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Background Currently, immunosuppression schemes are age-independent; however, physiological changes may alter drugs’ pharmacokinetics in the older population. We compared mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) pharmacokinetics among patients aged 60 years on the seventh day after renal transplantation. Methods We included 7 and 10 renal transplant recipients, aged >60 and Results In patients aged >60 years, mean MPA and MPAG concentrations before the next dose and ratio of MPAG area under the concentration-time curve (AUC0-12) to MPA AUC0-12 were higher by 1.6-fold, 1.4-fold, and 1.9-fold, respectively. Other MPAG concentrations appeared to be slightly higher (1.2- to 1.5-fold) in older patients. MPA apparent clearance was similar in both groups, whereas volume of distribution at steady state was slightly higher (1.6-fold) in patients aged >60 years. The variability of most MPA and some MPAG pharmacokinetics was greater in patients aged >60 years. The MPA AUC0-12 target was achieved in 40% and 14% of patients aged 60 years, respectively. The highest MPAG concentrations and AUC0-12 were observed for patients with the lowest glomerular filtration rate. Conclusions Higher variability of MPA and MPAG pharmacokinetic parameters, MPA AUC0-12 above the reference range, higher values of MPAG pharmacokinetics in patients with lower glomerular filtration rates, as well as lower proportion of patients achieving MPA targets all indicate the need for therapeutic drug monitoring in renal transplant recipients aged >60 years and to verify target MPA AUC0-12 for this population.

Limited sampling strategy (LSS) is a precise and relatively convenient therapeutic drug monitoring method. We evaluated LSSs for mycophenolic acid (MPA) in children with nephrotic syndrome treated with mycophenolic mofetil (MMF) and validated the LSSs using two different approaches. We measured MPA plasma concentrations in 31 children using HPLC-UV method and received 37 MPA pharmacokinetic profiles (0–12 h). For six children, MPA profiles were estimated twice after two MMF doses. LSSs were developed using multilinear regression with STATISTICA and R software and validated using validation group and bootstrap method, respectively. The best three time point equations included C1, C3, C6 (good guess 83%, bias − 2.78%; 95% confidence interval (CI) − 9.85–0.46); C1, C2, C6 (good guess 72%, bias 0.72%; 95% CI − 5.33–7.69); and C1, C2, C4 (good guess 72%, bias 2.05%; 95% CI − 4.92–13.01) for STATISTICA software. For R software, the best equations consisted of C1, C3, C6 (good guess 92%, bias − 2.69%; 95% CI − 27.18–33.75); C0, C1, C3 (good guess 84%, bias − 2.11%; 95% CI − 24.19–22.29); and C0, C1, C2 (good guess 84%, bias − 0.48%; 95% CI − 30.77–54.07). During validation, better results were obtained for R evaluations, i.e., bootstrap method. The most useful equations included C0, C1, C3 and C0, C1, C2 time points; however, the most precise included C1, C3, C6 time points because of MPA enterohepatic recirculation. Better results were obtained for bootstrap validation due to greater number of patients. Validated LSS should be used only in the population for which it was developed. As there is growing evidence that underexposure of MPA is associated with insufficient treatment response, we recommend the introduction of therapeutic drug monitoring for MPA in children with nephrotic syndrome.

Worldwide data indicate a growing number of energy homeostasis disorders, which are especially dangerous in childhood. The distribution and growing trends of overweight and obesity in children have been widely investigated, unlike the prevalence of too-low body weight and its determinants. This study aimed to estimate the frequency of body mass deficiency in Polish rural girls and differences among four Polish regions – Choszczno and Leszno in the north-west, and Ostrów Mazowiecka and Suwałki in the north-east. Data were taken from 7764 rural girls aged 9–18 years examined in 1987, when the country was in economic crisis, and 9431 such girls examined in 2001, when the country was undergoing political transformation. The frequency of weight deficiency was estimated based on BMI by applying the international standards of Cole. An Extent of Overweight (EOW) index was used to create an Extent of Thinness (EOT) index. A significant increase in weight deficiency was found in the rural girls – from 7.5% in 1987 to 8.9% in 2001 – and an increase in the EOT index from 0.37 in 1987 to 0.43 in 2001. Analysis by area of residence demonstrated significant differentiation. In the regions in north-west Poland, mainly inhabited by non-farming families, the prevalence of weight deficiency in girls almost doubled from 1987 to 2001, probably because of the mass and long-term unemployment that resulted from the closure of state farms in 1992. In contrast, in the north-east regions, the prevalence of weight deficiency remained almost unchanged over this period, with only a slight decrease, probably because the inhabitants were mainly farm and farm/working families with better living conditions. Despite the overall increase in thinness prevalence in rural girls in Poland, different living conditions have had different biological effects.

