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Biomedical subjects

H Nau

Publications and source records attributed to H Nau.

At least 127 records · Page 7Linked to original sources
PubMed1992

Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations.

We analyzed the influence of changes in the prescribing of antiepileptic drugs to pregnant women on frequency and pattern of malformations in their offspring by comparing two consecutive cohorts (1972 to 1979, cohort A; 1980 to 1985, cohort B). In cohort A, 15 (10%) of 151 exposed, live-born infants had one or more congenital anomalies, which consisted primarily of congenital heart defects, facial clefts, and syndromes of dysmorphia with developmental retardation, in association with polytherapy (carbamazepine plus phenobarbitone plus valproate, with or without phenytoin, or phenobarbitone plus phenytoin plus primidone). In cohort B, the prescribing of phenobarbitone, phenytoin, or primidone had dropped markedly, whereas monotherapy with valproate and carbamazepine had increased. Thirteen (7.6%) of 172 exposed, live-born infants had congenital anomalies. The most frequent anomalies were spinal defects (four) and glandular hypospadias (three), all in association with maternal therapy with valproate, carbamazepine, or both. The results underline the need for continuation of prospective studies to monitor the effect of change in prescribing policies and to evaluate the role of metabolic interactions between drugs prescribed in combination.

Abnormalities, Drug-Induced↗
PubMed1991

Isotretinoin (13-cis-retinoic acid) metabolism, cis-trans isomerization, glucuronidation, and transfer to the mouse embryo: consequences for teratogenicity.

It has been reported that fractionated doses of 13-cis-retinoic acid are disproportionately more embryotoxic in pregnant mice than is the same dose given in a single bolus. Here, we examined limited pharmacokinetic profiles of a single (100 mg/kg dose given to NMRI mice on day 11 of gestation) versus multiple (3 x 100 mg/kg, 4 h apart) doses in an effort to assess the relative contribution to teratogenicity made by the drug and/or its metabolites. The major plasma metabolite of 13-cis-retinoic acid in the mouse was 13-cis-retinoyl-beta-glucuronide, followed by the 4-oxo metabolites and all-trans-retinoic acid. Transfer to the mouse embryo was very efficient for all-trans-retinoic acid, whereas, it was tenfold less efficient for 13-cis-retinoic acid and 100-fold less efficient for 13-cis-retinoyl-beta-glucuronide. The isomer all-trans-retinoic acid was found in the placenta at concentrations two- to three-fold higher than in the plasma, suggesting placental accumulation as well as placental cis/trans isomerization. Since 13-cis-retinoyl-beta-glucuronide and 13-cis- and all-trans-retinoic acid were detected in the embryo after this multiple dosing schedule, any of the three or their combinations may have been involved in the induction of malformations, but all-trans-retinoic acid, a well-known potent teratogen detected at concentrations of between 590 and 80 ng/g for 10 critical hours during gestation, could have been the major component.

Administration, Oral↗
PubMed1991

Transplacental distribution of weak acids in mice: accumulation in compartments of high pH.

The transplacental distribution of three weak acids was measured in mice on gestational day 11. The ratio of drug concentration in maternal, embryonic, and extraembryonic compartments compared to maternal plasma followed a consistent hierarchy such that amniotic fluid greater than or equal to exocoelomic fluid greater than embryo greater than embryo plasma greater than maternal skeletal muscle. This distribution pattern correlates well with pH in these compartments and suggests that pH gradients between compartments are an influential factor in determining weak acid drug disposition during pregnancy.

Acids↗
PubMed1991

Lack of teratogenicity of trans-2-ene-valproic acid compared to valproic acid in rats.

