Paul Schepens

Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus

Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth.

Selected persistent organochlorine pollutants in Romania

Selected persistent organochlorine pollutants, including PCBs, DDT and its metabolites (DDTs) and hexachlorocyclohexane isomers (HCHs) were determined in soil, animal fat and human serum samples from Romania. All methods were rigorously tested and adequate quality control was ensured. Soil samples from lassy County showed a lower contamination with organochlorines than samples from other Romanian regions. While DDTs concentrations in soil were significantly higher at rural sites, only few samples (three out of 47) exceeded the official Romanian norms for DDTs. PCBs concentrations were low in rural sites (< 8 ng/g soil), but rather high (up to 134 ng/g soil) in urban soils collected mostly from parks (Bucharest, Arad, Baia Mare, Pitesti and Ploicsti). Animal fat samples from lassy showed high concentrations of organochlorine pesticides (HCHs concentrations up to 12370 ng/g fat), but similar PCB concentrations when compared with Arad samples. Two samples (from 24) exceeded the EU norms (1000 ng/g fat) for HCHs and DDTs in animal fat. Organochlorines were found in higher concentrations in some samples of human serum from Timisoara due to a broader age range. Samples of human serum from lassy mothers showed higher HCHs and DDTs concentrations than samples from a similar group from Antwerp, Belgium. HCB and PCBs were higher in Antwerp cohort. Romanian samples showed a higher ratio DDT/sigmaDDTs, but similar ratios PCB 153/sigmaPCBs.

An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age. WHAT THIS STUDY ADDS A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety. METHODS Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure. RESULTS Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated. CONCLUSIONS To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.

Human Pentachlorophenol Poisoning

Pentachlorophenol (PCP) was, and still is, one of the most frequently used fungicides and pesticides, Its toxicity is due to interference with oxidative phosphorylation. Acute and chronic poisoning may occur by dermal absorption, inhalation or ingestion. Chronic poisoning occurs mainly in sawmill workers or people living in log homes treated with PCPcontaining wood protecting formulations. Quantitative determination of PCP in urine and serum is useful to detect occupational or subclinical exposure. The clinical features of acute and chronic PCP poisoning can be classified systematically into effects on the skin, metabolism (fever), the haematopoietic tissue, the respiratory system, the central and peripheral nervous system, the kidney and the gastrointestinal tract. Although PCP is not classified as a human carcinogen, some epidemiological observations suggest that exposure to chlorophenols in general and PCP solutions in particular may result in an increased risk for certain malignant disorders such as nasal carcinoma and soft tissue sarcoma. There is concern that contamination of PCP-solutions with products such as chlorodibenzo-p-dioxins is the real cause of this suspected carcinogenicity. No specific antidote exists for the treatment of (acute) PCP poisoning. The basis of the treatment of acute poisoning is intensive supportive care with prevention of dangerous rise in temperature. Use of PCP-based products as indoor wood preservatives poses an unacceptable risk to human health.

Improved sample preparation method for selected persistent organochlorine pollutants in human serum using solid-phase disk extraction with gas chromatographic analysis

An improved solid-phase extraction (SPE) method was developed to isolate and concentrate trace levels of selected POPs (persistent organochlorine pollutants) in human serum prior to GC-MS in SIM mode or GC-ECD quantitation. The extraction involves denaturation of serum proteins with formic acid, SPE using C18 Empore disk cartridges, followed by elimination of lipid interferences using a sulfuric acid wash of the eluate. Use of the SPE disk improved assay throughput and gave a cleaner analytical matrix compared with previously reported solid-phase and liquid-liquid extraction techniques. The extraction method provided consistent recoveries at three fortification levels using 13C12 PCB 149 as internal standard. Recoveries ranged from 48 to 140% for organochlorine pesticides (6.25, 12.5 and 25 ng/ml) and 71 to 126% for polychlorinated biphenyls (0.625, 1.25 and 2.5 ng/ml).

