Psychotropic and other medicine use at time of death by suicide: a population-level analysis of linked dispensing and forensic toxicology data.

OBJECTIVES: To determine the numbers and types of medicines dispensed around the time of death to people who die by suicide; to compare the medicines recently dispensed and those recorded in post mortem toxicology reports. DESIGN, SETTING, PARTICIPANTS: Analysis of linked National Coronial Information System (NCIS) and Pharmaceutical Benefits Scheme (PBS) data from the Australian Suicide Prevention using Health Linked Data (ASHLi) study, a population-based case series study of closed coronial cases for deaths of people in Australia aged ten years or more during 1 July 2013 - 10 October 2019 deemed by coroners to be the result of intentional self-harm. MAIN OUTCOME MEASURES: Proportions of people to whom medicines were dispensed around the time of death, by medicine group, class, and specific medicine; comparison of medicines recently dispensed and those detected by post mortem toxicology. RESULTS: Toxicology reports were available for 13 541 of 14 206 people who died by suicide (95.3%; 10 246 men, 75.7%); poisoning with medicines contributed to 1163 deaths (8.6%). At least one PBS-subsidised medicine had been dispensed around the time of death to 7998 people (59.1%). For three medicine classes, the proportions of people in whom the medicines were detected post mortem and their death was deemed medicine-related were larger for those without records of recent dispensing than for people for whom they had been dispensed around the time of death: antidepressants (17.7% v 12.0%), anxiolytics (16.3% v 14.8%), and sedatives/hypnotics (24.3% v 16.5%). At least one recently dispensed medicine not detected post mortem was identified for 6208 people (45.8%). CONCLUSIONS: A considerable proportion of people who died by suicide were not taking psychotropic medicines recently dispensed to them, suggesting non-adherence to pharmacotherapy, and a smaller than expected proportion were using antidepressants. Conversely, medicines that had not recently been dispensed were detected post mortem in many people for whom poisoning with medicines was a contributing factor, suggesting medicine stockpiling.

Optimising alkalinisation and its effect on QRS narrowing in tricyclic antidepressant poisoning.

AIMS: The objectives were to determine the effect of NaHCO3 and/or mechanical ventilation on the biochemical profile and serum alkalinisation in tricyclic antidepressant (TCA) poisoning and investigate the impact of effective alkalinisation therapy on the QRS interval in TCA poisoning. METHODS: This was a retrospective review of TCA poisonings from three Australian toxicology units and a poisons information centre (Jan 2013 to Jan 2019). We included patients with TCA toxicity who ingested>10 mg/kg or had clinically significant toxicities consistent with TCA poisoning, and analysed patients' clinical, electrocardiogram and biochemical data. RESULTS: Of 210 patients, 84 received NaHCO3 and ventilation (dual therapy), 12 NaHCO3 , 46 ventilation and 68 supportive care treatment. When compared with single/supportive groups, patients who received dual therapy had taken a significantly higher median dose of TCA (1.5 g vs1.3 g, P < .001), a longer median maximum QRS interval (124 ms, interquartile ranges [IQR] 108-138 vs106 ms, IQR 98-115, P < .001) and were more likely to have seizures (14% vs3%, P = .006) and arrhythmias (17% vs1%, P < .001). The dual therapy group demonstrated greater increases in serum pH (median 0.11, IQR 0.04-0.17) compared to the single/supportive therapy group (median 0.03, IQR -0.01-0.09, p < .001). A greater proportion of patients reached the target pH 7.45-7.55 in the dual therapy group (59%) compared to the single/supportive therapy group (10%) (P < .001). For each 100 mmol bolus of NaHCO3 given, the median increase in serum sodium was 2.5 mmol/L (IQR 1.5-4.0). QRS narrowing occurred twice as quickly in the dual therapy vs single/supportive therapy group. CONCLUSIONS: A combination of NaHCO3 and mechanical ventilation was most effective in achieving serum alkalinisation and was associated with a more rapid narrowing of the QRS interval. We advise that the maximal dose of NaHCO3 should be <400 mmol (6 mmol/kg).

