The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific ...impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown. In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes. This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N-acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults. Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology.
Individuals with lower socioeconomic status are at increased risk of involuntary exit from paid employment. To give sound advice for primary prevention in the workforce, insight is needed into the ...role of mediating factors between socioeconomic status and labour force participation. Therefore, it is aimed to investigate the influence of health status, lifestyle-related factors and work characteristics on educational differences in exit from paid employment.
14,708 Dutch employees participated in a ten-year follow-up study during 1999-2008. At baseline, education, self-perceived health, lifestyle (smoking, alcohol, sports, BMI) and psychosocial (demands, control, rewards) and physical work characteristics were measured by questionnaire. Employment status was ascertained monthly based on tax records. The relation between education, health, lifestyle, work-characteristics and exit from paid employment through disability benefits, unemployment, early retirement and economic inactivity was investigated by competing risks regression analyses. The mediating effects of these factors on educational differences in exit from paid employment were tested using a stepwise approach.
Lower educated workers were more likely to exit paid employment through disability benefits (SHR:1.84), unemployment (SHR:1.74), and economic inactivity (SHR:1.53) but not due to early retirement (SHR:0.92). Poor or moderate health, an unhealthy lifestyle, and unfavourable work characteristics were associated with disability benefits and unemployment, and an unhealthy lifestyle with economic inactivity. Educational differences in disability benefits were explained for 40% by health, 31% by lifestyle, and 12% by work characteristics. For economic inactivity and unemployment, up to 14% and 21% of the educational differences could be explained, particularly by lifestyle-related factors.
There are educational differences in exit from paid employment, which are partly mediated by health, lifestyle and work characteristics, particularly for disability benefits. Health promotion and improving working conditions seem important measures to maintain a productive workforce, particularly among workers with a low education.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To investigate whether work engagement influences self-perceived health, work ability, and sickness absence beyond health behaviors and work-related characteristics.
METHODS:Employees of ...two organizations participated in a 6-month longitudinal study (n = 733). Using questionnaires, information was collected on health behaviors, work-related characteristics, and work engagement at baseline, and self-perceived health, work ability, and sickness absence at 6-month follow-up. Associations between baseline and follow-up variables were studied using multivariate and multinomial logistic regression analyses and changes in R were calculated.
RESULTS:Low work engagement was related with low work ability (odds ratio3.68; 95% confidence interval2.15 to 6.30) and long-term sickness absence (odds ratio1.84; 95% confidence interval1.04 to 3.27). Work engagement increased the explained variance in work ability and sickness absence with 4.1% and 0.5%, respectively.
CONCLUSIONS:Work engagement contributes to work ability beyond known health behaviors and work-related characteristics.
Aim
In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and ...obese adolescents.
Methods
Overweight (BMI for age ≥ 85th percentile) and obese (BMI for age ≥ 95th percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre‐operatively. Blood samples were collected until 6 or 8 h post‐dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2.
Results
Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62–149.8 kg), a mean BMI of 36.1 kg m−2 (24.8–55 kg m−2), and a mean age of 15.9 years (range 12.5–18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min−1 (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess) instead of body weight related to growth (WTfor age and length).
Conclusions
The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.
Purpose
Bariatric surgery is nowadays commonly applied as treatment for morbid obesity (BMI > 40 kg/m
2
). As information about the effects of this procedure on a drug’s pharmacokinetics is limited, ...we aimed to evaluate the pharmacokinetics of CYP3A probe substrate midazolam after oral and intravenous administration in a cohort of morbidly obese patients that was studied before and 1 year post bariatric surgery.
Methods
Twenty morbidly obese patients (aged 26–58 years) undergoing bariatric surgery participated in the study of which 18 patients returned 1 year after surgery. At both occasions, patients received 7.5 mg oral and 5 mg intravenous midazolam separated by 160 ± 48 min. Per patient and occasion, a mean of 22 blood samples were collected. Midazolam concentrations were analyzed using population pharmacokinetic modeling.
Results
One year after bariatric surgery, systemic clearance of midazolam was higher 0.65 (7%)
versus
0.39 (11%) L/min, mean ± RSE (
P
< 0.01), respectively and mean oral transit time (MTT) was faster 23 (20%)
versus
51 (15%) minutes (
P
< 0.01), while oral bioavailability was unchanged (0.54 (9%)). Central and peripheral volumes of distribution were overall lower (
P
< 0.05).
Conclusions
In this cohort study in morbidly obese patients, systemic clearance was 1.7 times higher 1 year after bariatric surgery, which may potentially result from an increase in hepatic CYP3A activity per unit of liver weight. Although MTT was found to be faster, oral bioavailability remained unchanged, which considering the increased systemic clearance implies an increase in the fraction escaping intestinal first pass metabolism.
Abstract Objective To investigate associations between employees' health locus of control (HLOC) and self-perceived health, health behaviors, and participation in health promotion programs (HPPs) and ...the mediating effect of self-perceived health and health behaviors on the relation between HLOC and participation. Method Between 2010 and 2012, a six-month longitudinal study was conducted among 691 Dutch employees. Using questionnaires, information was collected on health behaviors, self-perceived health, HLOC, and intention to participate at baseline. Actual participation was assessed at follow-up. Logistic regression analyses were used to study associations between HLOC and self-perceived health, health behaviors, and participation, and to examine whether associations between HLOC and participation were mediated by self-perceived health and health behaviors. Results Higher internal HLOC was associated with sufficient physical activity (moderate: OR:1.04, 95%CI:1.00–1.08; vigorous: OR:1.05, 95%CI:1.01–1.10) and fruit and vegetable intake (OR:1.05, 95%CI:1.01–1.09), a good self-perceived health (OR:1.20, 95%CI:1.11–1.30), a positive intention towards participation (OR:1.05, 95%CI:1.00–1.09), and actual participation (OR:1.06, 95%CI:1.00–1.13). Self-perceived health or health behaviors did not mediate associations between HLOC and participation. Conclusion Employees with a higher internal HLOC behaved healthier and were more likely to participate in HPPs, irrespectively of their health. Increasing internal HLOC seems a promising avenue for improving employees' health and participation in HPPs.