We evaluated mycophenolic acid (MPA) limited sampling strategies (LSSs) established using multiple linear regression (MLR) in children with nephrotic syndrome treated with mycophenolate mofetil (MMF). MLR-LSS is an easy-to-determine approach of therapeutic drug monitoring (TDM). We assessed the practicability of different LSSs for the estimation of MPA exposure as well as the optimal time points for MPA TDM. The literature search returned 29 studies dated 1998–2020. We applied 53 LSSs (n = 48 for MPA, n = 5 for free MPA [fMPA]) to predict the area under the time-concentration curve (AUCpred) in 24 children with nephrotic syndrome, for whom we previously determined MPA and fMPA concentrations, and compare the results with the determined AUC (AUCtotal). Nine equations met the requirements for bias and precision ±15%. The MPA AUC in children with nephrotic syndrome was predicted the best by four time-point LSSs developed for renal transplant recipients. Out of five LSSs evaluated for fMPA, none fulfilled the ±15% criteria for bias and precision probably due to very high percentage of bound MPA (99.64%). MPA LSS for children with nephrotic syndrome should include blood samples collected 1 h, 2 h and near the second MPA maximum concentration. MPA concentrations determined with the high performance liquid chromatography after multiplying by 1.175 may be used in LSSs based on MPA concentrations determined with the immunoassay technique. MPA LSS may facilitate TDM in the case of MMF, however, more studies on fMPA LSS are required for children with nephrotic syndrome.

Objective It is still unclear whether mycophenolic acid (MPA) doses should be adjusted for older patients. Therefore, we compared the pharmacokinetics of MPA, mycophenolic acid glucuronide (MPAG), and free MPA (fMPA) between older and younger renal transplant recipients. Methods We included 12 patients 60 years within the first year after renal transplantation, who were receiving enteric-coated mycophenolate sodium, tacrolimus, and steroids. Blood samples were collected up to 12 hours after drug administration. Results MPA and fMPA pharmacokinetics were similar for patients 60 years; however, the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) was 1.2-fold lower in the older patients. MPAG pharmacokinetics were more than 1.5-fold higher in patients >60 years, which might be related to deteriorated renal function in older people. Moreover, the mean (MPAG AUC0-12)/(MPA AUC0-12) ratio was more than 2-fold higher in patients >60 years. The second maximal MPA concentration was more frequently observed in patients 60 years had MPA AUC0-12 >30 μg·h/mL within 22 to 114 days after transplantation. Conclusions MPA therapeutic monitoring should be recommended in enteric-coated mycophenolate sodium--treated patients >60 years because MPA AUC0-12 exceeded the recommended value in half of the studied patients.

Activity of the enzyme thiopurine methyltransferase (TPMT) determines the anti-leukemic effect of thiopurines used in the chemotherapy of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). TPMT status and its effects on treatment outcome have been studied extensively in ALL and autoimmune disorders, but few data is available on TPMT in AML. The present study assessed the genetic polymorphisms and activity of TPMT in children with AML at different treatment stages, and compared the results with those obtained for children with ALL. The study included 33 children with AML (0.7–19.7 years) treated with 6-thioguanine (6-TG) according to the AML-BFM 2004 Protocol. Blood samples were collected at diagnosis, during and following maintenance chemotherapy from 8, 10 and 17 patients with AML (the assay was performed at two time points in 2 patients), respectively. Blood samples from 105 children with ALL were obtained at diagnosis, during the maintenance chemotherapy and following the cessation of the chemotherapy from 16, 55 and 34 children, respectively. The activity of TPMT in red blood cells lysates was measured using an enzymatic reaction based on the conversion of 6-mercaptopurine into 6-methylmercaptopurine, involving S-adenozyl-L-methionine as the methyl group donor. TPMT mutations were determined using a polymerase chain reaction/restriction fragment length polymorphism method. Median TPMT activity at diagnosis, during maintenance chemotherapy and following chemotherapy was 43.1, 47,3 and 41.7 nmol 6-mMP g−1 Hb h−1, respectively. All patients with AML exhibited the homozygous TPMT*1/*1 genotype, with the exception of 1, who was a heterozygote with the TPMT*1/*3C genotype and demonstrated a TPMT activity level at diagnosis of 42.5 nmol 6-mMP g−1 Hb h−1. At each chemotherapy stage, the median TPMT activities in children with AML were significantly increased compared with the median TPMT activities in children with ALL. The preliminary results suggest that the TPMT activity in AML may be increased compared with that in ALL. Comprehensive studies on the association between thiopurine metabolism and treatment outcome in AML are required, with regard to the cytogenetic and molecular factors currently used for AML risk stratification.

