Thirty‐two healthy volunteers with different SLCO1B1 genotypes ingested a 20 mg dose of atorvastatin and 10 mg dose of rosuvastatin with a washout period of 1 week. Subjects with the SLCO1B1 c.521CC ...genotype (n=4) had a 144% (P<0.001) or 61% (P=0.049) greater mean area under the plasma atorvastatin concentration–time curve from 0 to 48 h (AUC0–48 h) than those with the c.521TT (n=16) or c.521TC (n=12) genotype, respectively. The AUC0–48 h of 2‐hydroxyatorvastatin was 100% greater in subjects with the c.521CC genotype than in those with the c.521TT genotype (P=0.018). Rosuvastatin AUC0–48 h and peak plasma concentration (Cmax) were 65% (P=0.002) and 79% (P=0.003) higher in subjects with the c.521CC genotype than in those with the c.521TT genotype. These results indicate that, unexpectedly, SLCO1B1 polymorphism has a larger effect on the AUC of atorvastatin than on the more hydrophilic rosuvastatin.
Clinical Pharmacology & Therapeutics (2007) 82, 726–733. doi:10.1038/sj.clpt.6100220; published online 2 May 2007
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Acetaminophen is a widely used analgesic antipyretic agent. When used at low doses, it is a safe drug, but at higher doses it can cause acute hepatic necrosis in humans and experimental animals. The ...key mechanism in the hepatotoxicity is cytochrome P450 (CYP)-catalysed formation of the reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) that is capable of binding to cellular macromolecules and in that way an LC/MS liquid chromatography/mass spectrometry (LC/MS) method was developed to measure NAPQI formation by trapping it to reduced glutathione. This method was used to determine the bioactivation of acetaminophen at two concentrations: 50 μM therapeutic and 1 mM toxic by using nine human recombinant CYP enzymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4; and with different microsomes from experimental animals. At the toxic concentration the formation of NAPQI-glutathione was highest with CYP3A4 followed by CYP2E1, CYP1A2, and CYP2D6. At the therapeutic concentration, CYP3A4 had also the highest bioactivation capacity. In a comparison of the enzyme kinetics, CYP3A4 was the most efficient CYP with the lowest Km value 130 μM (95% confidence interval = 63-210 μM). Dexamethasone-induced rat liver microsomes had the most effective bioactivation capacity at therapeutic and toxic acetaminophen concentrations. This study suggests that CYP3A4 is the major CYP enzyme form catalysing acetaminophen oxidation to NAPQI in human liver.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Pregnant mothers are exposed to a wide variety of foreign chemicals. This exposure is most commonly due to maternal medication, lifestyle factors, such as smoking, drug abuse, and alcohol ...consumption, or occupational and environmental sources. Foreign compounds may interfere with placental functions at many levels e.g. signaling, production and release of hormones and enzymes, transport of nutrients and waste products, implantation, cellular growth and maturation, and finally, at the terminal phase of placental life, i.e. delivery. Placental responses may also be due to pharmaco-/toxicodynamic responses to foreign chemicals, e.g. hypoxia. On the other hand, placental xenobiotic-metabolizing enzymes can detoxify or activate foreign chemicals, and transporters either enhance or prevent cellular accumulation and transfer across the placenta. The understanding of what xenobiotics do to the placenta and what the placenta does to the xenobiotics should provide the basis for the use of placenta as a tool to investigate and predict some aspects of developmental toxicity.
This review aims to give an update of the fate and behavior of xenobiotics in the placenta from the viewpoint of xenobiotic-metabolizing enzymes and transporters. Their response levels will be described according to gestational status and methods used. The effects of foreign chemicals on placental metabolizing enzymes will be discussed. Also, interactions in the transporter protein level will be covered. The role of the placenta in contributing to developmental effects and fetotoxicity will be examined. The toxicological effects of maternal medications, smoking, and environmental exposures (dioxins, pesticides) as well as some possibilities for biomonitoring will be highlighted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Background
The occupational well-being (OW) of educators can be defined as a balance between resources and workload factors as seen from four aspects of working life: (i) individual, (ii) ...working conditions, (iii) professional competence and (iv) work community. The research in this study examined the individual aspect as particular importance to the physical and mental workability of educators.
Aims
To study the individual aspect of the OW of educators as well as the associating factors.
Methods
A cross-sectional survey design was conducted among educators working in health and social care education in Finland. The data were collected with an electronic survey using the ‘Occupational well-being of social and health care teachers—index questionnaire’. The data were analysed with an SPSS version 27 using descriptive statistics, explorative factor analysis and linear regression analysis.
