Exposure of the Swiss population by medical x-rays: 2008 review.

Nationwide surveys on radiation dose to the population from medical radiology are recommended in order to follow the trends in population exposure and ensure radiation protection. The last survey in Switzerland was conducted in 1998, and the annual effective dose from medical radiology was estimated to be 1 mSv y(-1) per capita. The purpose of this work was to follow the trends in diagnostic radiology between 1998 and 2008 in Switzerland and determine the contribution of different modalities and types of examinations to the collective effective dose from medical x-rays. For this reason, an online database (www.raddose.ch) was developed. All healthcare providers who hold a license to run an x-ray unit in the country were invited to participate in the survey. More than 225 examinations, covering eight radiological modalities, were included in the survey. The average effective dose for each examination was reassessed. Data from about 3,500 users were collected (42% response rate). The survey showed that the annual effective dose was 1.2 mSv/capita in 2008. The most frequent examinations are conventional and dental radiographies (88%). The contribution of computed tomography was only 6% in terms of examination frequency but 68% in terms of effective dose. The comparison with other countries showed that the effective dose per capita in Switzerland was in the same range as in other countries with similar healthcare systems, although the annual number of examinations performed in Switzerland was higher.

Dose-dependent positive association between cigarette smoking, abdominal obesity and body fat: cross-sectional data from a population-based survey.

ABSTRACT: BACKGROUND: Although smokers tend to have a lower body-mass index than non-smokers, smoking may favour abdominal body fat accumulation. To our knowledge, no population-based studies have assessed the relationship between smoking and body fat composition. We assessed the association between cigarette smoking and waist circumference, body fat, and body-mass index. METHODS: Height, weight, and waist circumference were measured among 6,123 Caucasians (ages 35-75) from a cross-sectional population-based study in Switzerland. Abdominal obesity was defined as waist circumference>=102 cm for men and >=88 cm for women. Body fat (percent total body weight) was measured by electrical bioimpedance. Age- and sex-specific body fat cut-offs were used to define excess body fat. Cigarettes smoked per day were assessed by self-administered questionnaire. Age-adjusted means and odds ratios were calculated using linear and logistic regression. RESULTS: Current smokers (29% of men and 24% of women) had lower mean waist circumference, body fat percentage, and body-mass index compared with non-smokers. Age-adjusted mean waist circumference and body fat increased with cigarettes smoked per day among smokers. The association between cigarettes smoked per day and body-mass index was non-significant. Compared with light smokers, the adjusted odds ratio (OR) for abdominal obesity in men was 1.28 (0.78-2.10) for moderate smokers and 1.94 (1.15-3.27) for heavy smokers (P=0.03 for trend), and 1.07 (0.72-1.58) and 2.15 (1.26-3.64) in female moderate and heavy smokers, respectively (P<0.01 for trend). Compared with light smokers, the OR for excess body fat in men was 1.05 (95% CI: 0.58-1.92) for moderate smokers and 1.15 (0.60-2.20) for heavy smokers (P=0.75 for trend) and 1.34 (0.89-2.00) and 2.11 (1.25-3.57), respectively in women (P=0.07 for trend). CONCLUSION: Among smokers, cigarettes smoked per day were positively associated with central fat accumulation, particularly in women.

A single high dose of oral vitamin D3 is insufficient to correct a deficiency in a rheumatologic population

