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Biomedical subjects

J L Dhondt

Publications and source records attributed to J L Dhondt.

At least 19 recordsLinked to original sources
PubMed1995

Changes of cerebral biopterin and biogenic amine metabolism in leukemic children receiving 5 g/m2 intravenous methotrexate.

Acute or subacute neurologic disorders can be observed in patients receiving high-dose methotrexate therapy for lymphoblastic leukemia or malignant tumor. Impairment of biopterin metabolism leading to decreased availability of monoamine neurotransmitters has been suggested to explain methotrexate neurotoxicity. To investigate such a mechanism, we have measured prospectively by HPLC the concentrations of total biopterin, homovanillic acid, and 5-hydroxyindolacetic acid in cerebrospinal fluid of 57 children with acute lymphoblastic leukemia. A sequential analysis of cerebrospinal fluid was performed for each patient: cerebrospinal fluid samples were obtained before therapy and after each of the four high-dose methotrexate infusions during the CNS prophylaxis phase. A significant increase of total biopterin concentrations in cerebrospinal fluid was observed after high-dose methotrexate therapy compared with the pretreatment values. No cumulative effect was noted. In contrast, no significant variation of the homovanillic acid and 5-hydroxyindolacetic acid levels was observed in cerebrospinal fluid. However, individual analysis revealed a transient decrease of homovanillic acid and 5-hydroxyindolacetic acid concentrations in cerebrospinal fluid of six children. The increase of total biopterin mimicking that observed in inherited dihydropteridine reductase deficiencies suggests that methotrexate inhibits the regenerating system of biopterin in the brain of patients undergoing high-dose methotrexate therapy.

Adolescent↗
PubMed1995

[Epidemiological data. Neonatal and prenatal screening].

Unlike what is generally thought, cystic fibrosis is not the most frequent hereditary disease. Its frequency is approximately 1/3 200 and varies with the geographic area. The frequency of heterozygous subjects is about 1/28. No country has established a generalized neonatal screening programme, for technical reasons and because there has been no demonstration of a beneficial effect from early care. It would nevertheless be useful to develop experimental programmes defining which protocols might best be established. Antenatal screening can be based on detecting heterozygous subjects, a technically feasible operation, although answers to a large number of questions would be required.

Cystic Fibrosis↗
PubMed1993

2,4-diamino-7-hydroxy-pteridines in biological fluids of patients on high-dose methotrexate.

Concentrations of 2,4-diamino-7-hydroxy-pteridines in plasma and cerebrospinal fluid (CSF) are reported for the 0.5-8 g/m2 dose range of methotrexate in children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma. This experiment has revealed that: (1) there is a wide inter-individual but relatively narrow intra-individual variability of the maximal concentrations of 2,4-diamino-7-hydroxy-pteridines in plasma during consecutive methotrexate cycles; (2) the increase in the level of the metabolites in plasma was related to increments of the methotrexate dose, but not above 5 g/m2: this can be explained by a saturable conversion of methotrexate to 2,4-diamino-7-hydroxy-pteridines; (3) significant correlations were found between simultaneous values of 2,4-diamino-7-hydroxy-pteridines in plasma and CSF; (4) the formation of 2,4-diamino-7-hydroxy-pteridines did not depend on the ages of patients receiving the same dose of methotrexate. The presence of these compounds in plasma and CSF in significant amounts creates the potential for a number of competitive interactions with pteridine-dependent metabolism which may open up new possibilities for understanding the metabolic side-effects of methotrexate therapy.

Adolescent↗
PubMed1992

Impairment of cerebral biogenic amine synthesis in a patient receiving high-dose methotrexate.

A transient acute neurologic syndrome occurred in a 15-year-old boy receiving high-dose methotrexate (MTX) for acute lymphoblastic leukemia. Cerebrospinal fluid analysis revealed a decrease of homovanillic acid and 5-hydroxyindoleacetic acid concentrations with a rise of biopterin levels. These findings suggest that MTX can induce a transient alteration of the metabolism of tetrahydrobiopterin leading to the defect of biogenic amine neurotransmitter synthesis.

Adolescent↗
PubMed1992

[Measurement of dihydropteridine reductase activity in dried blood eluates: physiological and pathological implications].