Results
The educators (n = 552, response rate 31%) assessed their resources for managing their mental workload as quite poor (2.41, standard deviation SD 0.98). In addition, workplace support promoting OW was assessed as being quite poor (2.37, SD 0.88), and as especially requiring more measures during working hours. Associations with the individual aspect of OW were found between the personal and work-related background variables as well as overall OW.
Conclusions
The perceptions of the educators indicated that resources to cope with workload factors should be promoted. Investing in educators’ resources at work, enabling well-being actions during working hours and avoiding backlog situations would all help promote the educators’ OW.
Context. Photometric monitoring of active galactic nuclei is often complicated by the presence of a strong host galaxy component, which adds unwanted flux to the measurement and introduces a ...seeing-dependence to the flux that can plaque e.g. microvariability studies. We are currently monitoring a sample of 24 TeV candidate BL Lacertae objects, many of which exhibit a prominent host galaxy component, using differential aperture photometry. Aims. In order to study our light curves free from the above effects, we have derived the host galaxy flux in differential aperture photometry as a function of aperture radius and FWHM for 20 resolved sources in our sample. Methods. We created accurate surface brightness models of the targets and any significant nearby sources using high-resolution R-band imaging obtained at the Nordic Optical Telescope (NOT) and performed differential aperture photometry of the models over a grid of aperture radii and FWHM values. Results. The results are given as correction tables, that list the fluxes (in mJy) of all “contaminating” sources (host galaxy + significant nearby objects) as a function of aperture radius and FWHM. We found that the derived fluxes depend strongly on aperture radius, but the FWHM has only a minor effect (a few percent). We also discuss the implications of our findings to optical monitoring programs and potential sources of error in our derived fluxes. During this work we have also constructed new calibration star sequences for 9 objects and present the finding charts and calibrated magnitudes.
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FMFMET, NUK, UL, UM, UPUK
To investigate whether a 6-month neuromuscular warm-up programme could improve muscle power, balance, speed and agility.
Cluster randomised controlled study.
27 top level female floorball teams in ...Finland.
222 players (mean age 24 years); 119 in the intervention group and 103 in the control group were followed-up for one league season (6 months).
A neuromuscular warm-up programme included sports-specific running technique, balance, jumping and strengthening exercises. The teams were advised to use the programme 1-3 times per week through the league season. One training session took approximately 25 min.
Performance tests were assessed before and after the 6-month intervention and included static jump, countermovement jump, jumping over a bar, standing on a bar and figure-of-eight running.
At 6 months, significant between-group differences were found in two outcome measures: jumping over a bar (number of jumps in 15 s) and standing on a bar (number of balance losses in 60 s). These differences were 2.3 jumps (95% CI 0.8 to 3.8, p = 0.003), favouring the intervention group, and -0.4 balance losses (95% CI -0.8 to 0.0, p = 0.050), again in favour of the intervention group.
A neuromuscular warm-up programme improved the floorball players' sideways jumping speed and static balance. The exercises were also safe to perform and can thus be recommended for weekly training of floorball players.
ISRCTN26550281.
Summary
This study showed that the prevalence of sarcopenia (low muscle mass and performance) among 70–80-year-old home-dwelling Finnish women is very low, while every third woman has WHO-based ...osteopenia (low bone mass). Muscle mass and derived indices of sarcopenia were not significantly related to measures of functional ability.
Introduction
This study aims to determine the prevalence of sarcopenia and osteopenia among four hundred nine 70–80-year-old independently living Finnish women. The study compared consensus diagnostic criteria for age-related sarcopenia recently published by the European Working Group on Sarcopenia in Older People (EWGSOP) and the International Working Group on Sarcopenia (IWG) and assessed their associations with functional ability.
Methods
Femoral bone mineral density and body composition were measured with dual-energy X-ray absorptiometry. Skeletal muscle mass index (SMI), gait speed, and handgrip strength were used for sarcopenia diagnosis. Independent samples
t
tests determined group differences in body composition and functional ability according to recommended diagnostic cutpoints. Scatter plots were used to illustrate the correlations between the outcome measures used for diagnosis.
Results
Prevalence of sarcopenia was 0.9 and 2.7 % according to the EWGSOP and IWG, respectively. Thirty-six percent of the women had WHO-based osteopenia. Women with higher gait speed had significantly lower body weight and fat mass percentage, higher lean mass percentage, and better functional ability. Women with a low SMI weighed significantly less, with no significant differences in other outcome measures. SMI, gait speed, and grip strength were significantly correlated.
