Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus.

OBJECTIVE: Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth. METHODS: Ibuprofen was administered on days 3, 4, and 5 by a 15-minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of closing the ductus arteriosus. Blood samples were drawn at time zero and at 0.5, 1, 2, 4, 12, and 24 hours after the first and third doses. Ibuprofen plasma concentrations were assayed by HPLC. RESULTS: A total of 27 premature infants were included (gestational age, 28.6 +/- 1.9 weeks; birth weight, 1250 +/- 460 g; values are mean +/- standard deviation). Ibuprofen pharmacokinetics followed a 2-compartment open model. Between the first and third doses (day 3 and day 5) there was a significant decrease of the volume of distribution of the central compartment (Vd(c)) (0.244 versus 0.171 L/kg; P =.03) and area under the plasma concentration-time curve (524 versus 447 mg. h/L; P =.01). The decrease in Vd(c) was most pronounced in patients with a closing ductus. Total body clearance and plasma half-life did not change significantly. No significant differences were observed in ibuprofen peak plasma concentrations after the first and third doses in relation to ductal status after treatment. CONCLUSION: Ibuprofen pharmacokinetics showed a large interindividual variation in premature infants during treatment for patent ductus arteriosus, and significant changes may occur between day 3 and day 5 after birth in those infants with a closing ductus. These findings may have implications for the treatment schedule with ibuprofen in patients with patent ductus arteriosus.

Comparison of chemical-activated luciferase gene expression bioassay and gas chromatography for PCB determination in human serum and follicular fluid.

We assessed exposure to dioxin-like compounds using chemical and bioassay analysis in different matrices in a female population. A total of 106 serum and 9 follicular fluid samples were collected from infertile women attending Centers for Reproductive Medicine in Belgium from 1996 to 1998. Major polychlorinated biphenyl (PCB) congeners were quantified by chemical analysis using gas chromatography with electron-capture detection, and the chemical-activated luciferase gene expression (CALUX) bioassay was used to determine the total dioxin-like toxic equivalence (TEQ) of mixtures of polyhalogenated aromatic hydrocarbons present in body fluids, such as serum and follicular fluid. To the best of our knowledge, this is the first investigation to determine TEQ values by the CALUX bioassay in follicular fluid. The TEQ levels in both matrices are well correlated (r = 0.83, p = 0.02). As the chemical and bioassay analysis executed in this study do not cover the same span of polyhalogenated aromatic hydrocarbons, we did not expect totally correlated results. Moreover, the sample workup and quantification of the analytes differed completely. Nonetheless, the TEQ values in human extracts correlated well with the sum of four major PCB congeners chemically determined in both serum and follicular fluid. These results indicate that the CALUX bioassay may serve as a simple, relatively inexpensive prescreening tool for exposure assessment in epidemiologic surveys.

Surprising findings following a Belgian food contamination with polychlorobiphenyls and dioxins.

We found that 12.1% of Belgian export meat samples from chicken or pork, unrelated to the PCB/dioxin crisis from 1999, contained more than 50 ng polychlorinated biphenyls (PCBs)/g fat and that 6.5% of samples contain more than 20 ng/g fat for the sum of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and its metabolites. Part of this background contamination stems from imported animal feed ingredients (fish flour and grains), sometimes contaminated by recent use of DDT, as can be deduced from the ratio between DDT and its main metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE). However, after comparing PCB concentrations in fish flour and grains with those found in meat, we suggest that the high concentrations stem from recycled fat. This is the first paper describing background concentrations of PCBs in animal meat from Belgium.

Acute poisoning with amphetamines (MDEA) and heroin: antagonistic effects between the two drugs.

A case of oral ingestion of large doses of both the amphetamine-derivative 3,4-methylene dioxyethamphetamine (MDEA) and heroin is reported. Despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. The patient recovered after symptomatic treatment. The possibility that opposite pharmacological properties of the two drugs prevented the patients death is discussed.

Propylene glycol-induced side effects during intravenous nitroglycerin therapy.

Propylene glycol, an alcohol frequently used as a solvent in medical preparations, is considered non-toxic. We found that this solvent, used in a commercially available IV nitroglycerin solution, may cause hyperosmolality, hemolysis and lactic acidosis. The influence of kidney function as the main determinant in causing accumulation of this solvent and consequently hyperosmolality is emphasized. A review of the literature dealing with propylene glycol is given. The possible mechanisms of neurological disturbances occurring during IV nitroglycerin therapy are discussed.

Simultaneous determination of p-aminobenzoic acid, acetyl-p-aminobenzoic acid and p-aminohippuric acid in serum and urine by capillary gas chromatography with use of a nitrogen-phosphorus detector.

In various studies during recent years, the use of p-aminobenzoic acid has been described in screening tests for exocrine pancreatic function. A synthetic three-unit compound N-benzoyl-L-tyrosyl-p-aminobenzoic acid has been administered orally and hydrolysed in the small intestine in the presence of chymotrypsin to N-benzoyl-L-tyrosine and p-aminobenzoic acid. This study describes a convenient procedure in which, after a selective extraction and derivatization with diazomethane, capillary gas chromatography is used combined with nitrogen-sensitive detection. With the proposed procedure, p-aminobenzoic acid and its major metabolites, acetyl-p-aminobenzoic acid and p-aminohippuric acid, can be monitored in serum and in urine samples.