Tetrahydrobiopterin deficiency in hyperphenylalaninemic babies has to be rapidly recognized since the disease requires a specific treatment. Although the measurement of pteridines in urine can detect most of tetrahydrobiopterin deficiencies, DHPR measurement has to be performed to circumvent the risk of missing DHPR deficiency, especially at the neonatal period. The possibility to measure DHPR activity in dried blood samples justifies itself by its convenience and simplicity. Expression of activity per mg of hemoglobin improves the precision of the assay by removing variation in the elution step (insufficient blood being loaded onto the filter paper, hematocrit variation, thickness of filter paper used). The distribution of DHPR activities, corrected from the progressive decrease with age, showed that 2.5% of the hyperphenylalaninemic or normal population have low levels of activity (below 50% of normal). This observation suggests that genetic variations may exist, as illustrated by the analysis of 11 families. Although blood DHPR measurement seems efficient for screening DHPR deficiency, the finding in a family of clinically normal subjects with zero activity illustrates the risk of false positive results of the enzymatic test.

Adolescent↗
PubMed1991

2,4-diamino-7-hydroxy-pteridines, a new class of catabolites of methotrexate.

Methotrexate remains a commonly used drug in the chemotherapy of various malignancies. The known catabolites are 7-hydroxy-methotrexate, formed in the liver, and diamino-methyl-pteroic acid formed in the gut. We report for the first time evidence that 2,4-diamino-7-hydroxy-pteridine derivatives are present in the biological fluids of patients on high-dose methotrexate protocols. So far, two major derivatives have been identified as 2,4-diamino-6-hydroxymethyl-7-hydroxy-pteridine and 2,4-diamino-6-methyl-7-hydroxy-pteridine. In regard to the actual knowledge of the catabolism of pteridines, these compounds are presumably formed by intestinal bacteria during enterohepatic circulation of the drug. Their slow clearance from the body raises the question of possible interference of these compounds on pteridine-dependent enzymes, which might explain in part some of the toxic effects of methotrexate.

Adolescent↗
PubMed1991

Economic evaluation of cost-benefit ratio of neonatal screening procedure for phenylketonuria and hypothyroidism.

A comparison between the cost of identification and care of patients with phenylketonuria (PKU) and congenital hypothyroidism (CH) and the expenditure for the care of untreated retarded patients has been established on the basis of the activity of the Nord-Pas-de-Calais regional screening centre and of interviews with patients' families. The analysis yields a benefit-cost ratio of 6.6 for PKU and 13.8 for CH prophylaxis. However, cost-benefit varies depending on the economic partner, i.e. the patient's family, Social Security or Administration.

Cost-Benefit Analysis↗
PubMed1991

Strategy for the screening of tetrahydrobiopterin deficiency among hyperphenylalaninaemic patients: 15-years experience.

Tetrahydrobiopterin deficiency in hyperphenylalaninaemic babies has to be rapidly recognized since the disease requires a specific treatment. Based on 15 years experience, we report on the evolution of a strategy for the detection of such patients. A total of 913 hyperphenylalaninaemic patients have been studied and 15 tetrahydrobiopterin deficiencies have been detected or confirmed. DHPR assay in dried blood samples and pteridine measurement in urine collected on filter paper combine convenient sampling and reliable tests for systematic investigation of hyperphenylalaninaemic patients for cofactor deficiency.

Belgium↗
PubMed1991

[Evaluation of fetal lung maturity with the measurement of enzymatic activities in amniotic fluid: comparison of three ratios].

Measurement, in amniotic fluid, of gamma-glutamyl-transferase (GGT) alkaline phosphatase and of thermostable and thermolabile (TLAP) isoenzyme allows to anticipate the unexpected risk of hyaline membrane disease. ROC method adapted to three ratio of these enzymatic activities shows that TLAP/GGT is the most performant at the level of 0.9 with a sensitivity of 96% and a specificity of 60%.

Alkaline Phosphatase↗
PubMed1991

[Value of amniotic gamma-glutamyl-transpeptidase assay in the diagnosis of fetal digestive stenosis after 24 weeks of amenorrhea].

