Duration of breastfeeding and serum PCB 153 concentrations in children.

Polychlorinated biphenyls (PCBs) are toxic, persistent, and bioaccumulative chemicals which, because of their lipophilic properties, are abundant in human breast milk. Breastfed infants are therefore at risk of being exposed to considerable amounts of PCBs. The commonly used exposure estimations, based solely on breast milk PCB levels and duration of breastfeeding, may lead to exposure misclassification. To improve assessments of exposure to PCBs, we determined PCB 153 serum concentration, as a model substance for PCBs, at the critical time of weaning for each child in 305 breastfed infants from 5 single time point concentration measurements spread over 7 years and data on duration of breastfeeding, using an earlier developed model of the system type. We approximated the dependence of PCB 153 serum concentration, Ctbf, adjusted to cord serum concentration, C0, on nursing period, by a polynomial function Ctbf/C0=0.596+0.278t-0.0047t(2) which reliably predicts exposure to PCB 153 of breastfed infants, important for assessment of dose-outcome relationships. Adjustment of current serum concentrations to cord serum concentration improved validity of exposure assessment.

Clearance approach in hyperinsulinemic-euglycemic clamp evaluation in lean and obese subjects.

PURPOSE/AIM: The main aim of this study was to propose a method to express whole body insulin sensitivity as estimated by a hyperinsulinemic-euglycemic clamp (HEC) as a dimensionless parameter. MATERIALS AND METHODS: Two groups of subjects were examined: The first group was comprised of seven healthy lean volunteers with BMI <25 kg/m(2) and a second group comprised of four obese subjects with BMI ≥30 kg/m(2). The dependence between the M/I index expressing the whole body insulin sensitivity, and the dimensionless whole human body effect E as a ratio of the clearance of glucose and the clearance of insulin after their exogenous administration during the last 40 min of the HEC test, was expressed by regression analysis. Unlike an expression of insulin sensitivity/resistance as a function of M taking into account the space corrections or the M/I index, our whole human body effect represents the insulin sensitivity/resistance as a dimensionless number. RESULTS: A linear dependence between the M/I index and the dimensionless effect E with zero intercept and slope at 2.2623 ± 0.157, r = 0.914, and between the M/I index and the effect E recalculated per kg of human body weight with zero intercept and slope at 0.03164 ± 0.00127, r = 0.978, were observed. CONCLUSIONS: The high correlation between the M/I index and new effect E in lean and obese volunteers confirms our proposal that the HEC test could be evaluated by a dimensionless parameter which eliminates potential unit mismatches in the expression of clamp results.

Estimation of influence of gastric emptying on shape of glucose concentration-time profile measured in oral glucose tolerance test.

AIMS: To develop a model for simulations of processes in the oral glucose tolerance test (OGTT), using tools of the theory of dynamic systems. METHODS: Frequent sampling OGTT was performed in 13 healthy subjects (6 males and 7 females). Subsequently, employing glucose and insulin concentration-time profiles of the subjects, the model was developed. RESULTS: In all subjects the model was able to simulate influences of the insulin plasma concentration and gastric emptying rate on glucose concentration and to determine time profiles of glucose fractions retained in stomach. CONCLUSIONS: The approach presented represents an opportunity for building models for data analyses in OGTT.

New mathematical methods in pharmacokinetic modeling.

In recent years, several new methods for the mathematical modeling have gradually emerged in pharmacokinetics, and the development of pharmacokinetic models based on these methods has become one of the most rapidly growing and exciting application-oriented sub-disciplines of the mathematical modeling. The goals of our MiniReview are twofold: i) to briefly outline fundamental ideas of some new modeling methods that have not been widely utilized in pharmacokinetics as yet, i.e. the methods based on the following concepts: linear time-invariant dynamic system, artificial-neural-network, fuzzy-logic, and fractal; ii) to arouse the interest of pharmacological, toxicological, and pharmaceutical scientists in the given methods, by sketching some application examples which indicate the good performance and perspective of these methods in solving pharmacokinetic problems.

Modeling behavior of protein C during and after subcutaneous administration.

