[Cotinine burden of infants due to exposure through passive smoking].
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Adult↗
Biomedical subjects
H Nau
Publications and source records attributed to H Nau.
Pregnancy-specific changes of antipyrine pharmacokinetics correlate inversely with changes of estradiol/progesterone plasma concentration ratios.
Antipyrine pharmacokinetics as well as estradiol and progesterone concentrations were measured in plasma of 11 healthy pregnant women during the first two trimesters and again in the same patients 6 to 20 weeks after interruption of pregnancy. During pregnancy, the clearance of antipyrine increased and its half-life decreased in all but two instances. A significant inverse relationship was found between the degree of pregnancy-specific changes of plasma clearance of antipyrine and estradiol-progesterone plasma concentration ratios: high estradiol-progesterone ratios during pregnancy corresponded to decreased plasma clearance of antipyrine; low ratios of the two hormones during pregnancy corresponded to increased plasma clearance of antipyrine. The current results indicate that the balance between circulating estrogens and progesterone may be an appropriate indicator for pregnancy-specific changes of a particular hepatic drug metabolism during pregnancy.
Adult↗
Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: an interspecies comparison.
This study was undertaken to assess the developmental toxicity and drug distributional and metabolic characteristics of prenatal valproic acid (VPA) exposure in rhesus monkeys. Oral administration of 20-600 mg/kg/day VPA (approximately 1-15 X human therapeutic dose) to 33 animals on variable gestational days (GD) during organogenesis resulted in dose-dependent developmental toxicity manifested as increased embryo/fetal mortality, intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic plasma elimination curves were observed for total and free VPA on the first (GD 21) and last (GD 50) days of treatment in the 100- and 200-mg/kg/day dose groups. VPA exhibited dose-independent elimination kinetics at the plasma concentrations observed in this study. There was no significant change in pharmacokinetic parameters (maternal plasma elimination rate, area under the curve, peak plasma concentration) between the first and last days of treatment at either dose level. Placental transfer studies indicated that embryos were exposed to half the free VPA concentrations present in maternal plasma on GD 37. Comparisons of interspecies sensitivity to VPA-induced developmental toxicity in the mouse, rat, monkey, and man are made.
Abnormalities, Drug-Induced↗
The enantiomers of the teratogenic thalidomide analogue EM 12: 1. Chiral inversion and plasma pharmacokinetics in the marmoset monkey.
The plasma pharmacokinetics of the enantiomers of 2-(2,6-dioxopiperidine-3-yl)-phthalimidine (EM 12) and the racemic mixture of this substance were investigated in Callithrix jacchus, a thalidomide-sensitive primate. Single doses of 5 mg/kg body wt were administered orally or intraperitoneally. Maximum plasma concentrations were reached 1 h after administration of the enantiomers, and 3 h after application of the racemate. The mean plasma elimination half-life was in the range of 5 h for the enantiomers, as well as for the racemic mixture, although there was a tendency toward slower elimination and higher plasma AUC values of the S-enantiomer: thus, after administration of the (greater than 99%) pure enantiomers, the plasma AUC value of the administered S-enantiomer was found to be more than one-third higher than that of the administered R-enantiomer. Racemisation of the R- and the S-form of EM 12 occurred both in vitro (phosphate buffer, pH 7.4, 37 degrees C) and in vivo. The maximum plasma concentrations of the antipodes produced via chiral inversion were between 13% and 21%; the plasma AUC values of the resulting antipodes were between 24% and 30% of the corresponding values of total EM 12. The plasma pharmacokinetic data, including the extent of the chiral inversion obtained after p.o. and i.p. application of the substances, were in the same range. The results indicate that both enantiomers racemise with appreciable rates; this may be expected to complicate the interpretation of studies designed to evaluate stereoselective differences with respect to teratological activities of EM 12 and related substances such as thalidomide.
Animals↗
Embryotoxic effects of thalidomide derivatives on the non-human primate Callithrix jacchus; 3. Teratogenic potency of the EM 12 enantiomers.
The teratogenic potencies of the enantiomers of 2-(2,6-dioxopiperidine-3-yl)-phthalimidine ( = EM 12), a teratogenic thalidomide analogue, were investigated in Callithrix jacchus, a primate very sensitive to the teratogenic action of this thalidomide analogue. The results indicate that the S-(-)-form of EM 12 is clearly more teratogenic than the R-(+)-form. The interpretation of the studies designed to evaluate stereo-selective differences in the teratogenicity of the enantiomers becomes difficult, since both enantiomers racemise in vivo with appreciable rates (Schmahl et al. 1988a, b). Therefore, it cannot be concluded as yet that the R-(+)-form lacks all teratogenic potential.
Abnormalities, Drug-Induced↗
Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats.
