Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Association between the implementation of tobacco control policies and adolescent vaping in 44 lower-middle, upper-middle, and high-income countries.

AIM: To (i) estimate the prevalence of adolescent vaping in 47 lower-middle, upper-middle and high-income countries, and (ii) test the association between implementation of World Health Organisation (WHO) tobacco control policies and adolescent e-cigarette use (also known as vaping) in 44 countries where implementation data were available. DESIGN: Cross-sectional surveys. SETTINGS: A total of 47 lower-middle, upper-middle and high-income countries. PARTICIPANTS: A total of 151 960 adolescents (typically ages 13-15) who participated in WHO's Global Youth Tobacco Survey between 2015 and 2018. MEASUREMENTS: Prevalence of past-30-day vaping and past 30-day frequent vaping (≥10 days) were estimated from the surveys. Data on the implementation of six tobacco control measures including monitoring, smoke-free policies, cessation programs, warning about the dangers of tobacco, advertising bans and taxation were taken from WHO's report on global tobacco epidemic. FINDINGS: The overall weighted prevalence of adolescent vaping and frequent vaping in the past 30 days was 8.6% (95% CI, 8.3-8.9) and 1.7% (95% CI, 1.6-1.8), respectively. For five of WHO's policies (monitoring, smoking-free environment, cessation programs, health warning and advertising bans), their association with adolescent vaping was inconclusive because of large variation of their effects across countries. Higher tax on combustible tobacco products was associated with higher adolescent vaping (> = 75% tax vs < 25% tax; odds ratio = 2.58; 95% CI, 1.25-5.21). CONCLUSION: In 47 lower-middle, upper-middle and high-income countries from 2015 to 2018, ~1 in 12 (8.6%) adolescents reported vaping in the past 30 days, but prevalence of frequent vaping was low (1 in 60; 1.7%). A higher tobacco tax was associated with higher adolescent vaping.

A wastewater-based assessment of the impact of a minimum unit price (MUP) on population alcohol consumption in the Northern Territory, Australia.

AIM: To test if there was a reduction in alcohol consumption in wastewater samples in the Northern Territory of Australia after the implementation of a minimum unit alcohol price policy (MUP) in October 2018. DESIGN, SETTING, CASES: Between August 2016 and February 2020, wastewater samples were collected across 66 sites in the Northern Territory and all other states and territories in Australia. Samples were collected every 2 months in capital cities and every 4 months in regional places during this period. Overall, 4917 samples were taken (2816 before MUP and 2101 after). MEASUREMENTS: The number of standard drinks per 1000 people per day in the respective catchment areas was estimated based on the concentration of an alcohol-specific metabolite, ethyl sulphate in the samples (using the excretion factor of ethyl sulphate, the flow of wastewater entering the wastewater treatment plants and the population of each wastewater catchment). FINDINGS: Results from a linear mixed model showed that there was a large drop in alcohol consumption immediately after the MUP in Northern Territory [estimated drop = 1231, 99% confidence interval (CI) = 830, 1633; 38.75%]. There was no significant drop in all other states/territories except for Queensland, which showed a significant but much smaller drop (estimated drop: 310; 99% CI = 114, 550). One year after the MUP, the drop narrowed to 520 (99% CI = 189, 851) and was no longer statistically significant in February 2020 (15 months after MUP; estimated drop = 283, 99% CI = -114, 681). CONCLUSIONS: Per-capita consumption of alcohol appears to have decreased substantially in the Northern Territory of Australia immediately after the implementation of a minimum unit price but consumption steadily recovered and almost returned to the pre-MUP consumption level after 15 months.

Conversion from Aranesp® to NESP® in dialysis patients-Exploration of dosing strategies and the feasibility of extending the dosing interval.

AIM: Darbepoetin alpha is available as Aranesp® and NESP®, which differ in the inactive component and maximum dose-strength of prefilled syringes. We conducted an observational cohort study to investigate optimal conversion strategies and the feasibility of extending dosing intervals with higher-dose preparations in dialysis patients converting from Aranesp® to NESP®. METHODS: Adult dialysis patients on Aranesp® with stable haemoglobin of 9-12 g/dL were converted to NESP® at the same monthly total dose according to one of three conversion regimens. Group A included patients on ≤80 mcg/month of Aranesp® who converted with dosing regimen unchanged. Group B patients converted to NESP® with extended dosing intervals using higher individual dose preparations. Group C were patients on 100 mcg Aranesp® who converted to NESP® 120 mcg with extended dosing intervals. Patients were observed for 6 months. RESULTS: Fifty patients were included. All 24 Group A patients maintained stable haemoglobin. In Group B, 10 patients (50%) maintained stable haemoglobin with extension of dosing interval from 1.04 ± 0.14 to 3.03 ± 1.28 weeks. Factors associated with success in extending dosing interval included a lower prevalence of cardiovascular disease and a higher Kt/Vurea in peritoneal dialysis patients. Four patients (80%) in Group C maintained stable haemoglobin after conversion to NESP® 120 mcg with extended dosing interval. The use of NESP® 120 mcg was well tolerated, and was associated with reduced patient-reported pain score and 38% reduction of drug cost. CONCLUSION: Dialysis patients on Aranesp® can be successfully converted to NESP® and the dosing interval can be extended successfully in a significant proportion of patients, which could reduce discomfort and drug cost.