Conclusions
Our study suggests that when using consensus definitions, sarcopenia is infrequent among older home-dwelling women while every third woman has osteopenia. In clinical practice, attention should be paid to the decline in functional ability rather than focusing on low muscle mass alone.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
Pravastatin is a hydrophilic substrate and fluvastatin a lipophilic substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 encoded by SLCO1B1. Our aim was to ...compare the effects of SLCO1B1 polymorphism on the pharmacokinetics of pravastatin and fluvastatin.
Methods
We recruited 4 healthy volunteers (3 men and 1 woman) with the homozygous SLCO1B1 c.521CC genotype, 12 (7 men and 5 women) with the heterozygous c.521TC genotype, and 16 (8 men and 8 women) with the homozygous c.521TT genotype (control subjects). In a crossover study each subject ingested a single 40‐mg dose of fluvastatin and pravastatin with a washout period of at least 1 week. Plasma fluvastatin and pravastatin concentrations were measured for 12 hours.
Results
In men with the c.521CC genotype, the mean peak concentration in plasma and area under the plasma concentration‐time curve from time 0 to infinity of pravastatin were 274% (95% confidence interval CI, 92%‐456%; P = .001) and 232% (95% CI, 74%‐391%; P = .002) greater than those in men with the c.521TT genotype and 120% (95% CI, 11%‐230%; P = .026) and 102% (95% CI, 3%‐200%; P = .040) greater than those in men with the c.521TC genotype. In addition, women with the c.521TT genotype had a 147% (95% CI, 12%‐281%; P = .028) greater peak concentration in plasma and a 142% (95% CI, 7%‐242%; P = .034) greater area under the plasma concentration‐time curve from time 0 to infinity than men with the c.521TT genotype. The pharmacokinetic variables of pravastatin were approximately similar among women with different SLCO1B1 genotypes. No significant differences were seen in the pharmacokinetics of fluvastatin between subjects with different SLCO1B1 genotypes or between the sexes.
Conclusions
SLCO1B1 polymorphism has a large effect on the pharmacokinetics of pravastatin but not fluvastatin. This suggests that the lipophilic fluvastatin can penetrate the hepatocyte plasma membrane via passive diffusion or that uptake transporters other than organic anion transporting polypeptide 1B1 mainly mediate its hepatic uptake. Moreover, the results suggest that sex may affect the pharmacokinetics of pravastatin and possibly the functional consequences of SLCO1B1 polymorphism.
Clinical Pharmacology & Therapeutics (2006) 80, 356–366; doi: 10.1016/j.clpt.2006.06.010
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To investigate whether individual counselling on diet and physical activity during pregnancy can have positive effects on diet and leisure time physical activity (LTPA) and prevent excessive ...gestational weight gain.
A controlled trial.
Six maternity clinics in primary health care in Finland. The clinics were selected into three intervention and three control clinics.
Of the 132 pregnant primiparas, recruited by 15 public health nurses (PHN), 105 completed the study.
The intervention included individual counselling on diet and LTPA during five routine visits to a PHN until 37 weeks' gestation; the controls received the standard maternity care.
The counselling did not affect the proportion of primiparas exceeding the weight gain recommendations or total LTPA when adjusted for confounders. The adjusted proportion of high-fibre bread of the total weekly amount of bread decreased more in the control group than in the intervention group (difference 11.8%-units, 95% confidence interval (CI) 0.6-23.1, P=0.04). The adjusted intake of vegetables, fruit and berries increased by 0.8 portions/day (95% CI 0.3-1.4, P=0.004) and dietary fibre by 3.6 g/day (95% CI 1.0-6.1, P=0.007) more in the intervention group than in the control group. There were no high birth weight babies (>or=4000 g) in the intervention group, but eight (15%) of them in the control group (P=0.006).
The counselling helped pregnant women to maintain the proportion of high-fibre bread and to increase vegetable, fruit and fibre intakes, but was unable to prevent excessive gestational weight gain.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
One major challenge in drug development is defining of the optimal animal species to serve as a model of metabolism in man. The study compared the hepatic drug metabolism characteristics of humans ...and six widely used experimental animal species. Classical in vitro model enzyme assays with known human cytochrome P450 (CYP) enzyme selectivity were employed and optimized to target human hepatic CYP forms. The profile of CYP activities best resembling the human was seen in mouse followed by monkey, minipig, and dog liver microsomes, with rats displaying the most divergent. The widest interindividual variability was found in CYP3A-mediated midazolam α-hydroxylase, and omeprazole sulphoxidase activities in human and monkey liver microsomes. These data demonstrate that if hepatic xenobiotic-metabolizing characteristics were to be the sole reason for the selection of animal species for toxicity studies, then the rat might not be the most appropriate model to mimic human CYP activity patterns.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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