This study was undertaken to assess the pharmacokinetics and developmental toxicity of the anticonvulsant, valproic acid (VPA), a human teratogen, in Sprague-Dawley rats. Oral administration of 200-800 mg/kg VPA (5-20x human therapeutic dose) from Gestational Days (GD) 8 to 17 resulted in increasing maternal toxicity at the higher doses with 100% maternal lethality at 800 mg/kg. Although there was an increased incidence of resorptions at 600 mg/kg (48 +/- 43%) compared to controls (18 +/- 24%), it was not statistically significant. Fetal examination on GD 20 revealed dose-dependent fetal growth retardation (p less than or equal to 0.05) as evidenced by decreased fetal weight and length in addition to underossification of both the axial and appendicular skeleton. The incidence of skeletal defects, including abnormal vertebrae, ribs, and craniofacial dysmorphia, also increased with higher doses of VPA. Cardiac anomalies observed in the two highest treatment groups consisted of great vessel malformations with or without associated ventricular septal defects (VSDs). Urogenital defects were also noted in the 600 mg/kg group. The plasma elimination half-life on GD 8 was 1.0 +/- 0.3 hr at 200 mg/kg and 2.3 +/- 0.7 hr at 600 mg/kg. Maximal concentrations of total and free drug were 341 +/- 18 micrograms/ml and 181 +/- 11 micrograms/ml, respectively, in the low-dose group and 911 +/- 379 micrograms/ml and 542 +/- 224 micrograms/ml in the high-dose group. No significant changes in any pharmacokinetic parameters (t1/2, AUC, Cmax, tmax) were observed over the 10-day treatment period at either dose level.
Administration, Oral↗
Transplacental pharmacokinetics of teratogenic doses of etretinate and other aromatic retinoids in mice.
The transplacental pharmacokinetics of single teratogenic doses of etretinate and motretinide were compared with particular emphasis on distribution and concentrations in the exposed embryos of the free acid metabolite, etretin. The three aromatic retinoids were also tested for their direct inhibitory effect on chondrogenesis in the limb bud mesenchymal cell "micromass" culture assay. After a standard dose of 100 mg/kg administered on day 11 of gestation in NMRI mice, all three compounds were teratogenic, but they differed from each other in potency. Etretinate was most active as a teratogen, equalling the potency of our standard all-trans-retinoic acid; every exposed fetus was deformed with severe shortening of all limb bones as well as cleft palate. Etretin was less potent than etretinate, and motretinide was considerably less active as a teratogen than the other two. In the in vitro assay, only etretin suppressed chondrogenesis and this activity was equivalent to that of all-trans-retinoic acid (IC50 of 12 ng/ml). Both etretinate and motretinide (which contain an ethyl ester and ethylamide terminal group, respectively) were essentially inactive in vitro, demonstrating the fact that a free carboxylic group may be a requirement for the in vitro suppression of chondrogenesis. These differences between the results obtained in vivo and in vitro could be resolved by pharmacokinetic investigations using HPLC methods. Both etretinate and motretinide were metabolized in vivo to etretin, their likely common teratogenic metabolite. The high teratogenic potency of etretinate was probably the result of high concentrations as well as AUC values of its metabolite etretin in the embryo. On the other hand, the comparatively low teratogenicity of motretinide could be related to approximately 5 x lower embryonic peak levels as well as AUC values of etretin. A comparison of these results with those previously obtained for all-trans- and 13-cis-retinoic acids confirms the correlation between embryonic exposure and teratogenic potency in the mouse. Our results indicate that pharmacokinetic studies are essential for the interpretation of relative teratogenic potencies of retinoids as well as apparent differences between in vivo and in vitro teratogenesis. A free carboxyl group at the terminal end of the tetraene chain was necessary for high activity of the retinoids studied.
Abnormalities, Drug-Induced↗
Primidone and phenobarbital during lactation period in epileptic women: total and free drug serum levels in the nursed infants and their effects on neonatal behavior.
A total of 35 newborns whose mothers had been treated with either primidone (PMD), phenobarbital (PB) or a combination of one of these drugs with other antiepileptic drugs were included in this study. Fetal/maternal serum concentration ratios at birth, milk/serum concentration ratios and neonatal half-lives were determined for PMD, PB and phenylethylmalondiamide (PEMA). Steady-state serum levels of PMD in 2 nursed infants were 2.5 and 0.7 micrograms/ml, respectively, for PEMA values of 1.4 and 0.4 micrograms/ml. PB steady-state concentrations ranged between 2.0 and 13.0 micrograms/ml (6 infants). Maternal PB serum protein binding did not change during and after pregnancy. Neonatal free-fraction values at birth were similar to maternal values: 63.2 +/- 17.2% (n = 11). In the postnatal period, however, PB free-fraction values rose to more than 90% in some infants. In one case, neonatal free concentrations of PB were even higher during the 1st week after birth than the corresponding maternal values. Symptoms of sedation were observed in these neonates for which elevated free-fraction values of PB could be responsible. Behavior problems, such as withdrawal symptoms, were observed in neonates who eliminated PMD with short half-lives, while other infants with longer PMD half-lives or slower elimination because of nursing showed no such symptoms.
