Liv Mathiesen

Inhibition of lipid peroxidation in low-density lipoprotein by the flavonoid myrigalone B and ascorbic acid☆

Lipid peroxidation in human LDL (0.05 mg protein/mL) incubated with Cu(2+)-ions (5 microM) in vitro was dose-dependently inhibited by the flavonoid myrigalone B (MyB) and by ascorbic acid. MyB at 6 microM increased the oxidation lag time by 135 +/- 24 min (approximately 5-fold compared to controls) and reduced the maximum oxidation rate by 46 +/- 5%. Ascorbic acid, at 9 microM, increased the lag time by 179 +/- 29 min (6-fold compared to controls) but did not affect the maximum oxidation rate. The increase in lag time induced by MyB was enhanced in the presence of ascorbic acid. Their effects were additive, except when both were present at the highest concentration tested, when a significant potentiation, giving an increase in lag time of approximately 2 hr more than the sum of separate effects, occurred. Concentration-time curves for MyB in the absence and presence of ascorbic acid showed that the vitamin protected MyB against deterioration during incubation, and indicated that the net consumption of MyB in the oxidation process was reduced. No differences were observed when ordinary ascorbic acid and Ester-C, a commercial vitamin C product, were compared. In conclusion, MyB and ascorbic acid seem to interact in a way that further improves the antioxidant status of the LDL particle relative to each substance separately.

Uncoupling of respiration and inhibition of ATP synthesis in mitochondria by C-methylated flavonoids from Myrica gale L.

Abstract The uncoupling activity of seven C-methylated flavonoids from the fruits of Myrica gale L. was studied. Myrigalone A, B and G (MyA, MyB and MyG) uncoupled the oxidative phosphorylation in rat liver mitochondria. MyA was most potent, at 45 μM causing an increase of 87±8 natoms O/min/mg in the state 4 respiration rate, which is more than twice the effect of 2,4-dinitrophenol (DNP). MyG was slightly less active than MyA, but its activity decreased from 45 to 90 μM. MyB was approximately equipotent with DNP. Myrigalone D and H were weak uncouplers, whereas myrigalone E and angoletin were inactive. The uncoupling activity of MyA, MyB and MyG was accompanied by an inhibitory effect on the ATP synthesis. The inhibition caused by MyA at 45 μM was about 70%. Whereas the effect of MyA or MyB was nearly constant throughout the incubation period, the effect of MyG had almost vanished after 15 min. The uncoupling activity of the myrigalones does not seem to be related to their antioxidative properties.

CYP3A5-mediated metabolism of midazolam in recombinant systems is highly sensitive to NADPH-cytochrome P450 reductase activity

Data from in vitro drug metabolism studies with recombinant enzyme systems are frequently used to predict human drug metabolism in vivo. However, for the CYP3A probe substrate midazolam (MDZ), considerable variability in enzyme kinetic parameters has been observed in different in vitro studies. The aim of this study was to explore the effect of varying activities of the electron donor NADPH-cytochrome P450 reductase (CPR) on CYP3A5-mediated metabolism of MDZ. Microsomes with similar levels of CYP3A5 but 12-fold difference in CPR activity showed a 30-fold difference in intrinsic clearance for the formation of 1′-OH-MDZ. Significantly higher Km and lower Vmax for the formation of 1′-OH-MDZ were found in microsomes with low CPR activity compared with microsomes with higher CPR activity (P = 0.024 and 0.001). In the microsomes with lowest CPR activity, the formation of 1′-OH-MDZ displayed Michaelis–Menten kinetics, whereas substrate inhibition was observed in the two preparations with higher CPR activity. The present study shows that the CPR activity in different recombinant enzyme preparations is crucial for in vitro CYP3A5-mediated clearance of MDZ. This suggests that the CPR activity of enzyme preparations could be an important factor for the ability of in vitro data to predict human drug metabolism in vivo.

Use of medicines, adherence and attitudes to medicines among persons with chronic spinal cord injury

Study design:A cross-sectional study.Objectives:To describe the use of medicines and adherence among persons with spinal cord injury (SCI). Further, to examine the influence of pain, spasms and beliefs about medicines on adherence.Setting:Sunnaas Rehabilitation Hospital, Norway.Methods:Persons (⩾18 years) with chronic SCI (more than 1-year post injury), using at least one drug regularly, and admitted for a follow-up stay at Sunnaas Rehabilitation Hospital were included. Participants were interviewed about their drug regimen and filled out validated self-report questionnaires: Morisky Medication Adherence Scale (MMAS-8), beliefs about medicines questionnaire (BMQ), visual analogue scale (VAS) for pain and modified Penn spasm frequency scale (mPSFS).Results:The 105 participants used in average 4.2 drugs regularly (range, 1–15), and 70% reported high or moderate adherence to their treatment. Of the 39 participants using oral spasmolytics, 74% reported high or moderate adherence to these drugs. A total of 97% of the participants reported high perceptions of necessity to their treatment and 54% reported a high level of concern.Conclusion:The persons with SCI included in this study used in average the same number of regular drugs compared to persons with other chronic conditions. Regardless of high overall adherence, the participants were more concerned about their medicines compared to other patient groups. Further studies are required for understanding adherence and attitudes toward medicines in this population, especially to help the persons with chronic SCI feel safe about their drug regimen.

Interdisciplinary collaboration across secondary and primary care to improve medication safety in the elderly (IMMENSE study): study protocol for a randomised controlled trial

Introduction Drug-related problems (DRPs) are common in the elderly, leading to suboptimal therapy, hospitalisations and increased mortality. The integrated medicines management (IMM) model is a multifactorial interdisciplinary methodology aiming to optimise individual medication therapy throughout the hospital stay. IMM has been shown to reduce readmissions and drug-related hospital readmissions. Using the IMM model as a template, we have designed an intervention aiming both to improve medication safety in hospitals, and communication across the secondary and primary care interface. This paper presents the study protocol to explore the effects of the intervention with regard to healthcare use, health-related quality of life (HRQoL) and medication appropriateness in elderly patients. Methods and analysis A total of 500 patients aged ≥70 years will be included and randomised to control (standard care) or intervention group (1:1). The intervention comprises five steps mainly performed by pharmacists: (1) medication reconciliation at admission, (2) medication review during hospital stay, (3) patient counselling about the use of medicines, (4) a comprehensible and patient-friendly medication list with explanations in discharge summary and (5) postdischarge phone calls to the primary care level. The primary outcome is the difference between intervention and control patients in the rate of emergency medical visits (acute readmissions and visits to emergency department) 12 months after discharge. Secondary outcomes include length of index hospital stay, time to first readmission, mortality, hip fractures, strokes, medication changes, HRQoL and medication appropriateness. Patient inclusion started in September 2016. Ethics and dissemination The trial was approved by the Norwegian Centre for Research Data and the Norwegian Data Protection Authority. We aim to publish the results in international peer-reviewed open access journals, at national and international conferences, and as part of two PhD theses. Trial registration number NCT02816086.