Determination of organohalogenated contaminants in liver of harbour porpoises (Phocoena phocoena) stranded on the Belgian North Sea coast

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Chromatographic aspects of the analysis of selected persistent organochlorine pollutants in human hair

SummaryDifferent incubation and extraction methods have been evaluated for determination of isomers of PCBs, DDT, and HCH in human hair. The best method was found to be overnight incubation in 3 M HCl at 40°C and liquid-liquid extraction with 4:1 hexane-dichloromethane. After clean-up on basic alumina and acid silica, the extract was analysed by GC-ECD or GC-MS. Recoveries of internal standards and the analytes under investigation ranged between 87 and 111%. Limits of detection were between 0.5 and 1 ng g−1 hair for ECD and 1 to 3 ng g−1 for MS. Good linearity (r2>0.999) was achieved for the ranges tested (1–30 ng g−1 for individual PCBs, 1–1000 ng g−1 for DDT isomers, and 1–100 ng g−1 hair for HCH isomers). There was no difference between the efficiency of extraction from powdered and cut hair. Similar PCBs profiles were found in human hair and in other parts of the body. Similar concentrations of persistent organic pollutants (POP; reported relative to the amount of lipid) were found in human milk and in hair from the same person. Concentrations of organochlorine compounds were measured, by use of the method, in several samples from Belgium, Romania, and Greece. It was concluded that hair can be used to monitor any subgroup of the population, with emphasis on those from which sampling of milk, adipose tissue, or blood is not possible, or is very difficult (e.g. children).

Patterns of PCBs and PCDD/PCDFs in chicken and pork fat following a Belgian food contamination incident

A food contamination incident involving polychlorobiphenyls (PCBs) and PCDD/Fs occurred in 1999 in Belgium. On heavily affected farms, concentrations of PCBs in chicken or pork fat exceeded the Belgium tolerance limit of 200 ng/g lipid weight for the sum of seven marker PCBs. Analysis of contaminated samples showed that the patterns for PCB and PCDD/F congeners differed among feed, chicken fat and pork fat. Lower chlorinated PCBs and polychlorodibenzofurans (PCDFs) including those with high TEFs (PCBs 105, 118, 126 and 2,3,4,7,8-PeCDF) were shown to either bioaccumulate more in chicken fat or to be eliminated more readily in pork. This leads to the possibility that consumption of chicken would result in a higher TEQ human body burden than that from the same consumption of pork. In addition, PCDF congeners with non-2,3,7,8-substitution (e.g., 1,2,4,7,8-PeCDF) were present in chicken fat but absent in pork fat. Since the residue pattern in this commercial episode changes less in the avian species, these results reinforce the value of birds rather than mammals as markers of the source of contamination with persistent organochlorine pollutants.

An unusual poisoning with the unusual pesticide amitraz

Amitraz, 1,5 di-(2,4-dimethylphenyl)-3-methyl-1,3,5-tria za-penta-1,4-diene, a formamidine pesticide, is used worldwide. It causes side-effects in animals that resemble those caused by pure α2-adrenergic agonist drugs such as clonidine. Data on poisonings in humans are scanty. We report on a case of human poisoning with amitraz with typical signs of α2-adrenoreceptor stimulation.

Comparison of accumulation of micropollutants between indigenous and transplanted zebra mussels (Dreissena polymorpha)

Zebra mussels (Dreissena polymorpha) were exposed at 12 canals and lakes situated in Flanders (Belgium), in cages for six weeks during the summer of 2002. Accumulation of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), hexachlorobenzene, and trace metals were measured in the transplanted mussels and levels compared to levels in indigenous mussels. Additionally, zebra mussels were exposed at a small lake in the vicinity of Antwerp (Belgium), and accumulation of contaminants was followed for an extended period from December 2001 to April 2002. Analysis of the pollutants in the indigenous mussels showed that the selected sites displayed a wide range of pollution from near to background to very high levels of metals and/or organic contaminants when compared to the literature. For organic contaminants and for most metals, comparison of levels between caged and resident mussels revealed no significant differences. Only for cadmium and nickel, significant differences were observed, with levels being either higher (cadmium) or lower (nickel) in caged mussels. For organic contaminants, significant correlations between levels in caged and resident mussels were found with r2 values up to 0.98. For some metals, no or poor correlations were found. At most sites, concentrations of those metals were of the same order of magnitude and comparable to levels in mussels from unpolluted sites. This might explain the absence of significant correlations. When mussels were exposed for an extended period, the concentration of some pollutants increased, whereas others decreased with time. Only in the case of certain metals did levels differ significantly because of the slow depuration of metals already present in the transplanted mussels. This is an additional indication that measured concentrations in transplanted mussels indeed reflected the local situation. With this study, we were able to prove the applicability of transplanted mussels as a biomonitoring tool for the accumulation of pollutants over a wide range of pollution.