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. We therefore phenotyped 64 non-human primates for debrisoquine and mephenytoin polymorphisms and identified poor metabolizers of both drugs. The frequency of poor metabolizers was 14% for debrisoquine (95% confidence limits, 6.5-25%) and 3% for mephenytoin (95% confidence limits, 0.5-10%). If family studies demonstrate a genetic basis for the two independent defects, this animal species could be used for in vivo and in vitro pharmacogenetic investigations.

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. Extensive metabolizers were taken as subjects with a high dextrorphan output (15.56 mumol/8 h) and a low metabolic ratio (0.0023), and poor metabolizers were those with a low dextrorphan output (0.39 mumol/8 h) and a high metabolic ratio (7.00). Individual 4-hydroxymephenytoin excretion and mephenytoin hydroxylation indices were also determined. Extensive metabolizers eliminated large amounts of 4 hydroxymephenytoin (133.2 mumol/8 h) and had a hydroxylation index of 1.99, and poor metabolizers, because of impaired mephenytoin metabolism, had a high hydroxylation index (277). The incidence of the poor metabolizer phenotype was 3% for dextromethorphan (95% confidence limits 0.5%-8.5%) and 6% for mephenytoin (95% confidence limits 2%-12.5%).

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 2.2 times greater than that in an unrelated Japanese population. In three families in which both parents were poor metabolizers of mephenytoin, all six children also exhibited the poor metabolizer trait. The phenotype distribution for each family studied was consistent with the hypothesis that mephenytoin 4-hydroxylation activity is under diallelic, monogenic control, with the poor metabolizer phenotype being the autosomal recessive homozygous genotype and the extensive metabolizer phenotype including both the autosomal dominant and heterozygous genotypes.

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. In contrast, only 2/17 patients who received amphotericin B with ticarcillin (with its obligatory sodium supplement) developed nephrotoxicity (P less than 0.01). All four patients, who were receiving the combination of amphotericin B and ticarcillin and who had their ticarcillin therapy stopped, developed nephrotoxicity in the subsequent week. In a prospective observational study at Essen, 20 patients had 24 courses of amphotericin B (target dose, 40 mg/day) with routine supplementation of 1 liter of 0.9% sodium chloride daily. Only two patients showed evidence of nephrotoxicity and no dosage modification of amphotericin B was required in any patient. Four patients with initial evidence of mildly impaired renal function received full supplements without adverse effects or the development of nephrotoxicity. These observations suggest that routine parenteral administration of sodium supplements can help minimize the nephrotoxic potential of amphotericin B.

[Importance of the study of the minimal bactericidal time of serum in the choice of optimal treatment of neonatal septicemias]. / Intérêt de l'étude du temps minimal bactéricide du sérum dans le choix du traitement optimal des septicémies néonatales.

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. Group I (n = 14) received cefotaxime IV (100 mg.kg-1 D-1) plus netilmicin (4 mg.kg-1 D-1); group II (n = 8) received amoxicillin/clavulanic acid IV (100/10 mg.kg-1 D-1) plus netilmicin (4 mg.kg-1 D-1). Both groups were identical. For all strains MICs of cefotaxime, amoxicillin/clavulanic acid, netilmicin were less than 0.2, 4 and 1 mg/l respectively. Serum bactericidal activity (SBA) was determined for each patient (peak sample). The SBA was defined as the greatest dilution in which 99,99% of the inoculum was killed. Time-kill curves were performed with 1:16 dilutions of peak serum samples to measure the kinetic of bacterial killing. The minimal bactericidal time of serum (MBTS) was defined as the minimal time required to observe a decrease of more than 4 log CFU/ml of the bacterial inoculum. Samples (10 microliters) were taken at 1 h intervals over a 6 h period and at 24 h for quantitative culture. All patients cured. Median SBA were respectively 1/128 and 1/64 for group I and II. However, mean MBTS for groups I and II were respectively 1.2 h +/- 0.8 and 3.9 h +/- 1.4. Killing was more rapid in group I (p less than 0.01). The MBTS may be a clinically useful adjunctive test when optimal therapy would be expected.

[Prevention of nephrotoxicity of amphotericin B during the treatment of deep candidiasis]. / Prévention de la néphrotoxicité de l'amphotéricine B au cours du traitement des candidoses profondes.

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). Prospective studies were then undertaken both in adults and children. Intravenous sodium supplement was given intravenously as routine prophylaxis with amphotericin B therapy. In all courses amphotericin B was successfully administered without deterioration in renal function. These results support the hypothesis that parenteral sodium supplementation reduces the frequency of developing impaired renal function during amphotericin B therapy.

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. fMean values for total NAG and NAGB were significantly higher in the treated group but the isoenzymatic profile (NAGB/total NAG X 100) was not modified by gentamicin treatment.

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. In hepatic devascularized dogs, there was a marked delay in morphine elimination due to a 47% reduction in clearance. The appearance of morphine glucuronide in plasma was not delayed, but the AUC of morphine glucuronide was reduced by 56% compared to control for the first 180 min. In bile duct- and ureter-ligated dogs, elimination of morphine was increased and morphine glucuronide elimination from plasma was decreased, suggesting that glucuronide normally excreted in bile is hydrolyzed back to the parent compound and reabsorbed in sham-operated control animals. In conclusion, morphine was glucuronidated by both hepatic and extrahepatic glucuronyltransferases to an approximately equal extent in the dog.

