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Biomedical subjects

H Nau

Publications and source records attributed to H Nau.

At least 217 records · Page 12Linked to original sources
PubMed1983

Differences in in vitro binding of diazepam and N-desmethyldiazepam to maternal and fetal plasma proteins at birth: relation to free fatty acid concentration and other parameters.

The in vitro protein binding of diazepam and its major plasma metabolite, N-desmethyldiazepam (DMD), was measured in women at full term of pregnancy, in mixed cord plasma (fetal plasma), and in control subjects. The free fraction of both drugs was determined by ultrafiltration at 37 degrees. The mean free fraction of diazepam was 0.023 +/- 0.0043 in control subjects and rose to 0.040 +/- 0.0071 in women at term, whereas in their fetuses the free fraction was 0.021 +/- 0.0057. The unbound fraction of DMD was 0.030 +/- 0.0084 in control subjects, 0.052 +/- 0.015 in women at term, and 0.035 +/- 0.010 in fetal plasma. The free fractions of both compounds differed in women at term and in their fetuses. The higher free fraction of the two drugs in maternal plasma than in cord plasma may be explained by elevated maternal concentrations of free fatty acids (and triglycerides), which may act as displacing agents in maternal plasma. The higher binding of these drugs in fetal plasma than in maternal plasma may explain their cumulation in vivo and may be responsible for the frequently observed adverse effects of maternal diazepam treatment on the newborn infant.

Adolescent↗
PubMed1983

Distribution of valproic acid and its metabolites in various brain areas of dogs and rats after acute and prolonged treatment.

Concentrations of valproic acid (VPA) and various metabolites were determined in plasma, cerebrospinal fluid and discrete brain areas in dogs after acute treatment with VPA as well as in rats during prolonged constant-rate application of the drug via osmotic minipumps. Highly sensitive gas chromatograph-mass spectrometer-computer methods were used for drug and metabolite analysis. Of several VPA metabolites present in plasma of dogs and rats only one could be found in the brain of both species, 2-propyl-2-pentenoic acid (2-en-VPA). Distribution of VPA and 2-en-VPA in the brain was rather homogenous, but during prolonged treatment accumulation of 2-en-VPA was found to occur in some brain regions. Determination of anticonvulsant potency of 2-en-VPA in mice indicated that the compound is about 1.3 times more potent than the parent drug when calculation is based on whole-brain concentrations. Administration of 2-en-VPA in a dog showed that pharmacokinetics of this substance are similar to those of VPA, although plasma protein binding of 2-en-VPA (97%) is much higher than of VPA. The results suggest that 2-en-VPA may contribute significantly to the anticonvulsant effect of (chronic) treatment with VPA.

Animals↗
PubMed1983

A new method for kinetic studies of drug interactions in experimental animals during steady state. Controlled-rate application of valproic acid, phenobarbital and their combinations via implanted osmotic minipumps in the mouse.

Human therapeutic levels of valproic acid (VPA) and phenobarbital (PB) could be maintained in the mouse for a period of one week by controlled rate application (CRA) via subcutaneously implanted osmotic minipumps. PB-levels dropped markedly during one week of application, possibly by autoinduction. The interaction of PB and VPA was investigated by CRA of a mixture of both drugs. PB-levels were increased by VPA, probably due to enzyme inhibition, while VPA-levels were decreased by PB, probably by enzyme induction. Our results indicate tha CRA of drugs such as VPA and PB via implantable osmotic minipumps may be a valuable procedure for drug interaction studies during steady-state conditions.

Animals↗
PubMed1983

Enzyme induction in neonates after fetal exposure to antiepileptic drugs.

The 13C-AP breath test is shown to be a convenient, noninvasive method to monitor velocity and capacity of P450-dependent AP N-demethylation in infancy and childhood. According to 13C-AP breath tests, neonates have a very low capacity to eliminate 13CO2, which is only 15 to 21% of the activity in adults. During the first year of life AP N-demethylation increases to reach its maximum at about 2 years; afterwards a slight decrease occurs. In 25 neonates exposed prenatally to different antiepileptic drugs 13C-AP breath test was efficiently used to prove that cytochrome AP N-demethylation was considerably stimulated. After primidone/phenobarbitone, especially in combination with phenytoin, 13C elimination reaches and even surpasses the range for older children. Valproate exposure during fetal life is not consistently followed by a significant increase in AP N-demethylation. The enzyme induction demonstrated by 13C-AP breath test was often accompanied by accelerated metabolic clearance and shortened half-life times of transplacentally acquired antiepileptic drugs. There was good agreement between 13C-AP breath tests and pharmacokinetic data for primidone/phenobarbitone but not for phenytoin. In contrast, in the case of phenytoin exposure during pregnancy the pharmacokinetic parameters and the 13C breath test data will transport very different informations about enzyme induction in these neonates.

Aminopyrine↗
PubMed1983

Serum protein binding of diazepam, desmethyldiazepam, furosemide, indomethacin, warfarin, and phenobarbital in human fetus, mother, and newborn infant.