Prescribed medicine use and extent of off-label use according to age in a nationwide sample of Australian children.

BACKGROUND: Medicine prescribing for children is impacted by a lack of paediatric-specific dosing, efficacy and safety data for many medicines. OBJECTIVES: To estimate the prevalence of medicine use among children and the rate of 'off-label' prescribing according to age at dispensing. METHODS: We used population-wide primarily outpatient dispensing claims data for 15% of Australian children (0-17 years), 2013-2017 (n = 840,190). We estimated prescribed medicine use and 'off-label' medicine use according to the child's age (<1 year, 1-5 years, 6-11 years, 12-17 years) defined as medicines without age-appropriate dose recommendations in regulator-approved product information. Within off-label medicines, we also identified medicines with and without age-specific dose recommendations in a national prescribing guide, the Australian Medicines Handbook Children's Dosing Companion (AMH CDC). RESULTS: The overall dispensing rate was 2.0 dispensings per child per year. The medicines with the highest average yearly prevalence were systemic antibiotics (435.3 per 1000 children), greatest in children 1-5 years (546.9 per 1000). Other common medicine classes were systemic corticosteroids (92.7 per 1000), respiratory medicines (91.2 per 1000), acid-suppressing medicines in children <1 year (47.2 per 1000), antidepressants in children 12-17 years (40.3 per 1000) and psychostimulants in children 6-11 years (27.0 per 1000). We identified 12.2% of dispensings as off-label based on age, but 66.3% of these had age-specific dosing recommendations in the AMH CDC. Among children <1 year, off-label dispensings were commonly acid-suppressing medicines (35.5%) and topical hydrocortisone (33.1%); in children 6-11 years, off-label prescribing of clonidine (16.0%) and risperidone (13.1%) was common. Off-label dispensings were more likely to be prescribed by a specialist (21.7%) than on-label dispensings (7.5%). CONCLUSIONS: Prescribed medicine use is common in children, with off-label dispensings for medicines without paediatric-specific dosing guidelines concentrated in classes such as acid-suppressing medicines and psychotropics. Our findings highlight a need for better evidence to support best-practice prescribing.

Vitamin and mineral supplement exposures: cases reported to Australia's largest Poisons Information Centre, 2014-2015 to 2018-2019.

Vitamin and mineral supplements (VMS) are widely available and commonly used. Little is known about patterns of poisoning exposures to VMS in the Australian population. We performed a retrospective study of calls to the New South Wales Poisons Information Centre (NSWPIC), July 2014-June 2019. NSWPIC is Australia's largest PIC, taking approximately 100 000 calls/year (50 % of Australian poisoning calls) from healthcare professionals and members of the public. We conducted additional analyses on Fe exposures due to their high risk of acute toxicity. There were 10 944 VMS exposures reported to NSWPIC during the study period, increasing 9·6 % per annum over a 5-year period (95 % CI, 7·2, 12·1 %). Toddlers (1-4 years) accounted for 41·5 % (4546) of cases. Agents most commonly involved were multivitamins (n 3610), vitamin D (n 2080), Fe (n 1533) and Mg (n 804). In 17·7 % (1934) of cases, the call originated from hospital or the patient was referred to hospital by NSWPIC. Fe exposures increased by 14·0 % per year (95 % CI, 9·5, 18·5 %), and most were associated with high-strength products (> 45 mg elemental Fe per unit dose, n 1036). Fe exposures were hospitalised in 38 % of cases (n 583). We conclude that VMS exposures are increasing in Australia. Although most exposures can be managed at home, many required hospitalisation. Fe exposures are increasing and had higher rates of hospitalisation than other agents. VMS are often considered safe and without the potential for adverse effects, highlighting the importance of public education into the potential risks of misuse of these products.

Opioid exposures in children under 5 years of age (2004-2019): A retrospective study of calls to Australia's largest poisons information centre.