Introduction Vitamin D plays a major role in bone metabolismand neuromuscular function. Supplementation with vitamin D iseffective to reduce the risk of fall and of fracture. However adherenceto oral daily vitamin D is low. Screening and correcting vitamin Dinsufficiency in a rheumatologic population could improve bothmorbidity and quality of life. After determining the prevalence ofvitamin D deficiency in this population, we evaluated if supplementationwith a single high dose of oral 25-OH vitamin D3 wassufficient to correct this abnormality.Methods During one month (November 2009), levels of 25-OHvitamin D were systematically determined in our rheumatology outpatientclinic and classified in: vitamin D deficiency (< 10 μg/l),vitamin D insufficiency (10 to 30 μg/l) or normal vitamin D (> 30 μg/l).Patients with insufficiency or deficiency received respectively a singlehigh dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition,all patients with osteoporosis were prescribed daily supplement ofcalcium (1 g) and vitamin D (800 IU). 25-OH vitamin D levels werereevaluated after 3 months.Results Vitamin D levels were initially determined in 292 patients(mean age 53, 211 women, 87 % Caucasian). 77 % had inflammatoryrheumatologic disease (IRD), 20 % osteoporosis (OP) and 12 %degenerative disease (DD). Vitamin D deficiency was present in 20(6.8 %), while 225 (77.1 %) had insufficiency. Of the 245 patientswith levels < 30μg/l, a new determination of vitamin D level wasavailable in 173 (71 %) at 3 months.Conclusion Vitamin D insufficiency is highly prevalent in ourrheumatologic population (84 %), and is not adequately correctedby a single high dose of oral vitamin D3 in > 50 % of the patientswith IRD and DD. In patients with OP, despite association of asingle high dose with daily oral vitamin D supplementation, 40 %of patients are still deficient when reevaluated at 3 months.

A Single High Dose of Oral Vitamin D3 Is Not Enough to Correct Insufficiency and Deficiency in a Rheumatologic Population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 μg/l), vitamin D insufficiency (10 to 30 μg/l) or normal vitamin D (>30 μg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300000 IU or 600000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1 g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30 μg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months. Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

A single high dose of oral Vitamin D3 is not enough to correct insufficiency and deficiency in a rheumatologic population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 µg/l), vitamin D insufficiency (10 to 30µg/l) or normal vitamin D (>30 µg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30µg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months (table 1). Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

How High Dose(s) of Oral Vitamin D3 Can Correct Insufficiency in a Non Supplemented Rheumatologic Population ?

Introduction: 700 to 1000 UI Vitamin D/day prevent 20% of fall and fracture. Higher dosage could prevent other health problems, such as immune diseases. Adherence to oral daily vitamin D supplementation is low. There is no guideline on how to supplement patients with rheumatic diseases. We evaluated if 1-2 dose(s) of 300'000 UI oral vitamin D3 was enough to reach an optimal level of 25-OH vitamin D in late winter in patients with insufficiency. Methods: During November 2009 (M0) patients attending our Rheumatology Outpatient Clinic had a blood test to measure 25-OH vitamin D. Results were classified as: deficiency <10µg/l, insufficiency 10µg/l to 30µg/l and normal >30µg/l. Patients on daily oral vitamin D3 or who received a single high dose of vitamin D3 in the last 6 months and patients with deficiency or normal results were excluded. Patients included received a single dose of 300'000 IU of oral vitamin D3 and were asked to come back for a blood test for 25-OH vitamin D after 3 (M3) and 6 months (M6). If they were still insufficient at M3, they received a second high dose of 300'000 IU of oral vitamin D3. Results: 292 patients had their level of 25-OH vitamin D determined at M0. 141 patients (70% women) had vitamin D insufficiency (18.5µg/l (10.2-29.1)) and received a prescription for a single dose of 300'000 IU of oral vitamin D3. Men and women were not statistically different in term of age and 25-OH vitamin D level at M0. 124/141 (88%) patients had a blood test at M3. 2/124 (2%) had deficiency (8.1µg/l (7.5-8.7)), 50/124 (40%) normal results (36.7µg/l (30.5-56.5)). 58% (72/124) were insufficient (23.6µg/l (13.8-29.8)) and received a second prescription for 300'000 IU of oral vitamin D3. Of the 50/124 patients who had normal results at M3 and did not receive a second prescription, 36 (72%) had a test at M6. 47% (17/36) had normal results (34.8µg/l (30.3-42.8)), 53% (19/36) were insufficient (25.6µg/l (15.2-29.9)). Out of the 54/72 (75%) patients who received a second prescription, 28/54 (52%) had insufficiency (23.2µg/l (12.8-28.7)) and 26/54 (48%) had normal results (33.8µg/l (30.0-43.7)) at M 6. Discussion: This real life study has shown that one or two oral bolus of 300'000 IU of vitamin D3 in autumn and winter was not enough to completely correct hypovitaminosis D but was a good way of preventing a nadir of 25-OH vitamin D usually observed in spring in a Swiss rheumatologic population.