Protein C is an important blood factor protein that regulates the blood coagulation process. Deficiency of protein C can lead to excessive coagulation that results in lack of tissue oxygenation, causing conditions such as deep vein thrombosis, pulmonary embolism, and stroke. Human protein C has been approved as a treatment for congenital protein C deficiency; however, the therapy requires frequent injections, due to the short residence time of the protein. Subcutaneous administration has been examined as an alternative to increase residence time and decrease injection frequency, thereby creating a more patient-friendly dosing regimen. In order to design an efficient injection or infusion protocol for subcutaneously administered proteins, it is important to accurately model the behavior (absorption, distribution, elimination) of these proteins in the body. However, several factors involved in a subcutaneous injection of the protein make modeling this behavior a challenging task. For example, absorption of the drug from the subcutaneous site into the blood stream can be variable depending on the site of injection, physical activity of the patient, etc. Furthermore, degradation of the protein can occur at the site of injection and further modify its absorption. The objective of this work was to demonstrate the utility of frequency response modeling as an alternative method to analyze the behavior of subcutaneously administered protein C. The results of our study indicate that if the dose range yielding the constant clearance of protein C is identified for the patient, models of that type, as presented in our study, can be used to adjust optimal dosing of protein C necessary to reach prescribed levels of the protein in this patient at desired time points, both specified by treatment requirements.

Short-term glucagon stimulation test of C-peptide effect on glucose utilization in patients with type 1 diabetes mellitus.

This work aimed to evaluate the use of a four-point glucagon stimulation test of C-peptide effect on glucose utilization in type 1 diabetic patients using a new mathematical model. A group of 32 type 1 diabetic patients and a group of 10 healthy control subjects underwent a four-point glucagon stimulation test with blood sampling at 0, 6, 15 and 30 min after 1 mg glucagon bolus intravenous administration. Pharmacokinetic and pharmacokinetic/pharmacodynamic models of C-peptide effect on glucose utilization versus area under curve (AUC) were used. A two-sample t test and ANOVA with Bonferroni correction were used to test the significance of differences between parameters. A significant difference between control and patient groups regarding the coefficient of whole-body glucose utilization and AUC C-peptide/AUC glucose ratio (p â‰ª 0.001 and p = 0.002, respectively) was observed. The high correlation (r = 0.97) between modeled coefficient of whole-body glucose utilization and numerically calculated AUC C-peptide/AUC glucose ratio related to entire cohort indicated the stability of used method. The short-term four-point glucagon stimulation test allows the numerically calculated AUC C-peptide/AUC glucose ratio and/or the coefficient of whole-body glucose utilization calculated from model to be used to diagnostically identify type 1 diabetic patients.

System-approach methods for modeling and testing similarity of in vitro dissolutions of drug dosage formulations.

System-approach based modeling methods are used to model dynamic systems describing in vitro dissolutions of drug dosage formulations. Employing the models of these systems, model-dependent criteria are proposed for testing similarity between in vitro dissolutions of different drug dosage formulations. The criteria proposed are exemplified and compared with the criterion called the similarity factor f(2), commonly used in the field of biomedicine. Advantages of the criteria proposed over this factor are presented.

Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on two thyroid outcomes.

BACKGROUND: Toxic equivalency factors (TEFs) are an important component in the risk assessment of dioxin-like human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these "intake" TEFs are commonly-but incorrectly-used by regulatory authorities to calculate "systemic" toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect. OBJECTIVES: We sought to determine relative effect potencies (REPs) for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum free thyroxine (FT4) concentration as the outcomes of interest. METHODS: We used a benchmark concentration and a regression-based approach to compare the strength of association between each dioxin-like compound and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. RESULTS: REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (ß)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, p = 0.01 and r = 0.62, p = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators. CONCLUSIONS: Our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of dioxin-like compounds.

System approach to modeling of liver glucose metabolism with physiologically interpreted model parameters outgoing from [18F]FDG concentrations measured by PET.