The aim of the study was to estimate target values of mycophenolate mofetil (MMF) pharmacokinetic parameters in children with proteinuric glomerulopathies by calculating the pharmacokinetic parameters of MMF metabolites (mycophenolic acid [MPA], free MPA [fMPA] and MPA glucuronide [MPAG]) and assessing their relation to proteinuria recurrence. One hundred and sixty-eight blood samples were collected from children, aged 3-18 years, diagnosed with nephrotic syndrome or lupus nephritis. MMF metabolites concentrations were examined before drug administration (Ctrough) and up to 12h afterward employing high-performance liquid chromatography. Dose-normalized MPA Ctrough and area under the concentration-time curve from 0 to 12h (AUC12) were within 0.29-6.47 μg/mL/600 mg/m(2) and 9.97-105.52 μg h/mL/600 mg/m(2), respectively. MPA Ctrough was twofold lower (p=0.024) in children with proteinuria recurrence. MPA, fMPA and MPAG concentrations correlated positively to respective AUC12. It may be suggested MMF metabolites monitoring in children with proteinuric glomerulopathies is justified by MPA Ctrough2 μg/mL in patients at risk of the proteinuria recurrence. Such a recurrence is most probably caused by not sufficient MPA concentration during proteinuric glomerulopathies treatment. MPA Ctrough3 μg/mL may be considered as an efficient one to avoid proteinuria recurrence. Finally, MPA target AUC12 should exceed 60 μg h/mL to ensure the safe and effective treatment in children with nephrotic syndrome, however, the upper limit is still to be established.

The impact of etoposide (VP-16) plasma concentrations on the day of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on leukemia-free survival in children with acute lymphoblastic leukemia (ALL) was studied. In addition, the in vitro effects of VP-16 on the lymphocytes proliferation, cytotoxic activity and on Th1/Th2 cytokine responses were assessed. In 31 children undergoing allo-HSCT, VP-16 plasma concentrations were determined up to 120 h after the infusion using the HPLC–UV method. For mentioned in vitro studies, VP-16 plasma concentrations observed on allo-HSCT day were used. In 84 % of children, VP-16 plasma concentrations (0.1–1.5 μg/mL) were quantifiable 72 h after the end of the drug infusion, i.e. when allo-HSCT should be performed. In 20 (65 %) children allo-HSCT was performed 4 days after the end of the drug infusion, and VP-16 was still detectable (0.1–0.9 μg/mL) in plasma of 12 (39 %) of them. Post-transplant ALL relapse occurred in four children, in all of them VP-16 was detectable in plasma (0.1–0.8 μg/mL) on allo-HSCT day, while there was no relapse in children with undetectable VP-16. In in vitro studies, VP-16 demonstrated impact on the proliferation activity of stimulated lymphocytes depending on its concentration and exposition time. The presence of VP-16 in plasma on allo-HSCT day may demonstrate an adverse effect on graft-versus-leukemia (GvL) reaction and increase the risk of post-transplant ALL relapse. Therefore, if 72 h after VP-16 administration its plasma concentration is still above 0.1 μg/mL then the postponement of transplantation for next 24 h should be considered to protect GvL effector cells from transplant material.

Measurement of body weight, height, waist and hip circumference is a standard procedure that allows to better define the risk of metabolic syndrome. The aim of the study is to determine the usefulness of anthropometric indicators such as BMI, WC (waist circumference), WHR, WHtR and percentage of body fat to predict the metabolic cardiovascular risk in the adult male population of Krakow, as well as an attempt to determine the metabolic cardiovascular risk with the original anthropometric risk index. The study included 405 men from the population working in the T. Sendzimir Steelworks in Kraków at the age of 30–69 years. Anthropometric measurements: body height measured to the nearest mm, circuits (waist, hips) measured to the nearest centimetre, the percentage of fat (the type of electronic scales Tanita BF 300) measured according to the standard protocol by the same technician and biomedical indicators assessing the functional status of organism, total cholesterol, HDL, LDL, triglycerides, glucose and blood pressure measured with a mercury manometer. As a measure of goodness of fit for the indices of risk (and their components), the AUC method was used for the ROC curves to evaluate the sensitivity and specificity of the diagnostic test. The results show that significant in predicting the risk of metabolic syndrome are not only standard anthropometric measurements specified in the standards of WHO, EGIR, NCEP and IDF. In addition, it is important to take into account the amount of fat and calculate the cumulative risk index based on all relevant measurements and indicators.

We assessed the relations between MPA, free MPA (fMPA) and MPA glucuronide (MPAG) pharmacokinetics and the clinical condition of renal transplant recipients treated with EC-MPS and tacrolimus (Tac) in the first post-transplant year. In 18 adult patients blood samples were collected up to 12 h after EC-MPS oral administration. EC-MPS metabolites’ plasma concentrations were determined using validated HPLC methods. All patients reached MPA area under the time–concentration curve (AUC0–12) above 30 µg h/mL. Most of the MPA, fMPA and all MPAG concentrations correlated significantly with respective AUC0–12 values. Some fMPA and all MPAG pharmacokinetic parameters correlated negatively with creatinine clearance and positively with creatinine concentration, whereas no such correlation was observed for MPA. Lower hemoglobin concentrations were observed in patients with higher MPA or fMPA C 0. The significant correlations between MPA C 3 as well as MPA C 4 and MPA AUC0–4 and MPA AUC0–12 may be of importance in further studies including larger number of patients in regard to establishing LSS. In patients treated with EC-MPS and Tac, monitoring MPA C 0 may be important, as too high MPA C 0 may contribute to anemia onset. In EC-MPS treated patients, MPAG concentration is related to renal function as MPAG pharmacokinetics were higher in patients with renal impairment.