Cytokines and hs-CRP levels in individuals treated with low-dose aspirin for cardiovascular prevention: a population-based study (CoLaus Study).

Pro-inflammatory cytokines and high-sensitive C-reactive protein (hs-CRP) are associated with increased risk for cardiovascular disease. Low-dose aspirin for CV prevention is reported to have anti-inflammatory effects. The aim of this study was to determine the association between pro-inflammatory cytokines and hs-CRP levels and low-dose aspirin use for cardiovascular prevention in a population-based cohort (CoLaus Study). We assessed blood samples in 6085 participants (3201 women) aged 35-75years. Medications' use and indications were recorded. Among aspirin users (n=1'034; 17%), overall low-dose users (351; 5.8%) and low-dose for cardiovascular prevention users (324; 5.3%) were selected for analysis. Pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α were assessed by a multiplex particle-based flow cytometric assay and hs-CRP by an immunometric assay. Cytokines and hs-CRP were presented in quartiles. Multivariate analysis adjusting for sex, age, smoking status, body mass index, diabetes mellitus and immunomodulatory drugs showed no association between cytokines and hs-CRP levels and low-dose aspirin use for cardiovascular prevention, either comparing the topmost vs. the three other quartiles (OR 95% CI, 0.84 (0.59-1.18), 1.03 (0.78-1.32), 1.10 (0.83-1.46), 1.00 (0.67-1.69) for IL-1β, IL-6, TNF-α and hs-CRP, respectively), or comparing the topmost quartile vs. the first one (OR 95% CI, 0.87 (0.60-1.26), 1.19 (0.79-1.79), 1.26 (0.86-1.84), 1.06 (0.67-1.69)). Low-dose aspirin use for cardiovascular prevention does not impact plasma pro-inflammatory cytokine and hs-CRP levels in a population-based cohort.

Area-under-the-curve monitoring of prednisolone for dose optimization in a stable renal transplant population

Background: Renal transplant recipients were noted to appear cushingoid while on low doses of steroid as part of a triple therapy immunosuppression of cyclosporin A (CsA), prednisolone, and azathioprine. Methods: The study group comprised adult renal transplant recipients with stable graft function who had received their renal allograft a minimum of 1 year previously (43 studies undertaken in 22 men and 20 women) with median daily prednisone dose of 7 mg (range 3-10). The control group was healthy nontransplant subjects [median dose 10 mg (10-30)]. Prednisolone bioavailability was measured using a limited 6-hour area under the curve (AUC), with prednisolone measured using specific HPLC assay. Results: The median prednisolone AUC/mg dose for all transplant recipients was significantly greater than the control group by approximately 50% (316 nmol(.)h/L/mg prednisolone versus 218). AUC was significantly higher in female recipients (median 415 versus 297 for men) and in recipients receiving cyclospotin (348 versus 285). The highest AUC was in women on estrogen supplements who were receiving cyclosporin (median 595). A significantly higher proportion of patients on triple therapy had steroid side effects compared with those on steroid and azathioprine (17/27 versus 4/15), more women than men had side effects (14/16 versus 7/22), and the AUC/mg prednisone was greater in those with side effects than without (median 377 versus 288 nmol-h/L/mg). Discussion: The results are consistent with the hypothesis that CsA increases the bioavailability of prednisolone, most likely through inhibition of beta-glycoprotein. The increased exposure to steroid increased the side-effect profile of steroids in the majority of patients. Because the major contributor to AUC is the maximum postdose concentration, it may be possible to use single-point monitoring (2 hours postdose) for routine clinical studies.