New mathematical models from physiologically interpreted parameters capable of evaluating glucose metabolism within the liver and/or the whole body were developed. The group of pigs in a fasting state and the group of pigs with euglycemic supraphysiological hyperinsulinemia were scanned by positron emission tomography after a single dose of [(18)F]FDG tracer. Simultaneously frequent sampling of the dynamic data of [(18)F]FDG plasma concentration in artery, portal vein and hepatic vein was obtained. A system approach to the liver and/or the whole-body system by the tools of linear dynamic sysztem theory was used. Three kinds of structural models, single input and single output or multiple outputs and multiple inputs and single output, were identified. Differences between the group of fasting pigs and the group of pigs in euglycemic supraphysiological hyperinsulinemia were identified by estimated parameters of the structural models. The suitability of the structural mathematical models for the estimation of physiologically interpreted parameters from PET was validated.

Assessment of exposure to PCB 153 from breast feeding and normal food intake in individual children using a system approach model.

Investigators have typically relied on a single or few discrete time points as measures of polychlorinated biphenyl (PCB) body burden, however health effects are more likely to be the result of integrative exposure in time, optionally expressed as an area under the time curve (AUC) of PCB serum concentration. Using data from a subgroup of 93 infants from a birth cohort in eastern Slovakia-a region highly polluted by PCBs-we fit a system type model, customized to our longitudinal measures of serum PCB concentrations in cord, 6, 16, and 45 month blood specimens. The most abundant congener, PCB 153, was chosen for modeling purposes. In addition to currently used methods of exposure assessment, our approach estimates a concentration time profile for each subject, taking into account mean residence time of PCB 153 molecules in the body, duration of breast feeding, hypothetical PCB 153 concentration in steady-state without breast feeding and alternately without normal food intake. Hypothetical PCB 153 concentration in steady-state without normal food intake correlates with AUC (r=0.84, p<0.001) as well as with duration of breast feeding (r=0.64, p<0.001). It makes possible to determine each subject's exposure profile expressed as AUC of PCBs serum concentration with a minimum model parameters. PCB body burden in most infants was strongly associated with duration of breast feeding in most, but not all children, was apparent from model output.

Physiologically motivated time-delay model to account for mechanisms underlying enterohepatic circulation of piroxicam in human beings.

The study was conducted to formulate a physiologically motivated time-delay (PM TD) mathematical model for human beings, which incorporates disintegration of a drug formulation, dissolution, discontinuous gastric emptying and enterohepatic circulation (EHC) of a drug. Piroxicam, administered to 24 European, healthy individuals in 20 mg capsules Feldene Pfizer, was used as a model drug. Plasma was analysed for piroxicam by a validated high-performance liquid chromatography method. The PM TD mathematical model was developed using measured plasma piroxicam concentration-time profiles of the individuals and tools of a computationally efficient mathematical analysis and modeling, based on the theory of linear dynamic systems. The constructed model was capable of (i) quantifying different fractions of the piroxicam dose sequentially disposable for absorption and (ii) estimating time delays between time when the piroxicam dose reaches stomach and time when individual of fractions of the piroxicam dose is disposable for absorption. The model verification was performed through a formal proof, based on comparisons of observed and model-predicted plasma piroxicam concentration-time profiles. The model verification showed an adequate model performance and agreement between the compared profiles. Accordingly, it confirmed that the developed model was an appropriate representative of the piroxicam fate in the individuals enrolled. The presented model provides valuable information on factors that control dynamic mechanisms of EHC, that is, information unobtainable with the models proposed for the EHC analysis previously.

Computer controlled sequential simulation method: reconsidering evaluation of measurements from frequently sampled intravenous glucose tolerance test.

This work describes quantification of regulatory mechanisms glucose-insulin, using data from a frequently sampled intravenous glucose tolerance test (FSIVGTT) and a mechanistically motivated model with time delays. FSIVGTT was performed on 14 young healthy volunteers. The constructed model computationally takes into account the form of the short-time glucose infusion used. Estimated model parameters are used to derive relationships quantifying the following mechanisms of regulatory systems glucose-insulin of the volunteers enrolled: (1) glucose uptake by body cells; (2) cessation (suppression) of glucose output from liver; (3) glucose clearance. The model presented correctly approximates initial peaks and subsequent waves in plasma glucose concentration-time profiles after the glucose infusion. These results indicate that the model presented is an appropriate tool for assessing glucose behavior during a FSIVGTT.