Behavior↗
[Pharmacokinetic principles of the teratogenicity of drugs].
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Abnormalities, Drug-Induced↗
Enzyme cytochemistry for the risk assessment of drug administration during pregnancy with special reference to proteases.
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Animals↗
Half lives of nicotine in milk of smoking mothers: implications for nursing.
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Breast Feeding↗
Valproic acid-induced neural tube defects: reduction by folinic acid in the mouse.
Neural tube defects were induced dose-dependently by single injections of the anticonvulsant drug valproic acid (VPA) as sodium salt in mice on gestational day 8. Folinic acid (5-CHO-THF) coadministration by i.p. injection or by a constant rate infusion via osmotic minipumps, implanted s.c., significantly reduced the exencephaly rates using a randomized double-blind experimental procedure. 5-CHO-THF supplementation cut the exencephaly rates into half even at high maternal plasma levels of VPA (p less than 0.005, chi 2-test); resorption rates were not affected. The VPA plasma kinetics were not changed by any of the application regimens of 5-CHO-THF. The investigation of the folate metabolite pattern (determined by HPLC) showed that 5-CHO-THF and 5-methyl-tetrahydrofolic acid (5-CH3-THF) were the main metabolites in untreated mice. After supplementation with 5-CHO-THF, only the concentrations of this folate vitamer were increased in the plasma from 0.3 microgram/ml (normal) to 0.6 or 1.9 micrograms/ml (after injection of 3 x 1 mg/kg or 3 X 4 mg/kg) and to 4.2 micrograms/ml (after infusion via osmotic minipumps). Our results indicate that VPA-induced exencephaly in mice combined with the investigation of the plasma levels of VPA and the different folate metabolites could be an appropriate animal model to study protective effects of folates on the occurrence of neural tube defects.
Animals↗
Low teratogenicity of 13-cis-retinoic acid (isotretinoin) in the mouse corresponds to low embryo concentrations during organogenesis: comparison to the all-trans isomer.
13-cis-Retinoic acid (isotretinoin) is teratogenic in man at therapeutic doses (0.5-1.5 mg/kg body wt), but only marginally teratogenic in the mouse at exceedingly high doses (greater than 100 mg/kg). On the other hand, the isomer all-trans-retinoic acid (tretinoin) is teratogenic in the mouse at dose levels which are 10 times lower than those for the 13-cis isomer. We have therefore studied whether the greatly different teratogenic potencies of these two compounds in the mouse are the result of differences in their transplacental kinetics. Following a single oral dose of 100 mg all-trans- or 13-cis-retinoic acid per kg body wt, concentrations of the parent drugs, of the C-13 isomerization products, as well as of their 4-oxo metabolites were determined in maternal plasma and embryo at two sensitive stages of organogenesis, i.e., Days 9 or 11 of gestation. All-trans-retinoic acid and its 4-oxo metabolite were transferred to the embryo to a much greater extent (embryo/maternal plasma concentration ratios, approximately 0.4) than the 13-cis-retinoic acid and its 4-oxo metabolite (embryo/maternal plasma concentration ratios, approximately 0.02). Embryo concentrations of all-trans-retinoic acid on Day 9 of gestation exceeded those on Day 11, whereas the embryo levels of 13-cis-retinoic acid were minimal at both gestational stages. The concentration of the 4-oxo metabolite of all-trans-retinoic acid was generally lower than that of the parent drug, whereas the level of the 4-oxo metabolite of the 13-cis-retinoic acid was comparable with or even higher than that of the parent compound. Concentrations of the C-13 isomerization products in maternal plasma were less than 20% of corresponding parent drug levels. However, due to the different extent of transfer of the two isomers, the concentration of all-trans-retinoic acid in the embryo exceeded that of the cis isomer even after administration of 13-cis-retinoic acid. Our results indicate that the low teratogenicity of 13-cis-retinoic acid in the mouse is the result of minimal placental transfer of this compound and of its 4-oxo metabolite, which contrast sharply with extensive placental transfer and high teratogenicity of the corresponding isomers with the all-trans configuration.
Abnormalities, Drug-Induced↗
Cyclophosphamide: interstrain differences in the production of mutagenic metabolites by S9-fractions from liver and kidney in different mutagenicity test systems in vitro and in the teratogenic response in vivo between CBA and C 57 BL mice.