AIM: To describe time trends in opioid exposures in children under 5 years, and to describe patient demographics, the medicines involved, the reasons for exposure and disposition. METHODS: A retrospective analysis of paediatric (<5 years of age) opioid exposure calls to the New South Wales Poisons Information Centre (NSWPIC, Australia's largest poison centre), 2004-2019. Joinpoint regression analysis was used to examine temporal trends. RESULTS: There were 4807 cases of paediatric opioid exposure during the 16 year study period, with an average of 300 exposures per year. Exposures increased, 2004-2007, with an annual percentage change (APC) of 14.6% (95% CI = 4.3 to 26.0%), then decreased, 2007-2016, APC -3.4% (95% CI = -5.3 to -1.3%). A steeper decrease was observed after 2016, APC -14.1% (95% CI = -21.8 to -5.6%). The overall APC was -2.3% (95% CI = -4.7 to 0.2%), 2004-2019. Accidental exposures accounted for 86% of calls (4137). The majority of calls were from family members regarding exposures that happened at home, highlighting the need for safety initiatives. The preparations most frequently involved were paracetamol/opioid combination products (primarily codeine), 53% (2566) and ibuprofen/opioid combinations 14% (650). Twenty-two percent of cases were referred to a hospital (1062), and a further 15% (719) of calls originated from hospital staff. CONCLUSION: Opioid exposures in young Australian children continue to occur; however, the rate has declined since 2007. Safe storage and parent education initiatives could further reduce the burden of paediatric opioid poisoning in Australia.

Changes in sales of analgesics to pharmacies after codeine was rescheduled as a prescription only medicine.

OBJECTIVE: To investigate changes in sales to pharmacies of over-the-counter (OTC) and prescription analgesics, cold and flu products, and cough suppressants after the rescheduling of codeine as a prescription only medicine in February 2018. DESIGN: Interrupted time series analysis of sales to pharmacies. SETTING: Pharmaceutical sales to community pharmacies in Australia, March 2015 - March 2019. The period January 2017 (month after rescheduling was announced) to January 2018 (month before rescheduling was implemented) was excluded from the time series analysis. MAIN OUTCOME MEASURES: Monthly pack and tablet sales per 10 000 population of OTC and prescription analgesics, cold and flu products, and cough suppressants. RESULTS: During 2016, 7586 packs and 248 127 tablets of OTC codeine per 10 000 population were sold to pharmacies; in the 14 months after rescheduling, a small level increase in monthly prescription codeine sales was evident (2247 tablets/capsules per 10 000 population; 95% CI, 1231-3264 per 10 000 population). Monthly OTC analgesic sales increased by 258 (95% CI, 151-365) packs per 10 000 population and 37 856 (95% CI, 26 143-49 569) tablet/capsules per 10 000 population. Monthly sales of single ingredient paracetamol (41 415 [95% CI, 31 374-51 456] tablets/capsules per 10 000 population), ibuprofen (1392 [95% CI 916-1868] tablets/capsules per 10 000 population), paracetamol/ibuprofen (1618 tablets [95% CI, 1567-1669] tablets/capsules per 10 000 population), and other paracetamol combinations (233 [95% CI, 112-353] tablets/capsules per 10 000 population) all increased, but not those of prescription analgesic products not containing codeine. Rises for OTC cold/flu products containing the opioid derivative dextromethorphan were small; sales of OTC cough suppressants containing opioid derivatives (dextromethorphan, pholcodine, dihydrocodeine) did not change. CONCLUSIONS: The rescheduling of codeine was followed by increased sales to pharmacies of paracetamol, ibuprofen, and paracetamol combination products. While these products carry no risk of dependence, their inappropriate use is also associated with harms that warrant adverse event monitoring.

Paracetamol poisoning-related hospital admissions and deaths in Australia, 2004-2017.

