Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug–drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3–4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4–4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.     

Drunken driving and riding with a drunken driver: adolescent types at higher risk

Abstract

The leading cause of death of adolescents in developed countries is injury. Alcohol is a major contributor to adolescent injury. Most of the injury deaths in youth are caused by traffic crashes. Driving under the influence (DUI) and riding with a driver who is under the influence (RUI) of alcohol increase the risk of road crash. The focus of this study is how adolescents’ risk of DUI and RUI differ in relation to their experience of parental control and peer pressure to substance use, other risky behaviours and leisure time activities. The analyses are based on data from the European School Survey Project on Alcohol and Other Drugs collected from 15- to 16-year-old Finnish adolescents in 2015 (n?=?4049, response rate 88.7%). The study shows that problems tend to entangle in some adolescent groups in which DUI and RUI are also more common. Adolescents with higher probability of using various substances, of starting alcohol use at young age, of experiencing weak parental control, and high peer pressure are at higher risk of DUI and RUI. The results indicate that professionals and authorities handling underage DUI and RUI ought to consider adolescents’ situation as a whole.     

Ten-year follow-up of health-related quality of life among ambulatory persons with multiple sclerosis at baseline

Purpose

The aim of this 10-year follow-up study was to determine changes in health-related quality of life (HRQoL) over time among ambulatory persons with MS (PwMS) at the baseline using generic and disease-specific instruments.

Methods

Of 109 independently walking PwMS included in a population-based study in 2002, 77 (70.6 %) were re-assessed in 2012. HRQoL was captured using the 36-Item Short Form Survey Instrument (RAND-36), 15D instrument (15D), and the Multiple Sclerosis Quality of Life-54 (MSQOL-54). Repeated-measures ANOVA and effect size (ES) calculations (Cohen’s d) were used in the statistical analysis.

Results

The RAND-36 physical health composite score (p = 0.003, ES = 0.26) and 15D total score (p = 0.012, ES = 0.25) declined from the baseline levels. In particular, lower scores were observed on the RAND-36 scales of physical functioning (p = 0.001, ES = 0.27), pain (p = 0.020, ES = 0.25), and general health perceptions (p = 0.002, ES = 0.36), on the MSQOL-54 scales of physical functioning (p = 0.001, ES = 0.27), pain (p = 0.040, ES = 0.21), sexual functioning (p = 0.003, ES = 0.43), and satisfaction with sexual functioning (p = 0.012, ES = 0.38), and in the 15D dimensions of mobility (p = 0.004, ES = 0.31) and sexual functioning (p ≤ 0.001, ES = 0.59). Improvement was observed on the RAND-36 scale of social functioning (p = 0.049, ES = 0.25). The other composite scores, scales, and dimensions remained unchanged.

Conclusion

The results of this study suggest that ambulatory PwMS at baseline reported reduced HRQoL in physical functioning after a 10-year follow-up period, while emotional well-being was maintained and social functioning improved. The scores in the other HRQoL dimensions and scales remained unchanged. More long-term population-based studies are needed to precisely determine the development of HRQoL among PwMS.

     

Physical activity and social status in adolescence as predictors of physical inactivity in adulthood

BACKGROUND: Physical inactivity is related to an increased risk of certain chronic diseases. The aim here was to evaluate how physical activity and social status in adolescence are associated with physical inactivity in adulthood. METHODS: The sample comprised 3664 males and 4130 females who answered questions on physical activity and social status at 14 and 31 years of age in follow-up surveys of the Northern Finland birth cohort of 1966. Associations between explanatory factors and physical inactivity in adulthood were analyzed using multivariable logistic regression. RESULTS: Infrequent participation in sports after school hours at 14 years of age and, in males, additionally a low grade in school sports, was associated with physical inactivity at the age of 31 years, independent of social circumstances in adulthood. Low social class of the childhood family was associated with physical inactivity in adolescence but not with inactivity at 31 years of age. Poor school achievement in adolescence was associated with adult inactivity independent of adolescent physical activity. CONCLUSION: Infrequent participation in sports, a low grade in school sports, and poor school achievements in adolescence were associated with physical inactivity in adulthood. Participation in sports is to be strongly supported among all adolescents because of its long-term beneficial effects on adult health through its tendency to reduce the probability of adult inactivity.     

Diagnostic characteristics of different carbohydrate-deficient transferrin methods in the detection of problem drinking: effects of liver disease and alcohol consumption

AIMS: Due to methodological heterogeneity, conflicting views have been expressed on the validity of CDT measurements in the detection of alcohol misuse. METHODS: We compared the characteristics of the conventional CDTect method and the Axis turbidimetric CDT assays in the assessment of 62 alcoholics, who were either with (n = 33) or without (n = 29) liver disease, as analysed by combined clinical, laboratory, and morphological indices. Controls were 45 healthy volunteers who were either social drinkers or abstainers. RESULTS: In the total sample of alcoholics, the sensitivity of the %CDT method, which excludes the trisialotransferrin isoform from the measurement, was 63% for men and 46% for women, as compared to 65% and 36% of CDTect, respectively. Both of these methods showed higher sensitivities than the %CDT-TIA method, which reacts with trisialotransferrin (32% and 25%, respectively). The assay specificities were 100% for men and 91% for women with %CDT, and 96% and 87% with the CDTect, respectively. The correlation between the CDTect and %CDT method was higher in men (r = 0.86) than in women (r = 0.57). The presence of liver disease was found to influence the results of the CDTect method, such that the highest CDT concentrations were observed in patients with mild to moderate liver disease, especially among women, whereas the %CDT method was less sensitive to the effect of liver pathology. The self-reported alcohol consumption from the 4 weeks prior to sampling showed a higher correlation between the %CDT results (r = 0.64, P < 0.0001) than with the CDTect results (r = 0.40; P < 0.01). CONCLUSIONS: The data indicate that the new %CDT method offers advantages over the previous versions of the CDT methods. The improved characteristics may be most useful in assays for excessive alcohol consumption in female alcoholics, patients with liver disease, and in patients with abnormal serum transferrin concentrations.     

Transmission of Streptococcus equi Subspecies zooepidemicus Infection from Horses to Humans

Streptococcus equi subspecies zooepidemicus (S. zooepidemicus) is a zoonotic pathogen for persons in contact with horses. In horses, S. zooepidemicus is an opportunistic pathogen, but human infections associated with S. zooepidemicus are often severe. Within 6 months in 2011, 3 unrelated cases of severe, disseminated S. zooepidemicus infection occurred in men working with horses in eastern Finland. To clarify the pathogen’s epidemiology, we describe the clinical features of the infection in 3 patients and compare the S. zooepidemicus isolates from the human cases with S. zooepidemicus isolates from horses. The isolates were analyzed by using pulsed-field gel electrophoresis, multilocus sequence typing, and sequencing of the szP gene. Molecular typing methods showed that human and equine isolates were identical or closely related. These results emphasize that S. zooepidemicus transmitted from horses can lead to severe infections in humans. As leisure and professional equine sports continue to grow, this infection should be recognized as an emerging zoonosis.