The formation of mutagenic compounds from cyclophosphamide (CPA) by S9-fractions from liver (S9L) or kidney (S9K) of pregnant CBA and C 57 BL mice was investigated, using point mutations in Salmonella typhimurium (TA 1535) and the induction of sister chromatid exchanges (SCE) in human peripheral lymphocytes (HPL) or Chinese hamster ovary (CHO) cells as end points. In addition, the teratological response of CBA and C 57 BL mice to CPA on day 11 of pregnancy was analysed in vivo. The results are as follows: (1) S9L from CBA mice was more effective than S9L from C 57 BL mice in metabolizing CPA to products inducing mutations in Salmonella and SCEs in HPL and CHO cells. (2) S9L was more effective than S9K from both strains of mice. (3) In vivo pretreatment of mice with a single dose of CPA (20 mg/kg) reduced the in vitro metabolizing capacity of S9L and S9K significantly and led to the disappearance of the interstrain difference. (4) The embryolethal and teratogenic effects of CPA were stronger in C 57 BL than in CBA mice; the types of teratological effects were partially different in the two strains.
Animals↗
Teratogenicity of valproic acid and related substances in the mouse: drug accumulation and pHi in the embryo during organogenesis and structure-activity considerations.
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Animals↗
Nicotine and cotinine concentrations in the milk of smoking mothers: influence of cigarette consumption and diurnal variation.
The relationship between nicotine and cotinine concentrations in mother's milk (including 24 h profiles) and the number of cigarettes consumed was studied. A total of 206 milk samples were collected from 34 nursing, smoking mothers. The mothers were distributed into three groups: Group I (1-10 cigarettes/day), group II (11-20 cigarettes/day) and group III (21-40 cigarettes/day). Milk samples from all nursing periods of a 24 h interval were collected. Nicotine and cotinine concentrations were measured by specific gas chromatographic techniques. The average milk nicotine and cotinine concentrations over a 24 h interval in the three groups were as follows: group I, 18 +/- 16 and 76 +/- 33 ng/ml; group II, 28 +/- 21 and 125 +/- 60 ng/ml; group III, 48 +/- 25 and 230 +/- 62 ng/ml (means +/- SD). Over a time interval of 24 h the nicotine concentrations varied greatly in the milk of smoking mothers, while the cotinine concentrations remained relatively constant. Because of the great intra- and inter-individual variations in the nicotine concentrations, the influence of the number of cigarettes smoked on the nicotine concentration in milk was most apparent if nicotine concentrations were measured repeatedly over a prolonged time interval. Our results indicate that the exposure of the nursed infant to nicotine and cotinine via milk depends on the daily cigarette consumption but also on individual smoking habits; the time of smoking, smoking frequency prior to nursing, and the time interval between nursing and the last cigarette.
Circadian Rhythm↗
Smoking and passive smoking during pregnancy and early infancy: effects on birth weight, lactation period, and cotinine concentrations in mother's milk and infant's urine.
The extent of smoke exposure via mother's milk and passive smoking was investigated in a prospective, longitudinal matched-pair study by comparison between children, whose mothers smoked substantially throughout pregnancy and nursing period and children whose mothers did not smoke. Our preliminary results show that not only infants of smoking mothers but also those of smoking fathers show reduction of birth weight. Smoking mothers weaned their babies earlier than non-smokers. Cotinine concentrations in breast milk depended on the number of cigarettes smoked. The highest urinary excretion of cotinine (as expressed by ng cotinine/mg creatinine ratios) were observed in infants fully breast-fed by smoking mothers. After weaning the values were in the same range as those of formula-fed infants of smoking mothers (exposed to passive smoking only). In the group of non-smokers only small or undetectable amounts of cotinine were found. Thus it is demonstrated that both nursing and--to a lower degree--passive smoking contribute to the exposure of infants to nicotine and its metabolite cotinine.
Birth Weight↗
Cadmium concentrations in milk and blood of smoking mothers.
Cadmium concentrations were measured by flameless atomic absorption spectrometry in blood and mature milk of 15 nonsmoking and 56 smoking mothers during the nursing period. Both blood and milk concentrations increased with increasing cigarette consumption. The median blood and milk concentrations in nonsmokers were 0.54 and 0.07 microgram/l, respectively; these values rose to 1.54 and 0.16 micrograms/l in blood and milk of mothers smoking more than 20 cigarettes per day. Milk concentrations of cadmium were approximately 10% of corresponding blood concentrations. The cadmium exposure of infants nursed by nonsmoking as well as by smoking mothers was far below the exposure of formula-fed infants or the provisional acceptable weekly intake level set by the WHO.
Adolescent↗