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme.

BACKGROUND AND AIMS: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes. METHODS: Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event]. RESULTS: In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death. CONCLUSIONS: During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

Availability of substances for use in personal vaporisers on three online cryptomarkets.

BACKGROUND: Personal vaporisers are gaining popularity as an alternative route of administration for a range of substances. Online cryptomarkets are becoming increasingly popular among people who use substances due to their perceived anonymity, ease of use, and reduced risk of violence compared to traditional face-to-face dealers. We examined the diversity of substances marketed for use in a personal vaporiser on these marketplaces. METHODS: Vaping related listings were extracted from three online cryptomarkets ('Agartha', 'Cryptonia', and 'Tochka') using The Onion Router browser. Data collection occurred between October and November 2019. RESULTS: We identified 1929 listings from 201 unique sellers. The top product on Agartha, Cryptonia, and Tochka were vape cartridges prefilled with the e-liquid (70.4 %, 39.4 %, 52.3 % respectively). The most common substance in these products was cannabis oil (96.1 %, 82.1 %, 87.8 %), followed by synthetic cannabinoids (3.7 %, 9.7 %, 9.8 %) and psychedelic substances (0.2 %, 6.4 %, 1.2 %). Vendors were primarily from the USA. Many products offered worldwide shipping (96.3 %, 42.4 %, 51.2 %). CONCLUSION: Vaping products listed on online cryptomarkets in 2019 primarily contained cannabis oils. Future studies should continue to examine cryptomarkets to identify emerging trends of substances that can be used in personal vaporisers.

Estimation of the proportion of population cannabis consumption in Australia that is accounted for by daily users using Monte Carlo Simulation.

AIM: To estimate the proportion of cannabis consumed in Australia by daily cannabis users. DESIGN: Monte Carlo simulation using parameters estimated from nationally representative and repeated cross-sectional household surveys in 2007, 2010, 2013 and 2016. SETTING: Australia PARTICIPANTS: Adult samples (mean age = 49.9; 55% females) from four National Drug Strategy Household Surveys (n = 92 243). MEASUREMENT: Frequency of cannabis use (daily/weekly/about once a month/every few months/once or twice a year). The weighted estimated prevalence of users in each of these frequency levels was multiplied by population size to estimate the total number of users. Quantity of cannabis use was measured as number of joints consumed. The consumption of those who reported using bongs was converted into joints based on the bong to joint ratio estimated from the survey data. We estimated the proportion of cannabis consumed by daily users by Monte Carlo simulation using parameters estimated from the household surveys. We conducted 10 000 simulation trials, and in each trial we [1] simulated the number of users at each consumption level (stratum) based on estimated prevalence and population size[2], for each simulated individual, we simulated the number of days of cannabis use in a year based on frequency data[3], for each consumption day, we simulated the quantity consumed [4] and lastly we calculated the total joints consumed at each consumption level and estimated the proportion of joints consumed by daily users out of the total consumption. FINDINGS: The prevalence of past-year cannabis use increased from 8.9% [95% confidence interval (CI) = 8.5-9.4] in 2007 to 10.5% (95% CI = 10.0-11.1) in 2016, 16% of whom were daily users. Between 2007 and 2016, daily users accounted for between 81.6 and 85.7% of all cannabis consumed. Weekly users accounted for an additional 12.1-15.9%. CONCLUSION: Between 2007 and 2016, only one in six Australian cannabis users were daily users, but they accounted for more than 80% of the estimated cannabis consumed in Australia.

Alcohol consumption and consequences in adolescents in 68 low and middle-income countries - a multi-country comparison of risks by sex.