OBJECTIVES: To assess the numbers of paracetamol overdose-related hospital admissions and deaths in Australia since 2007-08, and the overdose size of intentional paracetamol overdoses since 2004. DESIGN, SETTING: Retrospective analysis of data on paracetamol-related exposures, hospital admissions, and deaths from the Australian Institute of Health and Welfare National Hospital Morbidity Database (NHMD; 2007-08 to 2016-17), the New South Wales Poisons Information Centre (NSWPIC; 2004-2017), and the National Coronial Information System (NCIS; 2007-08 to 2016-17). PARTICIPANTS: People who took overdoses of paracetamol in single ingredient preparations. MAIN OUTCOME MEASURES: Annual numbers of reported paracetamol-related poisonings, hospital admissions, and deaths; number of tablets taken in overdoses. RESULTS: The NHMD included 95 668 admissions with paracetamol poisoning diagnoses (2007-08 to 2016-17); the annual number of cases increased by 44.3% during the study period (3.8% per year; 95% CI, 3.2-4.6%). Toxic liver disease was documented for 1816 of these patients; the annual number increased by 108% during the study period (7.7% per year; 95% CI, 6.0-9.5%). The NSWPIC database included 22 997 reports of intentional overdose with paracetamol (2004-2017); the annual number increased by 77.0% during the study period (3.3% per year; 95% CI, 2.5-4.2%). The median number of tablets taken increased from 15 (IQR, 10-24) in 2004 to 20 (IQR, 10-35) in 2017. Modified release paracetamol ingestion report numbers increased 38% between 2004 and 2017 (95% CI, 30-47%). 126 in-hospital deaths were recorded in the NHMD, and 205 deaths (in-hospital and out of hospital) in the NCIS, with no temporal trends. CONCLUSIONS: The frequency of paracetamol overdose-related hospital admissions has increased in Australia since 2004, and the rise is associated with greater numbers of liver injury diagnoses. Overdose size and the proportion of overdoses involving modified release paracetamol have each also increased.

A Review of Baclofen Overdoses in Australia: Calls to a Poisons Information Centre and a Case Series.

AIM: to describe trends in baclofen reports to Australia's largest Poisons Information Centre (PIC) and present a case series detailing severity of overdoses. SHORT SUMMARY: PBS data demonstrates baclofen use is increasing in Australia, while calls to NSWPIC illustrate an increase in number of exposures associated with toxicity. Baclofen toxicity may require prolonged intensive care admission. To minimize harms associated, especially with off-label baclofen prescribing for AUD, prescribers should pay careful attention to psychiatric comorbidities, and closely monitor treatment and dispensing. METHODS: this is a retrospective observational study of baclofen overdoses reported to New South Wales PIC (NSWPIC) from January 1 2004 to 31 December 2016. In addition, referrals to a metropolitan toxicology service relating to baclofen toxicity from 2014 to 2017 were analysed. The number of Pharmaceutical Benefit Scheme (PBS) claims for baclofen were also reviewed. RESULTS: during the 13-year study period, 403 cases of baclofen toxicity were reported to NSWPIC. There was a 230% increase in annual exposures over this period, 71% of patients were symptomatic, with 77% requiring hospitalization. Coingestants were reported in 53%, with 57% being psychoactive medications (including alcohol). An increase in number of baclofen dispensing episodes was also noted. From the five cases of deliberate self-harm reported to the metropolitan toxicology service, three obtained baclofen for management of alcohol use disorder (AUD) and required prolonged treatment in the intensive care unit (ICU). CONCLUSIONS: NSWPIC data shows an increase in number of calls regarding intentional baclofen exposures in parallel with increase the number of baclofen PBS claims. These closely parallel the increase in dispensing of baclofen since 2008. Case studies presented reinforce the severity of baclofen toxicity. Together, they demonstrate the potential risk of harm of baclofen prescribing, and the greater need for caution. Baclofen should be considered carefully in patients high risk of overdose or be used only in specialist services with close monitoring.

Person-level changes in oxycodone use after the introduction of a tamper-resistant formulation in Australia.