Population pharmacokinetics of single-dose intravenous paracetamol in children

Background To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children ≤15 yr of age. Methods After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3% at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM. Results One hundred and fifty-nine blood samples from 33 children aged 1.8–15 yr, weight 13.7–56 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V1 (central volume of distribution), Q (inter-compartmental clearance), and V2 (peripheral volume of distribution) were: 16.51×(WT/70)0.75, 28.4×(WT/70), 11.32×(WT/70)0.75, and 13.26×(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V1 and V2 in litres). Conclusions In children aged 1.8–15 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V1, V2).

Bioequivalence and pharmacokinetics of two zidovudine formulations in healthy Brazilian volunteers: An open-label, randomized, single-dose, two-way crossover study

Background: Zidovudine is a thymidine nucleoside reverse transcriptase inhibitor with activity against HIV type 1. Some (similar to 8) generic formulations of zidovudine are available in Brazil; however, based on a literature search, information concerning their bioavailability and pharmacokinetic properties in the Brazilian population has not been reported. Objective: The aim of this study was to compare the bioavailability and pharmacokinetic properties of 2 capsule formulations of zidovudine 100 mg in healthy Brazilian volunteers. Methods: This open-label, randomized, 2-way crossover study utilized a 1-week washout period between doses. Blood samples were collected for 8 hours after a single dose of zidovudine 100-mg test (Zidovudina, Fundaqdo para o Remedio Popular, Sao Paulo, Brazil) or reference formulation (Retrovir (R), GlaxoSmithKline, Philadelphia, Pennsylvania). Plasma zidovudine concentrations were determined using a validated high-performance liquid chromatography method with ultraviolet detection at 265 nm. C-max, T-max, AUC(0-t), AUC(0-infinity), t(1/2), and the elimination constant (k(e)) were determined using noncompartmental analysis. The formulations were considered bioequivalent if the 90% CIS for C-max, AUC(0-t), and AUC(0-infinity) fell within the interval of 80 % to 125 %, the regulatory definition set by the US Food and Drug Administration (FDA). Results: Twenty-four healthy volunteers (12 males, 12 females; mean age, 27 years; weight, 60 kg; height, 167 cm) were enrolled and completed the study. The 90% CIs of the treatment ratios for the logarithmic-transformed values of C-max, AUC(0-t), and AUC(0-infinity) were 80.0% to 113.6%, 93.9% to 109.7%, and 93.6% to 110.1 %, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition intervals of 80% to 125%. Conclusions: In this small study in healthy subjects, no statistically significant differences in C-max, AUC(0-t), and AUC(0-)infinity were found between the test and reference formulations of zidovudine 100-mg capsules. The 90% CIs for the mean ratio values for the test and reference formulations of AUC(0-t), AUC(0-infinity), and C-max indicated that the reported data were entirely within the bioequivalence acceptance range proposed by the FDA of 80% to 125% (using log-transformed data).

Effect of metabolic inhibitors on cyclosporine pharmacokinetics using a population approach

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Css(trough)) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Css(tough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) ratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered concomitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.

The anti-tumor activity of IL-12: Mechanisms of innate immunity that are model and dose dependent

IL-12 has been demonstrated to have potent anti-tumor activities in a variety of mouse tumor models, but the relative roles of NK, NKT, and T cells and their effector mechanisms in these responses have not been fully addressed. Using a spectrum of gene-targeted or Ab-treated mice we have shown that for any particular tumor model the effector mechanisms downstream of IL-12 often mimic the natural immune response to that tumor. For example, metastasis of the MHC class I-deficient lymphoma, EL4-S3, was strictly controlled by NK cells using perforin either naturally or following therapy with high-dose IL-12. Intriguingly, in B16F10 and RM-1 tumor models both NK and NKT cells contribute to natural protection from tumor metastasis, In these models, a lower dose of IL-12 or delayed administration of IL-12 dictated a greater relative role of NKT cells in immune protection from tumor metastasis. Overall, both NK and NKT cells can contribute to natural and IL-12-induced immunity against tumors, and the relative role of each population is turner and therapy dependent.