Pentachlorophenol concentrations in human cerebrospinal fluid.

Pentachlorophenol (PCP) is a widely applied insecticide and fungicide, particularly in wood preservation. Significant amounts of this compound have been reported in human serum, adipose tissue and urine. PCP is even found in people not occupationally exposed to this toxin or not living in PCP-treated log-houses. Substantial concentrations of this possible neurotoxic agent were detected in the cerebrospinal fluid (CSF) of 16 neurologic patients as measured by a high resolution gas chromatographic method using electron capture detection. This is the first report on PCP levels in (human) CSF. The observed level in CSF ranged from 0.24 up to 2.03 micrograms/L (ppb), with an average value of 0.75 +/- 0.49. The cerebrospinal fluid level did not correlate with the serum PCP concentration nor with the protein level of the cerebrospinal fluid.

Quantitative determination of nitroglycerin by capillary gas chromatography-electron capture detection.

A rapid and sensitive capillary gas chromatographic method based on the one described by Noonan et al. [1] was used to evaluate the nitroglycerin content in serum samples of healthy volunteers, who had orally received a special preparation of the drug (Nisconitrine 6.5, Bio-Therabel). Concentrations were monitored up to 12 h after administration. In accordance with other literature data [2], no detectable amounts of the mother compound were found (limit of detection: 50 pg ml-1). Yet, significant amounts of the active metabolites, 1,2- and 1,3-dinitroglycerine could be demonstrated. Due to the low mass spectrometric response (electron impact ionization) of the different nitroglycerins, positive confirmation of the results with GC-MS was not possible. However, the concentrations reported here do agree with literature data [2], i.e. the ng ml-1 level.

The relation between levels of selected PCB congeners in human serum and follicular fluid.

Individual congener and total PCB concentrations were determined in serum and follicular fluid obtained from women undergoing assisted reproductive technologies (in-vitro fertilization and embryo replacement). Although the mean individual PCB levels revealed varying degrees of contamination, the results fall in the same range as that observed by other investigators. Except for PCB 118, correlations between levels in serum and follicular fluid were strong, and statistically significant at p < 0.05. Moreover PCB 153, a major and very stable PCB congener has been shown to correlate to the total amount of PCBs (r = 0.994, and r = 0.987, for serum and follicular fluid, respectively). The same accumulation patterns of PCBs for serum and follicular fluid have been observed.

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 PCP-containing 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.

An unusual poisoning with the unusual pesticide amitraz.

Amitraz, 1,5 di-(2,4-dimethylphenyl)-3-methyl-1,3,5-triaza-penta-1,4-diene, a formamidine pesticide, is used worldwide. It causes side-effects in animals that resemble those caused by pure alpha 2-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 alpha 2-adrenoreceptor stimulation.

A 2,4-dichlorophenoxyacetic acid induced fatality.

This paper reports on a fatal intoxication by oral ingestion of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). At admission, the victim was unconscious. His condition deteroriated rapidly with blood loss from his mouth and nose. Since the cause of this condition was not known, gastroscopy was performed and haemorrhagic mucosa was observed in the mouth, oesophagus and stomach. Gastric contents (removed by lavage), urine and blood were submitted for toxicological analysis. Unfortunately, within 3 h of admission (about 5 h following ingestion of the toxin) profound cardiogenic shock developed and the patient died. The identity of the toxic xenobiotic was revealed by gas chromatography-mass spectrometry. Analytical quantification of the herbicide was performed by acid extraction prior to gas chromatographic examination using electron capture detection. His blood level of 2,4-D was 192 mg l-1.

On the de novo synthesis of polychlorinated dibenzo-p-dioxins and dibenzofurans.

Some possible intermediates or by-products in the synthesis of polychlorodibenzo-p-dioxins and dibenzofurans in municipal waste incinerators are presented. In stack gas samples from two different incinerators, the following compounds were tentatively identified: polychloromonobenzofurans, polychloromonobenzodioxins, monobromo-polychlorobenzenes and polychlorothiophenes. The occurrence of complete series of homologues and isomers with an increasing degree of chlorination suggests an analogous formation mechanism with common precursors. The presence of these compounds in the vapour phase, the non-regiospecific character of these reactions and the high reaction temperature and speed confirm a radical mechanism of formation.

Fungal tremorgens: the mechanism of action of single nitrogen containing toxins--a hypothesis.