The teratogenicity of trans-2-ene-valproic acid (300 and 400 mg/kg) was compared with that of valproic acid (VPA; 300 mg/kg) and controls (corn oil) administered by gavage to Sprague-Dawley CD rats on embryonic (E) days 7-18. At the 300 mg/kg dose, trans-2-ene-VPA produced no change in maternal weight, number of implantations, proportion of resorptions, proportion of malformations, or fetal weight. By contrast, the same dose of VPA (300 mg/kg) reduced maternal weight during gestation, increased malformations (12.0% vs. 0.7% in controls), and reduced fetal body weight by 25.1%. An even higher dose of trans-2-ene-VPA (400 mg/kg) produced a reduction in maternal body weight during treatment and reduced fetal body weight (by 7.9%), but did not increase resorptions or malformations in the fetuses. On day E18, maternal serum drug concentrations of VPA were higher in the VPA-treated group compared with those of trans-2-ene-VPA in the trans-2-ene-VPA-treated groups at 1 hr posttreatment. At 6 hr posttreatment the reverse was seen. trans-2-ene-VPA may be absorbed more rapidly and distributed differently than VPA. Overall, the data support the view that trans-2-ene-VPA at equal or higher doses than VPA is not teratogenic in rats.

Animals↗
PubMed1991

Influence of dose and pharmaceutical formulation of vitamin A on plasma levels of retinyl esters and retinol and metabolic generation of retinoic acid compounds and beta-glucuronides in the cynomolgus monkey.

Retinoid concentrations were analyzed in plasma of nonpregnant female cynomolgus monkeys after oral administration of retinol or retinyl acetate at doses of 2, 10, or 50 mg (as retinol) per kilogram body weight dissolved in acetone/soybean oil (1/9) or acetone/Tween 20/water (1/5/4). All-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxoretinoic acid, and 13-cis-4-oxoretinoic acid as well as the conjugates of retinol and all-trans-retinoic acid with beta-D-glucuronic acid represented major polar plasma retinoids after high doses of vitamin A. The relative bioavailability of vitamin A as well as the biotransformation to more polar retinoids was independent of the molecular form of vitamin A (retinol or retinyl acetate) used for dosing. After administration of 2 mg/kg and, in particular, after a 10 mg/kg dose, the metabolic formation of polar retinoids in plasma was much more extensive with the detergent-based vehicle compared to the oil-based vehicle. At 50 mg/kg, comparable metabolism was observed for both forms. Polar metabolites of retinol were increased in a more than linear fashion with the detergent-based vitamin A preparations between 2 and 10 mg/kg and with the oil-based preparations between 10 and 50 mg/kg. Since retinoic acid compounds have previously been shown to be potent teratogens in various animal species and humans, their metabolic formation may be of significance for the teratogenic activity of high doses of vitamin A. In addition to the dose, the pharmaceutical preparation of vitamin A could therefore be a major determinant of the developmental toxicity of vitamin A.

Animals↗
PubMed1991

Diurnal variation of folate concentrations in mouse embryo and plasma: the protective effect of folinic acid on valproic-acid-induced teratogenicity is time dependent.

The diurnal variation of folate concentrations in mouse plasma and embryo between day 8.5 and day 9.5 of gestation (light cycle = 0900-2100) were determined by high-performance liquid chromatography. Folate concentrations in the embryo were high during the evening hours, decreased during the night, reached their lowest levels at 0500, and then increased again during the day. High levels of folates may be related to increased food intake by the pregnant mice. Small changes of the two major maternal plasma folate metabolites were observed. The relative amount of each folate metabolite in the embryo, as compared to the total folate concentration, remained in a narrow range. The main metabolites were tetrahydrofolic acid (THF) (32.4% +/- 2.1% of total folates), 5-CHO-THF (24.2% +/- 2.3%), and 10-CHO-THF (17.0% +/- 1.9%). A dramatic alteration of these ratios occurred only between 1100 and 1400. The relative content of THF increased (52.7% +/- 2.5%), whereas the relative concentration of 5-CHO-THF in the embryo decreased (6.5% +/- 1.9%). Before 1000 when the ratios of folate metabolites were stable, the rate of valproic acid-induced neural tube defects was reduced from 49% of living fetuses to 12% by coapplication of folinic acid via subcutaneously implanted minipumps. During the period in which dramatic changes in ratios between the folate metabolites in the embryo occurred, no protective effect of folinic acid on valproic acid-induced exencephaly could be observed. Our results indicate that the diurnal variation of folate metabolism in the embryo is important in regard to valproic acid teratogenesis and its protection by folate supplementation.