BACKGROUND: Australia introduced tamper-resistant controlled-release (CR) oxycodone in April 2014. We quantified the impact of the reformulation on dispensing, switching and poisonings. METHODS: We performed interrupted time-series analyses using population-representative national dispensing data from 2012 to 2016. We measured dispensing of oxycodone CR (≥ 10 mg), discontinuation of use of strong opioids and switching to other strong opioids after the reformulation compared with a historical control period. Similarly, we compared calls about intentional opioid poisoning using data from a regional poisons information centre. RESULTS: After the reformulation, dispensing decreased for 10-30 mg (total level shift -11.1%, 95% confidence interval [CI], -17.2% to -4.6%) and 40-80 mg oxycodone CR (total level shift -31.5%, 95% CI -37.5% to -24.9%) in participants less than 65 years of age but was unchanged in people 65 years of age or older. Compared with the previous year, discontinuation of use of strong opioids did not increase (adjusted hazard ratio [HR] 0.95, 95% CI 0.91 to 1.00), but switching to oxycodone/naloxone did increase (adjusted HR 1.54, 95% CI 1.32 to 1.79). Switching to morphine varied by age (p < 0.001), and the greatest increase was in participants less than 45 years of age (adjusted HR 4.33, 95% CI 2.13 to 8.80). Participants switching after the reformulation were more likely to be dispensed a tablet strength of 40 mg or more (adjusted odds ratio [OR] 1.40, 95% CI 1.09 to 1.79). Calls for intentional poisoning that involved oxycodone taken orally increased immediately after the reformulation (incidence rate ratio (IRR) 1.31, 95% CI 1.05-1.64), but there was no change for injected oxycodone. INTERPRETATION: The reformulation had a greater impact on opioid access patterns of people less than 65 years of age who were using higher strengths of oxycodone CR. This group has been identified as having an increased risk of problematic opioid use and warrants closer monitoring in clinical practice.

Carols by glow sticks: a retrospective analysis of Poisons Information Centre data.

OBJECTIVE: To win a Christmas hamper. We also devised a study of our most festive seasonal poisoning, to demonstrate how hard we are working while everyone else is partying. DESIGN: Retrospective analysis of the New South Wales Poisons Information Centre database, which we searched for exposures to the substance code "Cyalume light sticks/glow toys" from 1 July 2013 to 30 June 2017. SETTING: A dimly lit basement with a constantly ringing phone. At the other end of the phone was a highly anxious parent and a luminescent child. MAIN OUTCOME MEASURES: Number of glow stick exposures, route of exposures, patient demographics and seasonal trends in exposures. RESULTS: There were 2918 glow stick exposures over the 4-year study period. The vast majority of exposures (94%) were in children aged 14 years and younger. Medical complications were very rare. Glow stick exposures were 4.38 times more likely in December (95% CI, 3.02-6.35; P < 0.001). Statistically significant increases were also observed in October, November, January, February and March. Glow stick exposures were 4.20 times more likely during the holiday period of 1 December to 7 January (95% CI, 3.42-5.15; P < 0.001), 2.52 times more likely over summer (95% CI, 2.12-3.00; P < 0.001), and 1.77 times more likely during school holidays (95% CI, 1.47-2.13; P < 0.001). CONCLUSIONS: This epidemic of poisoning is perhaps due to mass seasonal synaesthesia. The lack of any significant adverse consequences highlights the contribution that 50 years of injury prevention has made to everyone having a Merry Christmas and a Happy New Year.

Patterns of poisoning exposure at different ages: the 2015 annual report of the Australian Poisons Information Centres.