In 18 women compared with 1,181 controls, foetal digestive tract stenoses were discriminated, independently of the gestational age, by a more than 50 IU/l level of gamma-glutamyl transpeptidase in the amniotic fluid. This test had a specificity of 99% and a sensitivity of 85% which was accounted for by the inclusion in the study of distal stenoses and oesophageal atresias, all conditions where the gamma-glutamyl transpeptidase level is normal. In cases with ultrasonically detected abdominal wall abnormalities, this test is also useful in the diagnosis of subjacent digestive tract stenosis.

Amniotic Fluid↗
PubMed1991

[Early neurotoxicity of high-dose of methotrexate and tetrahydrobiopterin deficiency].

Transient neurologic dysfunction associated with high-dose methotrexate and citrovorum factor rescue (MTX-CF) has been previously reported. At the biochemical level, there are at least two important pathways in central nervous system metabolism which might be disturbed by MTX: MTX may deplete the cell of the de novo synthesis of purine nucleotides and thymidylate through its action on dihydrofolate reductase (DHFR), and also inhibit dihydropteridine reductase (DHPR), an enzyme maintaining the cofactor of phenylalanine-hydroxylase in its active tetrahydrogenated form (tetrahydrobiopterin), and hence interfere with the supply of the neurotransmitters derived from tyrosine and tryptophan. We describe such a neurologic disease in a patient with acute lymphoblastic leukemia (ALL) receiving chemotherapy. Significant increase in cerebrospinal fluid biopterins supports the hypothesis of an inhibition of dihydropteridine reductase by MTX, and provides additional suggestions in terms of etiology, diagnosis and treatment.

Biopterins↗
PubMed1991

[Immunoelectrophoresis or immunofixation: identification of monoclonal gammopathy].

Both methods enable the clinical laboratory to identify monoclonal gammapathies with a good sensitivity. The immunofixation method, more quickly used than the immunoelectrophoresis, is easier to obtain the best resolution. It is well adjust for the characterization of low concentration gammapathies like immunoglobulin light chains. Immunofixation appears to take a more and more important place in the clinical laboratory.

Humans↗
PubMed1991

[High-dose methotrexate and hyperphenylalaninemia].

The occurrence of increased levels of blood phenylalanine after therapeutic administration of folate analogues has been occasionally reported and attributed to the inhibition of dihydropteridine reductase, an enzyme maintaining the cofactor of phenylalanine hydroxylase in its active tetrahydrogenated form (tetrahydrobiopterin). To study further this metabolic effect, 46 patients receiving high dose methotrexate (5 to 8 g/m2) infusions have been studied. Significant increase in serum phenylalanine was observed in 95% of methotrexate cycles, occurring at the end of infusion. In contrast to the large inter-individual variations, maximal phenylalanine concentrations were of the same magnitude in each individual, suggesting individual predispositions. The hypothesis of an inhibition of dihydropteridine reductase by methotrexate was supported by the parallel course of serum biopterin and phenylalanine levels, but in some way contradicted by the rapid return to baseline values of both, 24 hours after the end of methotrexate infusion. This transient and often moderate hyperphenylalaniemia is probably harmless except if it reflects a more general inhibition of pteridine-dependent hydroxylases. Especially, such an inhibition of cerebral tyrosine- and tryptophan-hydroxylase activities might be the reason for transient neurological disturbances observed in some patients on high-dose methotrexate treatment.

Adolescent↗
PubMed1990

Pterins analysis in amniotic fluid for the prenatal diagnosis of GTP cyclohydrolase deficiency.

Hyperphenylalaninaemia due to tetrahydrobiopterin deficiency is a group of rare and severe diseases. Prenatal diagnosis of dihydropteridine reductase and pyruvoyltetrahydropterin synthetase deficiencies can be achieved by enzyme assay in cultured fluid cells and/or fetal blood. In contrast, prenatal diagnosis of GTP cyclohydrolase deficiency can only rely on the measurement of pterin metabolites in the amniotic fluid. A pregnancy at risk for GTP cyclohydrolase deficiency was investigated. HPLC analysis of amniotic fluid pterins revealed neopterin and biopterin concentrations below the lowest limit of normal age-matched gestations. The mother refused abortion. The early follow-up of the child confirmed the diagnosis of GTP cyclohydrolase deficiency (hyperphenylalaninaemia, abnormal profile of urinary pterins and neurological deterioration).

Amino Acid Metabolism, Inborn Errors↗