Abnormalities, Drug-Induced↗
PubMed1991

Human plasma all-trans-, 13-cis- and 13-cis-4-oxoretinoic acid profiles during subchronic vitamin A supplementation: comparison to retinol and retinyl ester plasma levels.

Plasma concentrations of retinyl esters, retinol, retinol-binding protein and the polar retinol metabolites all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxoretinoic acid and 13-cis-4-oxoretinoic acid were measured for six male volunteers who received 0.46 mg retinyl palmitate per kilogram body weight as oily drops (equivalent to 0.25 mg retinol per kilogram body weight) once daily over a 20-d period. Retinol and retinol-binding protein levels remained virtually constant throughout the study. Following absorption of vitamin A, retinyl esters as well as all-trans-retinoic acid and 13-cis-retinoic acid were transiently increased in plasma. 13-cis-4-Oxoretinoic acid increased gradually to a steady state level present on d 10 or 20. All-trans-4-oxoretinoic acid was not detected in plasma of the volunteers, with the exception of one on d 10 of the study. Plasma pharmacokinetic profiles of retinyl esters and polar metabolites of retinol displayed great interindividual differences (peak concentrations, time to peak, area-under-the-concentration-time curve values) among the volunteers. Because of the relatively high and consistent steady state concentrations of plasma 13-cis-4-oxoretinoic acid, we suggest that this compound be further investigated as a biochemical marker of vitamin A uptake in humans.

Administration, Oral↗
PubMed1991

Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms.

Administration of the antiepileptic drug valproic acid (VPA) during early pregnancy can result in a 1-2% incidence of spina bifida aperta, a closure defect of the posterior neural tube in the human. The predominant defect produced by VPA in the mouse is exencephaly, a closure defect of the anterior neural tube. Recent experiments demonstrate that an appropriate dosing regimen (consecutive doses of VPA on day 9 of gestation) can also result in a low incidence of spina bifida aperta, and a high incidence of spina bifida occulta in the mouse as a potential animal model. Relatively high doses and concentrations of VPA are needed in the mouse to produce neural tube defects, the human appears to be more sensitive in this regard. Maximal concentrations and not AUC (area under the concentration-time curve) values correlate with the incidence of neural tube defects in the mouse which could in part be explained by saturation of plasma protein binding, increased free drug available for placental transfer and the embryonic neuroepithelium acting as a "deep compartment". It is likely that the parent drug and not a metabolite is the proximate teratogen. Structure-activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an alpha-hydrogen atom, a carboxyl function, branching on carbon atom 2 with two chains containing 3 carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present such as the R- and S-enantiomers of 2-n-propyl-4-pentenoic acid (4-en-VPA), 2-n-propyl-4-pentynoic acid (4-yn-VPA) and 2-ethylhexanoic acid. These enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Pharmacokinetic studies indicate that both enantiomers of each compound reach the embryo to the same degree. Therefore, the intrinsic teratogenic activity of the enantiomers differ, suggesting a stereoselective interaction between the drugs and a chiral structure within the embryo, is involved in the mechanism of action. In sharp contrast to the teratogenic effect, the anticonvulsant activity and neurotoxicity of this compound class show broad structural specificity, opening the possibility for development of novel antiepileptic agents with low teratogenic potency such as 2-n-propyl-2-pentenoic acid (2-en-VPA). The molecular mechanism of the teratogenicity of VPA is quite unknown; of the several hypothesis suggested, the interaction of VPA with embryonic folate metabolism is discussed here.

Abnormalities, Drug-Induced↗
PubMed1991

Valproic acid hepatotoxicity in human liver slices.