SummaryThe aim of this study was to determine abdominal obesity risk factors in two successive cohorts of children and adolescents aged 4–18 from Cracow, Poland, examined during the years of political transformation. The influence of biological, socio-demographic and lifestyle factors on abdominal obesity was analysed by calculating odds ratios and 95% confidence intervals using logistic regression analysis. It was found that for girls obesity in both parents (OR=4.31; 95% CI 1.73–20.70) and high birth weight (OR=1.78; 95% CI 1.12–2.82) were significant risk factors for abdominal obesity in the 1983 cohort. In the 2000 cohort obesity in both parents for boys and girls (boys: OR=5.85; 95% CI 1.36–25.10; girls: OR=4.82; 95% CI 1.17–19.77), low level of parental education in girls (OR=2.06; 95% CI 1.15–3.69), having only one son (OR=1.96; 95% CI 1.36–3.40), parents' smoking habits in girls (OR=2.94; 95% CI 1.46–5.91) and lack of undertaking physical activity in sport clubs in boys (OR=6.11; 95% CI 1.46–25.47) were significant abdominal obesity risk factors. Higher number of hours of leisure time physical activity (OR=0.89; 95% CI 0.81–0.97) significantly lowered the risk of abdominal obesity in boys in the 2000 cohort. The greater differentiation of abdominal obesity risk factors in the 2000 cohort in comparison to the 1983 cohort may have resulted from the social and economic changes taking place in Poland at the end of the 20th century.

Etoposide (VP-16), a podophyllotoxin derivative, is used in conditioning regimens before allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia. The aim of this study was to develop a limited sampling strategy (LSS) suitable for the prediction of exposure to VP-16 defined as area under time-concentration curve (AUC).The study included 28 pediatric patients with acute lymphoblastic leukemia, who were administered a 4-hour infusion of 60 mg/kg VP-16. VP-16 concentrations were determined in samples collected 4-124 hours after the beginning of infusion. On obtaining the pharmacokinetic (PK) profiles, a population PK model was developed in NONMEM (ICON Development Solutions, Hanover, MD) with first-order conditional estimation with interaction algorithm. LSSs were chosen by means of a multivariate regression analysis and cross-validated with a leave-one-out approach. Predictive performance of LSSs was assessed by calculating relative prediction error (PE), mean PE, mean absolute PE, and root mean squared PE for model-predicted and observed AUC.VP-16 PKs was best described by a 2-compartment first-order model, and a large variability in the PK parameters was observed. A 3-sample strategy allowed the estimation of VP-16 with highest accuracy and precision (mean relative PE = 0.18%, 95% confidence interval, 1.73%-2.09%; mean absolute relative PE = 3.47%, 95% confidence interval, 2.28%-4.66%; root mean squared PE = 4.43%). The final equation was AUC = 6.85 × C6 h + 3.88 × C12 h + 46.11 × C28 h + 282.0 (adjusted R = 0.9540).In conclusion, developed LSS allows accurate and precise estimation of VP-16 AUC and might be useful for therapeutic drug monitoring.

SummarySeveral studies have documented increased prevalence of overweight and obesity in inhabitants of rural regions, but determinants of their prevalence are complex and not always in one direction. The aim of this study was to estimate both the prevalence and extent of overweight and obesity among rural girls in Poland between 1987 and 2001, as well as to assess differentiation of the phenomenon between regions of different social structures. The data come from two series of cross-sectional studies; the first in 1987 included 7764 girls, and the second in 2001 included 9431 girls aged 9–18. Body mass index (according to the International Obesity Task Force, IOTF) and the EOW index (extent of overweight), which shows by what mean BMI value the overweight boundaries are exceeded, were calculated. Overweight and obesity prevalences in the whole sample, were, respectively, 14.9% and 2.7% in 1987 and 15.5% and 2.5% in 2001, but significant differentiation in the direction of the changes was observed between the examined regions. In one of them, characterized by sudden, mass and long-term unemployment, there was a considerable decrease in overweight and obesity prevalence, whereas in a relatively wealthier region no changes were observed during the 14-year period. Two other regions with a relatively low standard of living and low incomes and education status presented a significant increase in overweight and obesity prevalence. The EOW index increased from 1.9 to 2.1 in the whole examined sample, and it also confirmed significant differences in expansion of overweight and obesity between the examined regions. The complex character of political and socioeconomic changes in Poland during the 1990s has resulted in two-directional changes in biological measures of living conditions. The analysis of the whole sample led to different results in comparison to separate analyses of each of the examined regions.