Introduction
Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In ...obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients.
Methods
Twenty morbidly obese patients (with a median total body weight TBW of 140.1 kg range 106–193.1 kg and body mass index BMI of 45.1 kg/m
2
40–55.2 kg/m
2
) and eight non-obese patients (with a TBW of 69.4 kg 53.4–91.7 and BMI of 21.8 kg/m
2
19.4–27.4) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM.
Results
In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC
0–8h
) of acetaminophen was significantly smaller (
P
= 0.009), while the AUC
0–8h
ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (
P
= 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight LBW (population mean relative standard error 0.0185 L/min 15 %,
P
< 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (
P
< 0.001). Glucuronidation clearance (0.219 L/min 5 %) and sulphation clearance (0.0646 L/min 6 %) also increased with LBW (
P
< 0.001).
Conclusion
Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment.
BackgroundExposure to acetaminophen and its metabolites in very-preterm infants is partly unknown. We investigated the exposure to acetaminophen and its metabolites upon 10, 15, or 20 mg/kg ...intravenous acetaminophen in preterm infants.MethodsIn a randomized trial, 59 preterm infants (24-32 weeks' gestational age, postnatal age <1 week) received 10, 15, or 20 mg/kg acetaminophen intravenously. Plasma concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined in 293 blood samples. Area under the plasma concentration-time curves (AUC
) was related to dose and gestational age.ResultsBetween 10 and 20 mg/kg dose, median AUCs of acetaminophen, glucuronide, sulfate, and cysteine increased significantly resulting in unchanged ratios of AUC of metabolite to acetaminophen. The AUC ratio of glucuronide to acetaminophen increased with gestational age, that of sulfate decreased, and the ratio of cysteine and mercapturate remained unchanged.ConclusionWe found a gestational-age-dependent increase in glucuronidation but no evidence for saturation of a specific pathway as there was a proportional increase in exposure of acetaminophen and all metabolites. Compared with adults, very low exposure to glucuronide but higher exposure to sulfate, cysteine, and mercapturate metabolites was found, of which the relevance is not yet known.
Workplace Health Promotion Rongen, Anne, MSc; Robroek, Suzan J.W., PhD; van Lenthe, Frank J., PhD ...
American journal of preventive medicine,
April 2013, Letnik:
44, Številka:
4
Journal Article
Recenzirano
Context An unhealthy lifestyle may contribute to ill health, absence due to sickness, productivity loss at work, and reduced ability to work. Workplace health promotion programs (WHPPs) aim to ...improve lifestyle and consequently improve health, work ability, and work productivity. However, systematic reviews on intervention studies have reported small effects, and the overall evaluation of effectiveness of WHPPs is hampered by a large heterogeneity in interventions and study populations. This systematic review aims to investigate the influence of population, study and intervention characteristics, and study quality on the effectiveness of workplace health promotion programs. Evidence acquisition A systematic literature search was conducted identifying RCTs, published before June 2012, evaluating the effect of a WHPP aimed at smoking cessation, physical activity, healthy nutrition, and/or obesity on self-perceived health, work absence due to sickness, work productivity, or work ability. Studies were included in the meta-analyses if quantitative information was present to calculate an effect size (ES). A meta-analysis, stratified meta-analyses, and meta-regression analyses were performed in Spring 2012 using Comprehensive Meta-analysis software 2.0 and PAWS 17.0.2. Evidence synthesis In 18 studies describing 21 interventions, the overall effect of a WHPP was small (ES=0.24, 95% CI=0.14, 0.34). The effectiveness of a WHPP was larger in younger populations, in interventions with weekly contacts, and in studies in which the control group received no health promotion. A 2.6-fold lower effectiveness was observed for studies performing an intention-to-treat analysis and a 1.7-fold lower effectiveness for studies controlling for confounders. Studies of poor methodologic quality reported a 2.9-fold higher effect size of the WHPP. Conclusions The effectiveness of a WHPP is partly determined by intervention characteristics and statistical analysis. High-quality RCTs reported lower effect sizes. It is important to determine the effectiveness of WHPPs in RCTs of high quality.
Aim
To investigate how work‐related characteristics and work ability influence nursing staff decisions to change employer or leave the profession.
Background
Previous cross‐sectional studies have ...indicated that decreased work ability and unfavourable work‐related characteristics are important determinants for the intention to leave the profession among nursing staff.
Methods
A 1‐year longitudinal study, using data from the European Nurses' Early Exit Study. The study population consisted of 9927 (66%) members of the eligible nursing staff of which 345 left their current employer. Work‐related characteristics, work ability and employment status were assessed by questionnaires.
Results
Nursing staff with a low work ability were more likely to either change employer or leave the profession. Among nursing staff with a low work ability the risk of changing employer increased significantly with unfavourable work‐related characteristics. However, among nursing staff with a good work ability the risk of changing employer barely changed with unfavourable work‐related characteristics.
Conclusion
The negative effects of decreased work ability on changing employer and leaving the profession are partly counterbalanced by favourable psychological and physical work‐related characteristics.
Implications for nursing management
Managers should implement strategies that focus on promoting the work ability of nursing staff in combination with improving work‐related characteristics in order to prevent unnecessary changes of employment.
PDF