OBJECTIVES: To characterise the types of calls received by Australian Poisons Information Centres (PICs) in Australia, and to analyse poisoning exposures by age group, circumstances of exposure, and the types of substances involved. Design, setting: Retrospective analysis of call records from all four Australian PICs (national coverage). MAIN OUTCOME MEASURES: Basic demographic information; exposure circumstances, substance types involved in each age group; recommendations for management (eg, stay at home, go to hospital). RESULTS: There were 204 906 calls to Australian PICs in 2015, 69.0% from the general public, 27.9% from health professionals; 16.2% of calls originated from hospitals. 170 469 calls (including re-calls about an exposure) related to 164 363 poison exposure events; 64.4% were unintentional, 18.1% were the consequences of medication error, and 10.7% involved deliberate self-poisoning. Most exposures were of 20-74-year-old adults (40.1%) or 1-4-year-old toddlers (36.0%). The PICs advised callers to stay at home for 67.4% of exposures, and to present to hospital for 10.9%. The most common substances involved in exposures overall were household cleaners (10.2%) and paracetamol-containing analgesics (7.3%). Exposures of infants and toddlers were most frequently to household cleaning substances (17.8%, 15.3% respectively) and personal care items (6.6%, 7.3%); callers were usually advised to stay at home (88.5%, 86.4%). Deliberate self-poisoning (49.1%) and hospital referral (23.9%) were most frequent for adolescents. Exposures of adults (20-74 years) frequently involved psychotropic pharmaceuticals (17.8%) or painkillers (15.1%). Exposures in adults over 74 were typically medication errors involving cardiovascular (23.6%), anticoagulant (4.6%), or antidiabetic (4.1%) medications. CONCLUSIONS: Poisoning is a significant public health problem throughout life, but the nature of the hazards differs markedly between age groups. PIC data could inform strategic public health interventions that target age-specific poisoning hazards.

Role of hepatic Annexin A6 in fatty acid-induced lipid droplet formation.

Annexin A6 (AnxA6) has been implicated in the regulation of endo-/exocytic pathways, cholesterol transport, and the formation of multifactorial signaling complexes in many different cell types. More recently, AnxA6 has also been linked to triglyceride storage in adipocytes. Here we investigated the potential role of AnxA6 in fatty acid (FA) - induced lipid droplet (LD) formation in hepatocytes. AnxA6 was associated with LD from rat liver and HuH7 hepatocytes. In oleic acid (OA) -loaded HuH7 cells, substantial amounts of AnxA6 bound to LD in a Ca2+-independent manner. Remarkably, stable or transient AnxA6 overexpression in HuH7 cells led to elevated LD numbers/size and neutral lipid staining under control conditions as well as after OA loading compared to controls. In contrast, overexpression of AnxA1, AnxA2 and AnxA8 did not impact on OA-induced lipid accumulation. On the other hand, incubation of AnxA6-depleted HuH7 cells or primary hepatocytes from AnxA6 KO-mice with OA led to reduced FA accumulation and LD numbers. Furthermore, morphological analysis of liver sections from A6-KO mice revealed significantly lower LD numbers compared to wildtype animals. Interestingly, pharmacological inhibition of cytoplasmic phospholipase A2α (cPLA2α)-dependent LD formation was ineffective in AnxA6-depleted HuH7 cells. We conclude that cPLA2α-dependent pathways contribute to the novel regulatory role of hepatic AnxA6 in LD formation.

Paediatric poisoning in rural Sri Lanka: an epidemiological study.

BACKGROUND: Acute paediatric poisoning is a common public health concern for both developed and developing countries. The type of agent and underlying cause differ depending on the social, cultural, economic and educational background. The objectives of this study were to identify the incidence and pattern of paediatric poisoning in a rural district in Sri Lanka and establish whether tertiary referral hospital data are a useful surrogate for estimating district level epidemiology of paediatric poisoning. METHODS: A subset of epidemiological data were obtained from March 2011 to February 2013 from a randomized controlled trial (SLCTR/2010/008) conducted in 45 hospitals in Kurunegala district. RESULTS: The age adjusted annual incidence of all cause of acute poisoning in children aged 1 to 12 years in the study area was 60.4 per 100,000. The incidence of poisoning of younger age group (1 to 6 years; 76 per 100,000) was significantly higher than older age group (7 to 12 years; 41 per 100,000) (p = 0.0001) in Kurunegala district. The annual incidence rate of paediatric admissions due to deliberate self-poisoning is 18 per 100,000 population. This study also established that admission data from primary hospitals provided the most accurate epidemiological information on paediatric poisoning. CONCLUSIONS: In rural districts of Sri Lanka, acute paediatric poisoning cases were less frequent and less severe compared to adult poisoning cases (426-446 per 100,000 population). The incidence of poisoning was significantly higher among young children with compared to old children. In this study, deliberate self-poisoning among older children was more frequently seen than in other comparable countries. Because most of the admissions are directed to and managed by primary hospitals, data from referral hospitals alone cannot be used to represent the true incidence of acute poisoning within a district. The data set from all the primary hospitals (n = 44) yielded more accurate poisoning incidence amongst a paediatric population.