Introduction Plasma antioxidant vitamins (retinol, α-tocopherol, β-carotene) were measured to establish the influence of clinical condition and mycophenolate mofetil (MMF) treatment on the nutritional status of renal transplant recipients. Material and methods In 106 adult patients plasma vitamins were measured and 24-h diet history questionnaires were conducted. The MMF influence on plasma vitamins was verified in 61 patients. Results The current dietary intakes of vitamins in daily food rations were lower than recommended. Plasma retinol was lower in patients suffering from gastrointestinal disorders (1.25 ±0.48 mg/l vs. 1.55 ±0.70 mg/l) and inversely associated with aminotransferases activity (p = 0.019) and creatinine clearance (p = 0.021). Retinol concentrations were positively associated with plasma creatinine (p = 0.027) and pharmacokinetic parameters of MMF phenyl glucuronide. β-Carotene concentrations were higher in women (0.39 ±0.46 mg/l vs. 0.28 ±0.23 mg/l; p = 0.041) and when MMF was co-administered with cyclosporine vs. tacrolimus (0.45 ±0.62 mg/l vs. 0.25 ±0.19 mg/l). Plasma α-tocopherol correlated negatively with the mycophenolic acid pre-dose concentration (p = 0.027) and was significantly lower in patients treated with calcineurin inhibitors (8.90 ±5.23 mg/l vs. 12.25 ±5.62 mg/l). A positive correlation was observed between α-tocopherol levels and aspartate aminotransferase (p = 0.006). In multivariate regression aspartate aminotransferase and MMF treatment significantly influenced retinol (p < 0.001). Conclusions The MMF treatment was associated with significantly lower retinol concentrations. The gastrointestinal disorders occurrence in MMF-treated patients may cause a decrease in retinol absorption. Diet adjustment and/or vitamin A supplementation should be considered.

Objectives: To examine the tracking of abdominal fat distribution from the age of 7 to 15 years and to estimate the risk of abdominal obesity at 15 based on the occurrence of abdominal obesity at the ages 7–14 years in boys and girls. Methods: The analysis was performed on 8-year longitudinal measurements of 315 boys and 198 girls from Cracow, Poland. The stability of waist circumference (WC) and waist-to-height ratio (WHtR) got assessed by inter-age correlations. The degree of abdominal fatness continuation level was evaluated applying contingency tables with the χ2 test based on quartiles of WC and WHtR distribution. The risk of abdominal obesity at 15 was estimated using odds ratio (OR) and 95% confidence interval. Results: Inter-age correlations between the 7th and 15th years were 0.73 and 0.67 in boys and 0.48 and 0.48 in girls for WC and WHtR, respectively. More than 51% girls and 62% boys with abdominal fat distribution at 7 remained in the same category in adolescence period, while only 2% of them moved to the thin category at 15. The risk of abdominal obesity (WHtR) was highest in boys and girls with abdominal obesity at 7 (OR = 5.46 and OR = 6.19, respectively) and, additionally, in girls at 12 (OR = 5.59). Conclusion: The risk of abdominal obesity was indicated already at 7 in boys and girls. Continuation of the abdominal fat distribution confirmed in about 60% acknowledges that the type of fat distribution seems to be determined as early as in the 7-year-olds. Am. J. Hum. Biol., 2012. © 2011 Wiley Periodicals, Inc.

The proper concentrations of plasma bioelements may favorably reduce the incidence of metabolic disorders, which often occur during immunosuppressive therapy. Mycophenolate mofetil (MMF) is currently one of the most frequently administered immunosuppressive agents; however, MMF treatment is often related to gastrointestinal side effects. The aim of this study was thus to verify whether the MMF treatment itself, or its metabolite pharmacokinetics, has an effect on the concentrations of plasma bioelements. To determine this, the effect of MMF on the levels of both major (sodium [Na], potassium [K], calcium [Ca], magnesium [Mg]), and trace (iron [Fe], zinc [Zn], copper [Cu]) plasma bioelements in 61 renal transplant recipients was assessed in comparison to a control group (n = 45). The pharmacokinetic parameters of mycophenolic acid were determined by the high-performance liquid chromatography method. All patients filled out a 24-h diet history questionnaire. The results showed high plasma concentrations of Fe and low plasma concentrations of Mg and Zn as compared with diagnostic norms. The patients treated with MMF had significantly lower plasma Na (P

Published studies world wide demonstrate that measures of human development and health status vary depending on the month of birth but these patterns are not always consistent and sometimes even conflict. Direct factors related to the birth season that may significantly differentiate morphological and functional traits and mechanisms causing these relations have not been found so far. On the basis of cross-sectional material, gathered in the years 1983 and 2000 by the Department of Anthropology of the Academy of Physical Education in Cracow, two main hypotheses have been verified: (1) average body height differences by month of birth are statistically insignificant, (2) the magnitude of these differences does not change with time. Metric data of 4672 girls aged 5-18 years, born in 1965-1978 and 1982-1995, were used. The total sample was also subdivided into prepubertal (5-9 years) and adolescent (10-18 years) groups. The age of the individuals was calculated to the nearest day and the procedure of standardization on the interpolated values of regional norms was applied. A highly significant relationship between the birth month and average values of height was revealed in preadolescent girls. The results obtained for the entire material proved insignificant. The patterns of the month-of-birth effect on body height for girls born in 60./70. and 80./90. show high similarity, though the effect seems weaker in the latter sample. Winter proved to be the most favorable birth season for later body height.