AIMS: Alcohol use is a leading risk factor for disease burden among youth. This study estimated sex differences in the prevalence of alcohol use and consequences among adolescents living in low and middle-income countries (LMIC). DESIGN: Multi-staged cross-sectional international standardized self-report questionnaires administered in the classroom. SETTING: The Global school-based student health survey (GSHS) comprised adolescents from 68 LMIC between 2003-2014. PARTICIPANTS: 271,156 students aged 13-17 years old. MEASUREMENTS: Alcohol measures included: past month alcohol consumption, history of intoxication and alcohol-related problems. Regions were based on the World Health Organization definitions: Africa, America, Eastern Mediterranean, Europe, South-east Asia, and Western Pacific. FINDINGS: Overall, males had higher odds of alcohol use (OR = 2.38 [1.91-2.96]), a history of intoxication (OR = 2.64 [2.11-3.31]), and alcohol-related problems (OR = 1.72 [1.41-2.10]) than females. All regions recorded overall greater odds of alcohol use by males versus females; five regions (excluding Europe) recorded greater odds of intoxication in males; and three regions (America, South-east Asia, and Western Pacific) recorded greater odds of alcohol-related problems amongst males. However, there were country-level differences - in some countries, adolescent drinking rates and consequences were comparable by sex. Countries with the highest odds of alcohol use among males compared to females were Indonesia, Myanmar, Cambodia, Tuvalu, Morocco, Senegal, Kiribati, and Thailand. CONCLUSIONS: Among adolescents living in LMIC, males had on average two-fold higher odds of drinking alcohol and experiencing adverse consequences. Growing affluence and improvements in sex equality in societies may increase the future prevalence of hazardous drinking in females in LMICs.

Aggression in the Australian night time economy: A comparison of alcohol only versus alcohol and illicit drug consumption.

INTRODUCTION AND AIMS: Associations between substance use and aggression may be amplified by simultaneous alcohol and illicit drug use. This study aims to compare differences in involvement in past aggression between people who use different substances while accounting for broader risk propensity. DESIGN AND METHODS: Self-reported data on past three-month involvement in verbal and physical aggression (victim or perpetrator) were drawn from interviews conducted in night-time entertainment districts in seven Australian cities (n = 5078). Using inverse probability of treatment weighting techniques, participants who reported alcohol versus alcohol and illicit drug use on the night of interview (including ecstasy, cannabis and other illicit stimulant subgroups) were weighted on the basis of drug use risk covariates (e.g. alcohol consumed, gender) to determine differences in involvement in aggression involvement. RESULTS: After weighting for covariates, individuals who reported consuming any illicit drug + alcohol and ecstasy + alcohol combinations were more likely to be involved in physical (33% and 105%, respectively) and verbal (36% and 116%, respectively) aggression in the previous 3-months when compared to those who consumed alcohol only. Cannabis + alcohol and other illicit stimulant + alcohol combinations were no more likely to be involved in either forms of aggression. DISCUSSION AND CONCLUSIONS: The likelihood of having been involved in past aggressive incidents was higher among those who reported any illicit drug + alcohol and ecstasy + alcohol combinations than those who reported alcohol exclusively, after accounting for covariates. These findings highlight individuals that may benefit most from the development of tailored health promotion/preventative safety interventions in night-time settings.

Social identity differentiation predicts commitment to sobriety and wellbeing in residents of therapeutic communities.

RATIONALE: Therapeutic communities (TC) for alcohol and other drug treatment rely strongly on social factors as agents of recovery; an approach known as 'community-as-method'. This study adopted a social identity approach in examining the relative strength of participants' recovery group identity and substance using group identity at admission (T1) and after six months (T2) in a TC. OBJECTIVES: Were to investigate whether identity differentiation - the extent to which respondents see themselves more as belonging to recovery groups than belonging to substance using groups - (a) is related to individuals' primary substance of concern (i.e., amphetamine type stimulants; alcohol; other drugs), and (b) predicts positive indicators of recovery six months after entering a therapeutic community. METHOD: Adults (N = 307) entering one of five Australian therapeutic communities (TC) completed measures of identification (user, recovery), commitment to sobriety, psychological distress, and personal wellbeing. RESULTS: Participants' endorsement of the user and recovery identity at T1 and T2 did not differ as a function of primary substance of concern. User identity diminished over the six months while recovery identity remained high, regardless of primary drug category. Identity differentiation measured at T2 accounted for 20-25% variance in commitment to sobriety and wellbeing, after accounting for participant demographics, addiction severity, and T1 identity variables. CONCLUSIONS: These findings highlight the importance of the relative strength of recovery over substance use related identities in supporting recovery indicators and the central role of the TC in supporting this trajectory.

Non-invasive assessment of kidney allograft fibrosis with shear wave elastography: A radiological-pathological correlation analysis.