Tremorgenic mycotoxins are fungal secondary metabolites with a specific effect on the central nervous system (CNS). Except for a few toxins that are produced by Claviceps paspali, a plant parasitic fungus, most tremorgenic mycotoxins are synthesized by common saprophytic moulds of the genera Penicillium and Aspergillus. Since these compounds produce sustained tremor in the abscence of other neurotoxic effects, several authors have suggested that they are the causative agents of a number of naturally occurring incoordination syndromes in ruminants. The nature of the tremor produced by these compounds in laboratory animals is clinically indistinguishable from that occurring naturally. In particular, the most implicated tremorgenic mycotoxins are those that contain a single nitrogen atom in their molecules. Although individual compounds within this group are produced by unrelated fungal species, they all contain a similar biologically active chemical moiety. To date, their mechanism of action is unknown, and their role in neuropharmacology has not yet been defined. However, the presence of a GABA-like conformation within their active nucleus and the limited torsional flexibility of this moiety suggest that they are partial agonists of GABA (gamma-aminobutyric acid). A hypothetical mode of action of these toxins at the GABA receptor sites is presented and discussed.

Positive confirmation of identity of doping agents using gas chromatography-mass spectrometry with Fourier transform infrared spectrometry.

During the past two decades, the use of retention times in gas chromatography has been augmented by mass spectrometric data. By providing both the retention indices and spectrometric data, this technique has greatly improved gas chromatographic identification analysis. However, although gas chromatography-mass spectrometry has become pre-eminent, several drawbacks still remain. The mass spectral library often gives erroneous identifications when concentrations near the detection limit are analysed, when gas chromatographically interfering substances are present, or when structural isomers or compounds exhibiting identical retention behaviour are analysed. Linked with gas chromatography-mass spectrometry, Fourier transform infrared spectroscopy can be a powerful complementary technique in peak identification analysis. Some spectral data to illustrate this point are presented.

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).

The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: a case-control study of infertile women.

BACKGROUND: A case-control study was designed to determine the possible association between chronic exposure to dioxins and polychlorinated biphenyls (PCBs), and the occurrence of endometriosis. The study group consisted of 42 infertile endometriosis cases and 27 mechanical infertile controls, both groups attending one of the collaborating Centres for Reproductive Medicine, enrolled between 1996-1998. METHODS: Exposure assessment to dioxin-like compounds was determined through CALUX (chemical-activated luciferase gene expression)-bioassay to measure dioxin-like total toxic equivalents (dioxins and co-planar PCBs), whereas non-co-planar PCBs were determined through chemical analysis. RESULTS: No association was found between median dioxin-like total toxic equivalents (TEQ) and the occurrence of endometriosis in infertile women [cases (n = 34): 29; controls (n = 27): 24; NS]. When patients were subdivided based on an arbitrary cut-off value of 100 pg TEQ/g serum lipids, no statistically significant association between very high exposure to dioxin-like compounds and endometriosis was found [crude odds ratio (OR) = 4.33; confidence interval (CI) 0.49-38.19; NS]. After adjusting for body mass index, and alcohol consumption, the risk increased slightly to OR = 4.6 (CI 0.48-43.62; NS). There was no confounding by age, ovulatory dysfunction, caffeine intake, smoking or exposure to non-co-planar PCBs. CONCLUSIONS: The study results showed no statistically significant association between exposure to dioxin-like compounds and the occurrence of endometriosis in infertile women.

Drugs of abuse and alcohol in weekend drivers involved in car crashes in Belgium.

STUDY OBJECTIVE: To determine levels of alcohol and drugs of abuse in weekend drivers injured in car crashes. METHODS: This study was the first systematic drug and alcohol testing of blood and urine samples of drivers injured in weekend car crashes in Belgium. Five collaborating hospital in Flanders participated. All injured weekend drivers admitted to the emergency units from July 1, 1994, to June 30, 1995, were included in the study sample. Sampling times were from Friday at 8 PM to Monday at 8 AM. RESULTS: Of the 211 injured drivers, 47.9% had positive test results for screenings for drugs or alcohol; 35.5% only for alcohol, 6.6% only for drugs, and 5.7% had positive results for both alcohol and drugs. Of the 87 weekend drivers with positive alcohol test results, 8% had a blood alcohol concentration (BAC) level below 80 mg/dL, 25.3% had a concentration between 150 and 190 mg/dL, and 39% had a BAC of 200 mg/dL or greater. There seems to be a consistent association between the consequences of the weekend crashes and the use of alcohol, drugs, or both. More than 50% of those who had negative results for drugs and alcohol could leave the hospital within 24 hours after their car crash. For the majority of those with positive findings for alcohol only or for drugs and alcohol (respectively, 72% and 78%), hospitalization in a general hospital unit or ICU was necessary. CONCLUSION: The results suggest that testing drivers for use of alcohol alone is insufficient.

Comparison of persistent organic pollutant residues in serum and adipose tissue in a female population in Belgium, 1996-1998.

This study was performed to determine and compare persistent organic pollutant (POP) levels in different matrices in a female population. A total of 96 serum and 46 adipose tissue samples were collected from infertile women (n = 101) attending Centers for Reproductive Medicine in Belgium from 1996 to 1998. Gas chromatography with electron-capture detection was used to quantify residue levels on a lipid basis of seven organochlorine pesticides (OCPs) and seven polychlorinated biphenyls (PCBs). There was a strong association between adipose tissue and serum residues. The adipose tissue levels of CB-138, 153, 180 and p,p'-DDE were explained by the serum residues. Besides, the accumulation pattern for CB-153 and CB-180 in serum and adipose tissue are mirror images of each other.