The aim of this study is to examine changes in prevalence of overweight and obesity, using International Obesity Task Force criteria, in three cohorts of children and youth living in Cracow, Poland, in 1971, 1983 and 2000. Rates of overweight and obesity doubled among boys and girls, from 7.5% and 6.5% in 1971, to 15.2% and 11.8% in the year 2000. The greatest increases in prevalence occurred in the youngest age groups (7-12 years for boys and 7-10 years for girls), increases being less extensive among adolescents, and lowest of all in the oldest age groups (16-18 years in boys and 14-18 years in girls). The absence of a positive secular trend in BMI among adolescent females relative to males may be due to sociocultural pressures associated with transition to a free market economy in Poland. The extent to which girls attempt to achieve the ideal body, as portrayed by media and society more generally, increases across adolescence.

Three isoquinoline alkaloids, (−)-salsolidine 2 , (+)-carnegine 6 and (−)-1-phenyl-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 7 , were obtained in high yield and with 17–46% e.e. by the enantioselective additions of organolithium reagents to dihydroisoquinolines 1 and 5 , in the presence of (−)-sparteine as a chiral ligand.

The metabolism of azathioprine (AZA) was studied by monitoring the concentrations of red blood cell (RBC) 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) in 27 renal transplantation recipients and in 10 patient subjects with glomerulonephritis (GN). Concentrations of 6-TGNs and 6-mMP metabolites were measured using high-performance liquid chromatography (HPLC). Six patients from the group of renal transplantation recipients were also administered allopurinol. Median values of RBC 6-TGN and of 6-mMP metabolites concentrations in 21 renal transplantation recipients (without allopurinol) were 122 pmol/8x10(8) RBCs (range

Mycophenolic acid (MPA) is widely used in solid organ transplantation. MPA absorption from enteric-coated mycophenolate sodium (EC-MPS) is delayed, which results in a delayed enterohepatic recirculation and subsequently higher and more variable MPA 12-hour trough concentration and tmax values. Therefore, MPA trough level monitoring cannot be used to monitor MPA exposure in patients who are given EC-MPS. The aim of the study was to develop and validate a limited sampling strategy (LSS) for accurate prediction of the 12-hour area under the concentration-time curve (AUC0-12h) for MPA in patients who receive concomitant EC-MPS and Tacrolimus (Prograf or Advagraf) within 196 months posttransplantation. According to our knowledge, the LSS for MPA AUC estimation using high-performance liquid chromatography to determine MPA concentrations in plasma samples of kidney and liver transplant patients receiving EC-MPS and Tacrolimus (Advagraf) has not been previously evaluated.Seventy-four renal and liver transplant patients receiving EC-MPS and concomitant tacrolimus (either Prograf or Advagraf) provided a total of 74 pharmacokinetic profiles. MPA concentrations were measured using a validated high-performance liquid chromatography method for 9 plasma samples collected at predose and at 0.5, 1, 2, 3, 4, 6, 9, and 12 hours after the morning dose of EC-MPS after an overnight fast. LSS were developed and validated by stepwise multiple regression analysis with the use of a 2-group method (test, n = 37; and validation, n = 37).The 3 and 4 time point equations using C1h, C3h, C9h and C1h, C2h, C3h, C6h, respectively, were found to be superior to all other models tested. When these LSS models were tested in the validation group, the results were acceptable [for 3 time points equation: r = 0.824, percentage of prediction error: 6.32 ± 25.75, 95% confidence interval (CI): -40.71 to 79.76; percentage of absolute prediction error: 27.45 ± 29.89, 95% CI: 0.04-199.92, predictive performance, 71% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.03 ± 0.24; for 4 time points equation: r = 0.898, percentage of prediction error: 3.32 ± 18.26, 95% CI: -49.35 to 51.06; percentage of absolute prediction error: 14.05 ± 11.89, 95% CI 0.13-49.86, percentage of predictive performance, 83% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.01 ± 0.19].LSS equations using concentrations at 1, 3, and 9 hours or 1, 2, 3, and 6 hours time points provided the most reliable and accurate estimations of the MPA AUC in stable renal and liver transplant recipients treated with EC-MPS and tacrolimus. Further studies on independent groups of patients are required to confirm clinical utility of the presented LSS models.