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). After mephenytoin dosing alone, the 8-hour urinary enantiomeric (R/S) ratio indicated one poor (PM), one intermediate (IM), and six extensive (EM) metabolizers. Total intrinsic clearance of S-mephenytoin varied more than 100-fold, whereas the range for R-mephenytoin was only twofold. The urinary R/S ratio correlated (r = 0.92) with the enantiomeric ratio of the plasma AUCs over the same period, indicating no stereoselectivity in renal clearance. When mephenytoin was taken in the presence of mephobarbital, peak levels and AUC of S-mephenytoin increased while those of the R-enantiomer remained unchanged. Accordingly, the R/S ratios in both plasma and urine were reduced, with the change rank order-related to the control value of the total intrinsic clearance of S-mephenytoin (i.e., greatest in the most extensive EM). Thus the urinary R/S ratio can be used as a measure of the enantiomeric ratio of the plasma concentrations over the same time period of collection. Moreover, this ratio may be used to detect drug interactions that involve the cytochrome P-450 isozyme(s) responsible for the polymorphic 4-hydroxylation of mephenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

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. However, the information available about carbaryl's disposition in humans is inadequate to interpret the relevance of animal studies to humans. Limited long-term exposure studies in rats and dogs have not demonstrated unexpected adverse effects. However, long-term exposure in pigs results in a progressive neuromyopathy that is associated with structural damage and is not acutely reversible with atropine. Published information on the effects of long-term exposure to carbaryl in humans is limited and has not identified any adverse effects. It is concluded that not enough information is available to exclude the possibility that sustained high levels of exposure to carbaryl could be associated with neurotoxic or myotoxic responses in humans.

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. This report describes the experience of a 75-year-old man who had long-term excessive exposure to carbaryl and in whom a debilitating syndrome, including headaches, memory loss, proximal muscle weakness, muscle fasciculation, muscle cramps, and anorexia with marked weight loss, developed. At the time of diagnosis, serum pseudocholinesterase levels were low, and his major symptoms resolved on termination of exposure. Late clinical features were sleep apnea and progressive development of a peripheral neuropathy. The difficulty in diagnosing the cause of a group of relatively nonspecific symptoms raises the question of whether chronic carbaryl neurotoxicity might be occurring more frequently than previously suspected.

[A Parisian case of congenital malaria]. / Un cas parisien de paludisme congénital.

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). In newborns, the circulation levels of 6-oxo-PGF1 alpha after four hours of life were low and comparable to adult levels. Large quantities of prostacyclin are produced by the uteroplacental unit during parturition, but only small amounts are transmitted to the newborn during a normal delivery. The low plasma concentrations of 6-oxo-PGF1 alpha in newborns suggest that prostaglandin I1 is not a circulating vasodilator during the first week of life.

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 2.7% for debrisoquin and mephenytoin, respectively. In contrast, in Japanese subjects no PMs of debrisoquin were identified, while the incidence of PMs of mephenytoin was 18%. These substantial differences (P less than 0.001) in polymorphic distributions of oxidative drug metabolizing ability have implications for interethnic efficacy and toxicity of drugs and other xenobiotics that are metabolized by the involved cytochrome P-450 isozymes.

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.o. dose of racemic mephenytoin in normal subjects with different metabolizing ability for mephenytoin [extensive metabolizer (EM) vs. poor metabolizer (PM) phenotypes]. In the EM subjects, the disposition of S- and R-mephenytoin was markedly different with a 100- to 200-fold difference in mean oral clearance (4.7 vs. 0.027 liters/min) and a 30- to 40-fold difference in elimination half-life (2.1 vs. 76 hr). In these same subjects, R-PEH concentrations significantly accumulated over several days and then very slowly declined with an apparent half-life of about 200 hr. Plasma levels of S-PEH were essentially negligible. In contrast, the stereoselective elimination of mephenytoin was reduced markedly in subjects of the PM phenotype, with the disposition of the S-enantiomer being the same as that for R-mephenytoin, which in turn was similar to that observed for this enantiomer in EMs. Almost comparable plasma levels of S- and R-PEH were also present in PMs. Only a small amount (less than 5%) of unchanged mephenytoin was excreted in the urine regardless of phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

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. Hypercalcemia in the three children with elfin facies was controlled by a low-calcium diet. Serum calcium levels fell to the normal range, and plasma 1,25-(OH)2D levels were normal for age (18 to 105 pg per milliliter) at 14 to 47 months of age, even after appropriate therapy had been discontinued. These observations suggest that hypercalcemia may be the consequence of abnormal synthesis or degradation of 1,25-(OH)2D in children with the elfin facies syndrome.

[Circulating metabolites of vitamin D in 14 children with hypercalcemia]. / Métabolites circulants de la vitamine D chez 14 enfants en état d'hypercalcémie.

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. Results are as follows: a) Children with vitamin D intoxication (n = 2) had elevated serum 25-(OH)D and 24,25-(OH)2D concentrations but their 1,25-(OH)2D concentrations were similar to those found in normocalcemic children (10-110 pg/ml); b) Children with familial idiopathic hypercalcemia and hypocalciuria (n = 5), children with hypercalcemia and either Bartter's syndrome (n = 1), hemangiomatosis (n = 1), osteopetrosis after medullary graft (n = 1), also had 1,25-(OH)2D concentrations in the normal range; c) In contrast, 1,25-(OH)2D were elevated (160-470 pg/ml) in the four children with severe idiopathic hypercalcemia and elfin facies.