The non-human primate: a possible model for human genetically determined polymorphisms in oxidative drug metabolism.

Genetic polymorphisms of drug oxidation are major determinants of interindividual variations in drug response and toxicity. Many animal models, including rats, have been used for clinical investigations of pharmacogenetics. However, because of large interspecies differences, these data are difficult to extrapolate to humans.

Phenotyping polymorphic drug metabolism in the French Caucasian population.

Because of the large interethnic differences in the incidence of poor metabolizer phenotypes, French Caucasians have been studied for two independent polymorphisms, debrisoquine/dextromethorphan and mephenytoin metabolism. One hundred and thirty-two unrelated French Caucasians were phenotyped using oral doses of dextromethorphan 20 mg and mephenytoin 100 mg. Individual dextrorphan excretion over 8 h and the dextromethorphan/dextrorphan metabolic ratio were calculated.

S-mephenytoin 4-hydroxylase is inherited as an autosomal-recessive trait in Japanese families.

The 4-hydroxylation of S-mephenytoin exhibits polymorphism in both whites and Japanese such that the populations can be divided into extensive and poor metabolizers. To determine whether genetic constitution is a primary determinant in the expression of such metabolism, four extended Japanese families containing 13 sets of parent/offspring relationships were phenotyped for their mephenytoin 4-hydroxylation activity using the 8-hour urinary ratio of unchanged R- and S-mephenytoin as the trait measurement. The incidence of the poor metabolizer phenotype in these families was 2.

Amphotericin-B nephrotoxicity in humans decreased by sodium supplements with coadministration of ticarcillin or intravenous saline.

Previous observations suggest that salt loading can help reverse amphotericin-B induced nephrotoxicity. Evidence is presented indicating that sodium supplements provide prophylaxis against the development of amphotericin-B nephrotoxicity. In a retrospective study at Vanderbilt University, 14/21 patients receiving amphotericin B (target dose, 25 mg/day) without salt supplements developed impaired renal function; in 10 instances amphotericin B was temporarily withdrawn.

[Importance of the study of the minimal bactericidal time of serum in the choice of optimal treatment of neonatal septicemias].

Rapid eradication of bacteria in bloodstream is critical for the outcome in neonatal bacterial sepsis. Two groups of neonates with E. coli K1 sepsis without purulent meningitis were studied.

[Prevention of nephrotoxicity of amphotericin B during the treatment of deep candidiasis].

Previous observations suggest that tubulo-glomerular feedback could be involved in amphotericin B nephrotoxicity. We then investigated the influence of sodium status on the occurrence of renal damage during amphotericin B therapy. A retrospective survey demonstrated that impaired renal function occurred during therapy in 67 per cent of the patients who received amphotericin B alone and in 12 per cent of the patients who received amphotericin B and ticarcillin (parenteral sodium supplement of 100-150 meq per day).

Urinary excretion of N-acetyl-glucosaminidase and beta-2-microglobulin as early markers of gentamicin nephrotoxicity in neonates.

A prospective study in 16 healthy and 16 gentamicin-treated neonates was undertaken to compare the urinary excretion of proximal tubular markers such as beta 2-microglobulin (beta 2-m) and total N-acetyl-beta-D-glucosaminidase (NAG) and its isoenzymatic form NAGB. beta 2-m excretion was not related to postnatal age in control full-term neonates; it was significantly increased in gentamicin-treated full-term neonates. The urinary excretion of the lysosomal markers, total NAG and NAGB, rose significantly with postnatal age in control group.

Extrahepatic glucuronidation of morphine in the dog.

The pharmacokinetic disposition of morphine was studied in sham-operated dogs, dogs with hepatic devascularization, and dogs with bile duct and ureter ligation after iv administration of 1 mg/kg of morphine. In sham-operated dogs, morphine is rapidly distributed and eliminated, with a terminal half-life of 65 +/- 30 min. Morphine glucuronide appeared in plasma within 5 min and rose rapidly to levels an order of magnitude higher than morphine levels, before both declined in parallel.

Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital.

The simultaneous dosing of two drugs with co-regulated genetic polymorphisms determined by a single cytochrome P-450 isozyme could result in competitive inhibition of metabolism. We investigated this hypothesis in vivo by studying the interaction of mephobarbital and mephenytoin in eight normal subjects with wide variability in S-mephenytoin 4-hydroxylation. Each received oral racemic mephenytoin (100 mg) alone and, on a separate occasion, 1 hour after oral racemic mephobarbital (200 mg).

Subacute neurotoxicity following long-term exposure to carbaryl.

Carbaryl, a widely used insecticide, is reputed to have a wide safety margin. It can induce acute cholinesterase poisoning, which is rapidly reversible on discontinuation of exposure. Long-term sequelae from long-term exposure have not previously been described in humans.

Is carbaryl as safe as its reputation? Does it have a potential for causing chronic neurotoxicity in humans?

The observation of neurotoxicity in a subject with long-term exposure to high levels of carbaryl has prompted the review of the potential for carbaryl to cause toxicity. Short-term studies in animal species and humans confirm that carbaryl can cause toxicity due to cholinesterase inhibition. Wide variations in the dosage required to induce toxicity in either different species or in one species by different routes of administration can in part be explained by differences in drug disposition.

[A Parisian case of congenital malaria].

A case of symptomatic congenital malaria (Plasmodium vivax) was diagnosed and treated in a 3 week-old girl in Paris. This led to discuss the characteristics of transplacental contamination and symptomatology of congenital malaria and the methods for diagnosis and treatment of this very rare disease.

Prostacyclin concentrations in cord blood and in the newborn.

The levels of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) were measured in cord blood and in peripheral venous blood in newborns using gas chromatography coupled with negative ion chemical ionization mass spectrometry. The plasma concentrations of 6-oxo-PGF1 alpha in cord blood increased significantly between delivery and placental expulsion (P less than .005).

Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations.

Interethnic differences in debrisoquin and mephenytoin hydroxylation have been compared between normal white (n = 183) and Japanese (n = 100) subjects with the 8-hour urinary metabolic ratio of debrisoquin and the urinary S/R enantiomeric ratio of mephenytoin to identify extensive (EM) and poor (PM) metabolizers. In white subjects the frequency of PMs was 8.7% and 2.

Phenotypic differences in mephenytoin pharmacokinetics in normal subjects.

The urinary metabolic profile of mephenytoin and its oxidative metabolites indicates significant stereoselective metabolism of its two enantiomers. Also, polymorphic oxidation, which is present in about 2 to 5% of the Caucasian population, has been demonstrated by an impaired ability to 4-hydroxylate this anticonvulsant. In order to determine the consequences of such metabolism, the plasma concentration/time profiles of the enantiomers of mephenytoin and its N-demethylated metabolite, phenylethylhydantoin (PEH), were investigated after a single p.

Elevated plasma 1,25-dihydroxyvitamin D concentrations in infants with hypercalcemia and an elfin facies.

We measured plasma concentrations of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in the course of a 6-to-37-month survey of four children with hypercalcemia and an elfin facies (Williams syndrome). Levels of 1,25-(OH)2D were elevated (160 to 470 pg per milliliter) during the hypercalcemic phase of the disease, when the children were five to nine months old, and they decreased thereafter. Plasma 1,25 (OH)2D levels were higher than those found in three children (16 to 60 months old) with the elfin facies syndrome and no hypercalcemia (42 to 71 pg per milliliter) and eight children (1 to 36 months old) with hypercalcemia and no dysmorphy (12 to 140 pg per milliliter), including two children with vitamin D intoxication.

[Circulating metabolites of vitamin D in 14 children with hypercalcemia].

Circulating vitamin D metabolite concentrations, i.e. 25-(OH)D, 24,25-(OH)2D, 1,25-(OH)2D have been assayed in 14 hypercalcemic children.