observed for flare (AUC) (-38% in affected leg, 95% CI for difference -19% to -52%). Both hand dominance and sex were significant covariates of response to capsaicin.ConclusionsIt cannot be concluded that minocycline is unsuitable for further evaluation as an anti-neuropathic pain drug as pregabalin, our positive control, failed to reduce capsaicin-induced neuropathic pain. However, the anti-hyperalgesic effect of minocycline observed pre-capsaicin injection is promising pilot information to support ongoing research into glial-mediated treatments for neuropathic pain. The differences in flare response between limbs may represent a useful biomarker to further investigate neuropathic pain. Inclusion of a positive control is imperative for the assessment of novel therapies for neuropathic pain.

Colorectal cancer is the second leading cause of cancer death in Australia. Nutrition, particularly intake of vegetables and certain plant components, has been reported to have a major role in cancer risk reduction. Recently, there has been a growing research interest in rosemary, a common household plant grown in many parts of the world. This study aims to review scientific evidence from all studies, published from 1996 to March 2010 that examined the protective effects of rosemary on colorectal cancer and other types of cancer. Literature evidence from animal and cell culture studies demonstrates the anticancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid. No evidence for other rosemary constituents was found. The reported anticancer properties were found to arise through the molecular changes in the multiple-stage process of cancer development, which are dose related and not tissue or species specific. This is evidenced by the ability of rosemary to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells. The results suggested that the different molecular targets modulated by rosemary and its active constituents are useful indicators of success in clinical cancer chemo-prevention trials. Refereed/Peer-reviewed

Sarcoptic mange, caused by Sarcoptes scabiei var. wombati, could be a significant threat to populations of southern hairy-nosed wombats (Lasiorhinus latifrons; SHNW) in Australia. Treatment is currently based on the off-label use of various parasiticidal drugs, with limited clinical efficacy trials. Our primary aim was to determine the pharmacokinetic parameters of a macrocyclic lactone, moxidectin, to assist in the development of effective treatment protocols. Pharmacokinetic parameters were determined in four female SHNW following a single subcutaneous injection of 0.2 mg/kg moxidectin. Blood samples were collected for 38 days following injection (August-September 2008), for analysis using liquid chromatography and tandem mass spectrometry. The mean peak plasma concentration occurred at 13.6 hr, with a mean peak plasma level of 98.6 ng/ml. The mean elimination half-life was 5.03 days, resulting in a mean area under the curve of 377 ng.day/ml. The peak plasma moxidectin concentration was higher than that seen in livestock species but the plasma elimination half-life was shorter. This study suggests that a single injection of 0.2 mg/kg moxidectin may not be sufficient to clear a mange infection in this species. Refereed/Peer-reviewed

To compare the dose-response relationships of two formulations [Tween- or hydroxypropyl-b-cyclodextrin (HP-b-CD)-based] of intradermal capsaicin in healthy volunteers and to assess the effect of potential covariates of response. One, 10, 30 and 100 microg in 10 ml were compared for the outcomes of flare, spontaneous pain, mechanical allodynia and hyperalgesia in eight healthy men and eight healthy women.The formulations produced comparable responses at doses 1, 10 and 30 microg, but in all parameters the response was less at 100 microg with the Tween formulation.Mean area for hyperalgesia was 9 cm(2) [95% confidence interval (CI) 5, 13] higher with the HP-beta-CD formulation. Flare area was 5 cm(2) (95% CI 8, 13) greater with the HP-beta-CD formulation. There was a significant difference between pain responses from the injection site on the upper forearm compared with the lower forearm on all four pain assessments. In contrast, significant differences were seen in pain response between nondominant and dominant arm for flare, allodynia and hyperalgesia but not for spontaneous pain. A significant difference in sex was seen only for hyperalgesia. The nominal 100-microg dose of the Tween formulation contained only 39% of label strength in the aqueous phase, which may explain the lower pharmacodynamic response.The formulations are comparable over the dose range 1-30 microg. The significantly lower pain response at the 100 microg dose in the Tween compared with the HP-beta-CD formulation is likely to be due to limitations in solubility at the 100 microg level. Given the greater ease of formulation and the superior dose-response relationship, the HP-beta-CD formulation is preferable for use in the model in future studies.