Mycophenolate mofetil (MMF), an immunosuppressant administered after solid organ transplantation, is generally well tolerated; however, it frequently causes hematological toxicity. In this study, we aimed to assess the relation between the pharmacokinetic parameters of MMF metabolites (mycophenolic acid [MPA] and 7-O-MPA glucuronide [MPAG]) and the adverse effects on the hematopoietic system in renal transplant recipients. The four-h pharmacokinetic profiles of MPA and MPAG were determined using the HPLC method for MMF-treated patients (n = 61) among 106 renal transplant recipients (during the late post-transplant period) participating in the study. Anemia was more frequently observed in the study group compared with the control group (30.7% vs. 20.0%) and although the difference was insignificant, plasma iron concentrations were significantly higher in patients treated with MMF (32.9 ± 9.4 μmol/L vs. 28.7 ± 9.4 μmol/L; p = 0.032). Iron supplementation was more frequently applied to patients with anemia (48.2%) compared with patients with hemoglobin within the norm (20.3%; p = 0.005). As all MPAG pharmacokinetic parameters correlated negatively with hemoglobin and hematocrit, and MPAG pharmacokinetic parameters were higher in patients with anemia, MPAG may be the predicting factor of MMF side effects. In renal transplant recipients, especially with deteriorated renal function, extensive iron supplementation may be ineffective as anemia was associated with declined renal function and was not caused by low iron concentration.

SummaryThe aim of this study was to assess the usefulness of the decision trees method as a research method of multidimensional associations between menarche and socioeconomic variables. The article is based on data collected from the rural area of Choszczno in the West Pomerania district of Poland between 1987 and 2001. Girls were asked about the appearance of first menstruation (a yes/no method). The average menarchal age was estimated by the probit analysis method, using second grade polynomials. The socioeconomic status of the girls' families was determined using five qualitative variables: fathers' and mothers' educational level, source of income, household appliances and the number of children in a family. For classification based on five socioeconomic variables, one of the most effective algorithms CART (Classification and Regression Trees) was used. In 2001 the menarchal age in 66% of examined girls was properly classified, while a higher efficiency of 70% was obtained for girls examined in 1987. The decision trees method enabled the definition of the hierarchy of socioeconomic variables influencing girls' biological development level. The strongest discriminatory power was attributed to the number of children in a family, and the mother's and then father's educational level. Using this method it is possible to detect differences in strength of socioeconomic variables associated with girls' pubescence before 1987 and after 2001 during the transformation of the economic and political systems in Poland. However, the decision trees method is infrequently applied in social sciences and constitutes a novelty; this article proves its usefulness in examining relations between biological processes and a population's living conditions.

Chrzanowska M, Sobiak J, Grund G, Wachowiak J. Pharmacokinetics of high-dose etoposide administered in combination with fractionated total-body irradiation as conditioning for allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia. Pediatr Transplantation 2011: 15:96–102. © 2010 John Wiley & Sons A/S. Abstract: Etoposide (VP-16) is one of the most widely used antitumor agents in pediatric oncology as well as chemotherapeutic agents used in conditioning regimen prior to allo-HSCT for childhood ALL. This study included 21 children with ALL who underwent allo-HSCT after conditioning with FTBI and high-dose of VP-16 (60 mg/kg) given intravenously as single four-h infusion on day −3 (n = 2) or day −4 (n = 19) prior to allo-HSCT. Blood samples were collected at defined time intervals until 120 h elapsed from the end of infusion. VP-16 plasma concentrations were determined using validated HPLC method. Three-compartment model was assumed for assessing PK parameters of VP-16. The median value of VP-16 Cmax measured at the end of infusion was 188.0 μg/mL (range 148.0–407.0 μg/mL). Out of 21 studied children, VP-16 was still detectable in 17 patients 72 h (median concentration 0.31 μg/mL) and in eight patients 96 h (median concentration 0.31 μg/mL) after the end of infusion. VP-16 concentration 96 h after the end of infusion was positively correlated with VP-16 AUC and negatively correlated with VP-16 CL normalized to body weight.

INTRODUCTION The aim of the study was to analyse the influence of renal impairment on the pharmacokinetic parameters (PK) of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in renal transplant recipients. MATERIAL AND METHODS The study included 43 adult patients during the maintenance period (> 6 months) following renal transplantation, treated with mycophenolate mofetil (MMF), calcineurin inhibitors (CNI) (tacrolimus or cyclosporine) and steroids. The study compared patients with normal renal function (n = 17; creatinine clearance (C(cr)) > 60 ml/min) and with renal impairment (n = 26; C(cr) < 60 ml/min). Areas under the 4-h curve (AUC(0-4 h)) of MPA and MPAG were determined using a validated HPLC method. RESULTS The renal impairment group showed significantly increased AUC(0-4 h) and pre-dose (C(0)) for MPAG compared to patients with normal renal function and increased MPA C(0). However, there was no significant difference in MPA AUC(0-4 h) between patients with renal impairment and patients with normal renal function. In multivariate analysis some MPA and MPAG PK parameters were correlated with sex, CNI co-administered and body weight. CONCLUSIONS Although MPAG is an inactive metabolite, its accumulation in patients with renal impairment can be unfavourable. The results of our study indicate that solely MPA C(0) determination in patients receiving MMF may be insufficient in clinical practice because of great inter-patient variability of this PK parameter caused mainly by enterohepatic recirculation.