Novel approach to bioequivalence assessment based on physiologically motivated model.

The study was conducted to exemplify an approach capable of obtaining a new insight into bioequivalence (BE) assessment, by the use of a physiologically motivated model. Data from an oral BE study of two piroxicam (PXM) products was used as an example. The BE study was carried out with 24 healthy European subjects according to a two-sequence crossover-randomized design. The test and reference formulations were a PXM generic formulation (LaborMed Pharma, Romania) and Feldene (Pfizer, USA), respectively. Plasma concentrations of PXM were monitored by a validated high-performance liquid chromatography over a period of 144 h after administration. After the structure of the optimal model was selected, parameters that characterized the whole-body disposition behavior of PXM in the subjects were derived. The paired Student's t-test and Wilkoxon's test were performed on the derived parameters. The null hypothesis of no differences in the parameters of the whole-body disposition behavior of PXM related to the test and reference product was not rejected at 5% level of significance. This result suggested that the compared products were bioequivalent and could be used interchangeably in clinical setting. The presented approach might show a new way, worth incorporating in future BE guidelines.

Long-term follow-up of renal function in patients after surgery for obstructive uropathy.

In this prospective study, selected biochemical markers of glomerular and tubular function, proteinuria, and ultrasound findings in 62 pediatric patients who underwent surgery for obstructive uropathy were examined. Patients were younger than 12 months, normocreatininemic at the time of surgery, and examined at a mean age of 6.3+/-0.9 years. Out of the markers tested, serum concentration of cystatin C was significantly higher in patients when compared with the control group (p<0.001), and serum creatinine concentration was within reference interval in all patients. With respect to tubular function, 26% of patients had decreased concentration ability. Proteinuria was detected in 4.8% of patients. On ultrasound, 66.7% of kidneys after surgery had residual dilatation of the renal pelvis. The patients thrive well, and their somatic parameters do not differ from their peers. Half of the patients had one or more urinary tract infections from the date of surgery to the date of examination. Study results support the need for long-term nephrologic follow-up in patients after surgery for obstructive uropathy. The hypothesis that renal function in patients undergoing surgery aged younger than 3 or 6 months is better when compared with those aged 6 to 12 months has not been confirmed.

Etiology and epidemiology of end-stage renal disease in Dutch children 1987-2001.

In this retrospective study 351 children (<16.0 years) with end-stage renal disease (ESRD) accepted for renal replacement therapy (RRT) in the four Dutch pediatric centers were analyzed for the period 1987-2001. The data were compared with a previous study performed in 1979-1986. Eighty patients were of non-Dutch origin. An annual ESRD incidence of 5.8 patients per million of the child population (p.m.c.p.) was calculated, without significant changes with time. The final prevalence in Dutch children under 15 years of ESRD was 38.7 p.m.c.p. The most frequent primary renal disease leading to ESRD was urethral valves, with a significant increase vs. the previous observation period (14% vs. 6%). The distribution of primary renal diseases was similar in patients of non-Dutch origin and in Dutch patients. Peritoneal dialysis was the most frequent dialysis procedure initially applied (62% vs. 26% in the earlier observation period). Thirteen percent of all first transplantations (n=278) were pre-emptive and 19% from living donors. Five-year graft survival after a living-donor and a cadaver graft was 80% and 73%, respectively. Overall patient survival after 10 years on RRT was 94%.

A system-approach method for the adjustment of time-varying continuous drug infusion in individual patients: a simulation study.

The aim of this simulation study was to present a system-approach method for adjustment of continuous drug infusions at time-varying rates, aimed at achieving and then maintaining required drug concentration-time profiles in patients. The method presented can be used for safe and cost-effective individualization of drug dosing by computer-controlled infusion pumps. Utilization of this method is exemplified by simulation experiments, aimed at adjusting continuous infusions of Factor VIII (FVIII) at time-varying rates, which would theoretically yield required concentration-time profiles of FVIII in hemophilia A patients over several days.