Precision cut human liver slices were incubated in organ culture with valproic acid (VPA) to identify patterns of sensitivity to VPA-induced hepatotoxicity. The slices were incubated in Krebs-HEPES buffer supplemented with 25mM glucose and 84 micrograms/ml gentamycin. At 2, 4, 6, 12, 18 and 24 hr slices were taken and analyzed for K+ retention, synthesis of protein and LDH leakage. All three of these viability indicators showed that certain human livers were more susceptible to VPA-induced hepatotoxicity than others. In the limited group of human livers investigated (n = 9) we found one to be particularly sensitive and two relatively insensitive to VPA toxicity. The remaining tissues were of intermediate sensitivity towards VPA. At this time there is no correlation between the human livers that were susceptible to VPA induced hepatotoxicity and age or sex. This study was designed to show that VPA does induce hepatotoxicity in vitro at therapeutically relevant concentrations. Future studies will show whether VPA hepatotoxicity correlates with VPA metabolism, nutritional status or concomitant therapy.

Adolescent↗
PubMed1991

[Plasma level and metabolism of vitamin A (Vitadral) in women of reproductive age].

Using a sensitive HPLC method, plasma concentrations of vitamin A and metabolites were measured from 6 female volunteers who had taken once daily 0.46 mg/kg BW retinol palmitate (Vitadral) for 10 days. The metabolites all-trans- and 13-cis-retinoic acid were increased significantly (2- and 5-fold, resp.) 6 h after the ist intake. 13-cis-4-oxo retinoic acid the 10th intake in the morning of the 10th day (9.22 +/- 2.77 ng/ml, 4-fold increase). The results show continuous increase of retinoic acids, which have to be considered as potential teratogens, after administration of vitamin A. The plasma concentration of retinol itself did not change, whereas only short-term increases were observed for retinol esters.

Adolescent↗
PubMed1990

Characterization of oxidized and glucuronidated metabolites of retinol in monkey plasma by thermospray liquid chromatography/mass spectrometry.

Eight metabolites of retinol were isolated by high-performance liquid chromatography (HPLC) from the plasma of the non-human primate Macaca fascicularis after acute exposure to 150,000 IU of vitamin A per kilogram body weight. After enrichment and further chromatographic purification, the metabolites were reinjected individually into a second HPLC system which was connected on-line by a thermospray interface to a mass spectrometer operated in the positive ionization mode. Six retinoids were identified by (i) a comparison of their retention times with those of appropriate reference compounds in the two chromatographic systems and (ii) by comparison of their mass spectra with those of reference compounds. These retinoids were: 13-cis-4-oxoretinoic acid, all-trans-4-oxoretinoic acid, 13-cis-retinoic acid, all-trans-retinoic acid, all-trans-retinoyl beta-glucuronide and all-trans-retinyl beta-glucuronide. One further metabolite could be identified for the first time as all-trans-4-oxoretinoyl beta-glucuronide by its mass spectrum and, after treatment of the unknown metabolite with beta-glucuronidase, by its hydrolysis product all-trans-4-oxoretinoic acid. The molecular structure of one metabolite could not be elucidated. A major metabolic pathway of high-dose vitamin A in the non-human primate is apparently the oxidation of the primary alcohol group of retinol resulting in the formation of all-trans-retinoic acid. Subsequently, a broad spectrum of various metabolites of all-trans-retinoic acid, including beta-glucuronides and retinoids with a 13-cis configuration, appear in the plasma.

Animals↗
PubMed1990

Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis.

Valproic acid, an antiepileptic drug, causes neural tube defects in mice and man. 14C-labeled valproic acid (sodium-salt) was administered to pregnant mice on days 8 and 9 of gestation (period of high sensitivity in regard to formation of neural tube defects in this species). Two dose levels of valproic acid (1 and 400 mg/kg) were used; in each case the total radioactivity administered was the same: 400 microCi/kg or 14.7 MBq/kg. Autoradiography combined with computerized densitometry revealed that in low-dose animals most of the radioactivity was confined to maternal liver and kidney, while at high doses more activity was observed in soft tissues and fluids, including amniotic fluid. In the embryo, the neuroepithelium showed the highest concentration, irrespective of dose and survival interval (30 min, 3 h, and 6 h). Upon administration of the high dose, up to five times more radioactivity (approximately 2,000 times more valproic acid) was recovered in embryonic tissues than after the low dose. It is concluded that high doses of VPA saturate the capacities of metabolism, excretion, and protein binding in the maternal organism, resulting in a higher proportion of the dose reaching the embryo, allowing more of the drug to be accumulated by the target organ, the neuroepithelium.