ADHD medication overdose and misuse: the NSW Poisons Information Centre experience, 2004-2014.

OBJECTIVES: To describe Australian trends in overdoses with medications used to treat attention deficit hyperactivity disorder (ADHD). DESIGN, SETTING AND PARTICIPANTS: This was a retrospective observational study of intentional exposures to methylphenidate, dexamphetamine, modafinil and atomoxetine reported to the New South Wales Poisons Information Centre (NSWPIC) from 1 January 2004 to 31 December 2014. The NSWPIC takes calls from New South Wales, Tasmania and the Australian Capital Territory between 6 am and midnight each day, and, as part of a national after-hours roster, from all Australian states between midnight and 6 am on seven nights each fortnight. The target population included Australian residents aged 10-75 years. MAIN OUTCOME MEASURES: Demographic characteristics of the patients, changes in numbers of exposures with time, co-ingestants, route of exposure, and disposition of patients. RESULTS: During the 11-year study period, 1735 intentional exposures to the four medications were reported to NSWPIC. There was a 210% increase in intentional exposures to methylphenidate over this period, whereas the number of dexamphetamine exposures declined by 25%. Illicit use (defined as co-ingestion with alcohol or a street drug) increased by 429% across the study period. At least 93% of overdose patients required hospitalisation. Trends in exposures paralleled trends in the dispensing of these medications, as recorded in Pharmaceutical Benefits Scheme data. CONCLUSIONS: NSWPIC data show a dramatic increase in intentional exposures to ADHD medications between 2004 and 2014, mainly to methylphenidate. Further, the data suggest that illicit use of these substances is increasing. The potential harm related to misuse of prescription stimulants and the close correlation between these exposures and the prescribing of these drugs causes concerns about their diversion, and highlights the importance of the quality use of medicines (ie, ensuring that they are used safely, appropriately and in an evidence-based manner, including considering non-medical or non-stimulant alternatives) and of risk assessment for misuse when prescribing ADHD drugs.

A decade of Australian methotrexate dosing errors.

OBJECTIVE: Accidental daily dosing of methotrexate can result in life-threatening toxicity. We investigated methotrexate dosing errors reported to the National Coronial Information System (NCIS), the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN) and Australian Poisons Information Centres (PICs). DESIGN AND SETTING: A retrospective review of coronial cases in the NCIS (2000-2014), and of reports to the TGA DAEN (2004-2014) and Australian PICs (2004-2015). Cases were included if dosing errors were accidental, with evidence of daily dosing on at least 3 consecutive days. MAIN OUTCOME MEASURES: Events per year, dose, consecutive days of methotrexate administration, reasons for the error, clinical features. RESULTS: Twenty-two deaths linked with methotrexate were identified in the NCIS, including seven cases in which erroneous daily dosing was documented. Methotrexate medication error was listed in ten cases in the DAEN, including two deaths. Australian PIC databases contained 92 cases, with a worrying increase seen during 2014-2015. Reasons for the errors included patient misunderstanding and incorrect packaging of dosette packs by pharmacists. The recorded clinical effects of daily dosage were consistent with those previously reported for methotrexate toxicity. CONCLUSION: Dosing errors with methotrexate can be lethal and continue to occur despite a number of safety initiatives in the past decade. Further strategies to reduce these preventable harms need to be implemented and evaluated. Recent suggestions include further changes in packet size, mandatory weekly dosing labelling on packaging, improving education, and including alerts in prescribing and dispensing software.

Identification of dual PPARα/γ agonists and their effects on lipid metabolism.

The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50µM and 100µM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid ß-oxidation in HuH7 hepatocytes.