Obesity indices describe the percentage of overweight and obese children in a given population but they do not show the extent to which the norms have been exceeded. The aim of this work was to determine the extent of overweight index (EOW), suggested by Jolliffe (2004a,b), by examining children and adolescents from Cracow in order to obtain information on overweight and obesity prevalence and on the amounts by which the BMI age- and sex-specific norms are exceeded, emphasising usefulness of EOW in population studies. The study material comprises three randomly selected groups, representative for Cracow: (1) measured in 1971 which includes 4090 individuals of both sexes and aged 7-19 years, (2) measured in 1983 with 6542 individuals aged 3-19 years and (3) measured in 2000 with 4524 boys and girls aged 3-19 years. The EOW index of overweight is a mean relative deviation from BMI threshold, assuming that for values lower than the threshold ones, the deviation amounts to zero. The EOW index values in boys increased from 0.9 in 1971 up to 2.2 in 2000 i.e. by 144%, indicating an increase of both prevalence of overweight and obesity and an increase of the amount by which the limits of overweight are exceeded. In girls the index also increased, though less dramatically, from 0.7 in 1971 to 1.5 in 2000 i.e. by 114%. An analysis of the results showed that the increasing prevalence of overweight and obesity in children and adolescents is accompanied by an increase of the amount by which the BMI threshold values are exceeded.

The aim of the work was to analyze the direction and tempo of subcutaneous fat redistribution during ontogenesis, appearing sex differences and relations to puberty on the basis of 12-year longitudinal data of 270 boys and 154 girls from Cracow, Poland. They all had complete data (from 7 to 18-years old) of three trunk (subscapular, abdominal, suprailiac) and three extremity (triceps, knee, medial calf) skinfold thicknesses. The type of subcutaneous adipose tissue distribution was determined based on trunk to extremity ratio to analyze the process of fat redistribution. The analysis included medians of extremity and trunk skinfolds and medians of their sums and age altered frequency of central and peripheral type of fat distribution. To present empirical values, the median variability of the sums of three trunk and extremity skinfolds was calculated using a third degree polynomial as an age function. Polynomial regression of extremity skinfolds median explained 88% of its variability (F = 71.2, P < 0.001) and for trunk skinfolds as far as 96% (F = 111.65, P < 0.001). The median variability curves of both types of distribution crossed at the age of 11.88 in girls and 13.45 in boys directly preceding puberty stage, which indicated clear dependencies between fat redistribution and puberty. The results showed a tight connection between the process of subcutaneous fat redistribution and puberty, and also sex dimorphism of the process. More dynamic fat redistribution in boys contrasted trunk and extremity fatness, while in girls less dynamic changes resulted in more even fatness.

Azathioprine is an important drug used in the therapy of autoimmune disorders and in preventing graft rejection. Its molecule is composed of two main moieties: mercaptopurine and imidazole derivative. It is an immunosuppressive agent whose biological activity results from its in vivo mercaptolysis mediated by a nucleophilic attack on the C(5i) atom of imidazole ring of the azathioprine molecule. Solvation model SM5.4 with the PM3 Hamiltonian have been applied to model the reaction of azathioprine with cysteine. The employed quantum mechanical method shed new light on the mechanism of the reaction of azathioprine with cysteine in aqueous solution. The obtained results indicated that the first step in the reaction most likely involves the nucleophilic attack of the COO(-) of cysteine on the C(5i) atom of the imidazole ring of azathioprine, followed by a subsequent intramolecular attack of the SH group of the cysteine residue. It was shown that biogenic thiols such as glutathione or cysteine facilitate the first and crucial step of azathioprine metabolism, due to the presence of COO(-), SH, and NH(3)(+) groups in their molecules.

Intracellular concentrations of 6-mercaptopurine metabolites, i.e. of 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) were analysed in red blood cells (RBC) of 19 children with acute lymphoblastic leukemia (ALL), the subjects of a maintenance chemotherapy of their first remission. Interpatient variations in concentrations of both metabolites were high; concentrations of 6-TGN varied from

In the total synthesis of (±)-peshawarine (1) hydrastinine derivative 6 was acylated with 1,3-dithian 7 applied as an acyl anion equivalent. The dithian masking group in addition product 8 was reductively removed using Raney nickel.

Cryptopleurospermine ( 1 ), a 1,2-secobenzylisoquinoline alkaloid was synthesized from hydrastinine derivative 2 and isovanillin 1,3-propylene dithioacetal 3 . The formation of C-C bond between these two synthons involved addition of dilithio salt of dithian 3 to aldehyde group in 2 . Reduction and hydrolysis of the masking group in addition product 4 furnished the synthesis.

Cryptopleurospermine ( 1 ), a 1,2-secobenzylisoquinoline alkaloid was synthesized from hydrastinine derivative 2 and isovanillin 1,3-propylene dithioacetal 3 . The formation of C-C bond between these two synthons involved addition of dilithio salt of dithian 3 to aldehyde group in 2 . Reduction and hydrolysis of the masking group in addition product 4 furnished the synthesis.

In the total synthesis of (±)-peshawarine (1) hydrastinine derivative 6 was acylated with 1,3-dithian 7 applied as an acyl anion equivalent. The dithian masking group in addition product 8 was reductively removed using Raney nickel.