Animals↗
PubMed1990

Teratogenicity of the 13-cis and all-trans-isomers of the aromatic retinoid etretin: correlation to transplacental pharmacokinetics in mice during organogenesis after a single oral dose.

NMRI mice were treated on day 11 (day 0 = plug day) of gestation with a single oral dose of 100 mg/kg of either all-trans-etretin (acitretin) or 13-cis-etretin. For teratology studies mice were sacrificed on day 18 of gestation, and the fetuses were examined for malformations. For pharmacokinetic studies, groups of 5 mice were sacrificed after 5, 10, and 30 min and 1, 2, 4, and 8 h. The concentrations of retinoids in maternal plasma and in embryos were determined by a newly developed HPLC gradient method. All-trans-etretin induced malformations in 94% of the fetuses, mainly in fore and hind limbs and cleft palate. 13-cis-etretin did not show any teratogenic or embryo-lethal effects at the dose level used. These findings could be explained by a transplacental pharmacokinetic study. The maximum peak level and also the AUC (area under the concentration-time curve) value of all-trans-etretin in the embryos was 7-8 times higher than corresponding values for 13-cis-etretin, probably due to extensive transport of the trans-isomer and limited transport of the cis-isomer from maternal plasma to the embryos. The concentration quotient between embryo and the maternal plasma was between 0.43 and 1.10 for all-trans-etretin, and only 0.16-0.31 for 13-cis-etretin over the time period studied. An in vivo isomerization of the compounds was also observed which was more extensive for 13-cis-etretin than for all-trans-etretin. Our results indicate that the low teratogenic potency of 13-cis-etretin is due to a limited placental transfer of this compound; on the other hand, the potent teratogen all-trans-etretin is rapidly and extensively transferred to the embryo.

Abnormalities, Drug-Induced↗
PubMed1990

Effects of valproic acid, some of its metabolites and analogues on prenatal development of rats in vitro and comparison with effects in vivo.

Using a whole-embryo culture system valproic acid (VPA) and some of its metabolites (2-en-VPA, 4-en-VPA, 4,4'-dien-VPA) and analogues (ethyl-propyl-acetic acid, propyl-butyl-acetic acid, di-butyl-acetic acid, 2-methyl-2-ethyl-hexanoic acid, 1-methyl-1-cyclohexanoic acid) were tested for their potential to induce abnormal development. With regard to embryonic growth, development and abnormality rate, the tested compounds showed a wide range of "teratogenic potency" in vitro. In order to verify some of the in vitro results, in vivo experiments were performed. Pregnant rats were treated subcutaneously on day 10 of gestation with 2 x 330 mg VPA/kg, or 2 x 400 mg 2-en-VPA/kg, respectively. Evaluation of the embryos was performed on day 11.5 of gestation, corresponding to the in vitro experiments. VPA showed a high potential to induce abnormal development in vivo as well as in vitro, whereas 2-en-VPA was inactive under our experimental conditions. Problems connected with the evaluation of the predictive value of an in vitro test system for the detection of embryotoxic effects, such as "validation" and significance of pharmacokinetic data, are discussed.

Animals↗
PubMed1990

Vitamin A supplementation increases levels of retinoic acid compounds in human plasma: possible implications for teratogenesis.

The concentrations of retinoic acid compounds were monitored by a newly developed highly sensitive HPLC procedure in plasma of six volunteers who received 833 IU vitamin A per kg body weight per day during a 20-day period. There was a significant increase of all-trans-retinoic acid (two-fold), 13-cis-retinoic acid (7-fold) and 13-cis-4-oxoretinoic acid (5-fold) over endogenous plasma levels of these retinoids. The same compounds had previously been found after treatment with the teratogenic drug isotretinoin (Roaccutan, Accutane). Our results raise the possibility that high vitamin A intake may carry a teratogenic risk attributable to increased levels of retinoic acid compounds generated from retinol by metabolic processes.

Adult↗