OBJECTIVES: To evaluate the use of shear wave elastography in assessment of kidney allograft tubulointerstitial fibrosis. METHODS: Shear wave elastography assessment was carried out by two independent operators in kidney transplant recipients who underwent allograft biopsy for clinical indications (i.e. rising creatinine >15% or proteinuria >1 g/day). Allograft biopsies were interpreted by the same pathologist according to the 2013 Banff Classification. RESULTS: A total of 40 elastography scans were carried out (median creatinine 172.5 µmol/L [interquartile range 133.8-281.8 µmol/L]). Median tissue stiffness at the cortex (22.6 kPa [interquartile range 18.8-25.7 kPa] vs 22.3 kPa [interquartile range 19.0-26.5 kPa], P = 0.70) and medulla (15.0 kPa [interquartile range 13.7-18.0 kPa] vs 15.6 kPa [interquartile range 14.4-18.2 kPa]) showed no significant differences between the two observers. Interobserver agreement was satisfactory (intraclass correlation coefficient of the cortex 0.84, 95% CI 0.70-0.92 and intraclass correlation coefficient of the medulla 0.88, 95% CI 0.78-0.94). The areas under the receiver operating characteristic curves for detection of tubulointerstitial fibrosis were estimated to be 0.75 (95% CI 0.61-0.89), 0.85 (95% CI 0.75-0.95) and 0.65 (95% CI 0.53-0.78) for cortical, medullary tissue stiffness and serum creatinine, respectively. CONCLUSIONS: Shear wave elastography can be used as a non-invasive tool to evaluate kidney allograft fibrosis with reasonable interobserver agreement and superior test performance to serum creatinine in detecting early tubulointerstitial fibrosis.

Socio-economic differentials in cannabis use trends in Australia.

AIM: To test if the degree of change in cannabis use between 2001 and 2013 differed according to socio-economic status. DESIGN: Repeated cross-sectional household surveys that were nationally representative. SETTING: Australia. PARTICIPANTS: Adult samples from the 2001 and 2013 National Drug Strategy Household Surveys (n = 23 642 in 2001 and n = 21 353 in 2013), the largest nationally representative survey on drug use in Australia. MEASUREMENTS: Frequency of cannabis use coded as daily use, weekly use, less than weekly use and non-current use; socio-economic status (SES) as measured by personal income and educational level. FINDING: There were significant differences in changes to levels of cannabis use between SES groups. Among participants who completed high school, the probability of daily use decreased from 0.014 to 0.009 (P < 0.001), and the probability of weekly use decreased from 0.025 to 0.017 (P < 0.001). These probabilities remained stable for participants who did not complete high school. The probability of weekly cannabis use decreased from 0.032 to 0.023 among participants with middle level income (P = 0.004), and from 0.021 to 0.013 among those with high income (P = 0.005). There were no significant changes in these probabilities among those with low income (0.026 in 2001 and 0.032 in 2013; P = 0.203). CONCLUSION: The decline in cannabis use in Australia from 2001 to 2013 occurred largely among higher socio-economic status groups. For people with lower income and/or lower education, rates of frequent cannabis use remained unchanged.

Assessment of Ex Vivo Transport Function in Isolated Rodent Brain Capillaries.

The blood-brain barrier plays an important role in neuroprotection; however, it can be a major obstacle for drug delivery to the brain. This barrier primarily resides in the brain capillaries and functions as an interface between the brain and peripheral blood circulation. Several anatomical and biochemical elements of the blood-brain barrier are essential to regulate the permeability of nutrients, ions, hormones, toxic metabolites, and xenobiotics into and out of the brain. In particular, high expression of ATP-driven efflux transporters at the blood-brain barrier is a major obstacle in the delivery of CNS pharmacotherapeutics to the brain. The complete understanding of these elements can offer insights on how to modulate barrier functions for neuroprotection against CNS drug toxicity and to enhance drug delivery to the brain. In the literature, preclinical models of the blood-brain barrier are widely utilized to predict drug pharmacokinetics and pharmacodynamics properties in the brain. In addition, these models are essential tools to investigate cellular mechanisms and novel interventions that alter barrier function and permeability. This unit presents procedures to isolate fresh and viable rodent brain capillaries for the assessment of ex vivo transport activity at the blood-brain barrier. © 2017 by John Wiley & Sons, Inc.

Risky dieting amongst adolescent girls: Associations with family relationship problems and depressed mood.

OBJECTIVE: This study examined the association of risky dieting amongst adolescent girls with depressed mood, family conflict, and parent-child emotional closeness. METHOD: Grade 6 and 8 females (aged 11-14years, N=4031) were recruited from 231 schools in 30 communities, across three Australian States (Queensland, Victoria, and Western Australia). Key measures were based on the Adolescent Dieting Scale, Short Mood and Feelings Questionnaire, and widely used short measures of family relationship quality. Controls included age, early pubertal onset, and socioeconomic status. RESULTS: Risky dieting was significantly related to family conflict and depressed mood, depressed mood mediated the association of family conflict and risky dieting, and these associations remained significant with controls in the model. CONCLUSION: Family conflict and adolescent depressed mood are associated with risky dieting. IMPLICATIONS: Prevention programs may benefit from a broadening of behavioural targets to include depressed mood and family problems.