The protein binding of diazepam, desmethyldiazepam, furosemide, indomethacin, warfarin, and phenobarbital in maternal and fetal cord serum at the time of birth, and in serum of neonates between 1 and 11 days of age was studied. The protein binding of diazepam and desmethyldiazepam was higher in the fetus than in the mother, thus explaining the fetal cumulation of these drugs in vivo. After birth, both drugs were partially displaced from neonatal binding sites. The decreased protein binding capacity in the mother and the neonate related to increased free fatty-acid levels. The pattern of protein binding of warfarin in the groups investigated was a mirror image of those of diazepam and its metabolite. The protein binding of indomethacin progressively decreased in the neonate during the first two postnatal weeks, while that of furosemide remained at lowered levels throughout this time interval. The protein binding of phenobarbital was similar in the groups investigated. Our results suggest that drugs such as diazepam, which can be displaced from binding sites by free fatty acids, may cumulate in the fetus and may exhibit much decreased protein binding and possibly unexpectedly strong effects in the neonate after birth.

Blood Proteins↗
PubMed1983

Carbamazepine and carbamazepine-10,11- epoxide during pregnancy and postnatal period in epileptic mother and their nursed infants: pharmacokinetics and clinical effects.

A total of 11 epileptic mothers treated with carbamazepine (CBZ) as well as their 12 newborns were included in this study. Maternal CBZ concentrations remained rather constant during pregnancy and slightly increased after parturition. Carbamazepine-10, 11-epoxide ( CBZE ) levels were less predictable and either increased or decreased during pregnancy. Fetal/maternal serum concentration ratios at birth were 0.78 +/- 0.14 (n = 5) for CBZ and 0.75 +/- 0.09 (n = 5) for CBZE . Neonatal half-lives were 28 +/- 11 hours (n = 4) for CBZ and 20 and 24 hours (n = 2) for CBZE . maternal milk/serum concentration ratios of CBZ and CBZE were 0.39 +/- 0.22 (N = 11) and 0.49 +/- 0.28 (n = 6), respectively. The steady-state CBZ serum levels of nursed infants were about 1.0 micrograms/ml in all cases but one, where a maximum concentration of 4.7 micrograms/ml was reached. One of the infants had major malformations. Minor anomalies were less frequent in the CBZ group, compared to the whole group of infants exposed to anticonvulsive drugs other than CBZ and as frequent as in a matched pair control group of unexposed neonates. Neonatal somatic data were found to be below the corresponding values of neonates exposed to antiepileptic drugs other than CBZ.

Abnormalities, Drug-Induced↗
PubMed1982

Placental transfer of etozolin and ozolinone during the first half of gestation in man.

The placental transfer of etozolin and its pharmacologically active metabolite ozolinone was studied in 48 patients during the first (44 patients) and second (4 patients) trimester. 24 patients received a single oral dose of etozolin 400 mg 2-20 h prior to interruption of pregnancy by curettage or prostaglandin infusion. 24 other patients received 3 oral doses of etozolin 400 mg (11 patients) or 800 mg (13 patients) on 3 consecutive days, and pregnancy was terminated 2-10 h after the last dose. The fetal tissue/maternal serum and placental tissue/maternal serum ratios of etozolin and ozolinone were found to lie between 0.3 and 0.6. The serum levels were lower in pregnant than in non-pregnant patients. The low placental and fetal concentrations of etozolin and ozolinone suggest that these drugs may prove useful when a diuretic is indicated in the treatment of oedema and hypertension during pregnancy.

Administration, Oral↗
PubMed1982

Mutagenic, teratogenic and pharmacokinetic properties of cyclophosphamide and some of its deuterated derivatives.

To elucidate which metabolic pathway leads to the ultimate mutagenic and teratogenic metabolite of cyclophosphamide (CPA), the mutagenicity in vitro as well as the teratogenicity in vivo and the pharmacokinetics of CPA and several deuterated analogs (5,5-d2-CPA, 4,4-d2-CPA and 4,4-6,6-d4-CPA) were compared. 5,5-d2-CPA was less mutagenic (isotope effects between 1.7 and 12.3 were found for sister-chromatid exchanges and structural chromosomal aberrations in CHO cells and in the Ames test) and less teratogenic (deuterium isotope effect between 2 and 3) than CPA and the other deuterated analogs. Because the concentrations of 5,5-d2-CPA in pregnant mice and their embryos were equal to or even exceeded those of CPA and the other deuterated analogs, a particular metabolic pathway involving a fission of the C-D or C-H bond on the C-5 rather than the parent drug must be responsible for the isotope effect observed. It had previously been shown (Cox et al., 1976) that the 5,5-d2-CPA has a decreased anti-tumor activity in vivo (isotope effect 7-13) which was accompanied by a decreased formation of phosphoramide mustard and acrolein in vitro (isotope effect 5.3). Our results suggest that phosphoramide mustard is an important proximate metabolite of CPA with regard to the mutagenicity and teratogenicity of the drug. These results show for the first time that labeling of drugs with stable isotopes offers a promising approach to the study of the mechanism of the mutagenic and teratogenic actions of drugs.

Animals↗
PubMed1982

Teratogenic and pharmacokinetic studies of primidone during pregnancy and in the offspring of epileptic women.

Fourteen epileptic women treated with primidone, either alone or in combination with other antiepileptic drugs, were studied prospectively during their pregnancy. Plasma levels of primidone and its metabolites were monitored and correlated to findings in the offspring. Maternal serum concentrations of primidone and metabolites were generally low during pregnancy. The levels of its main metabolites--phenobarbital and PEMA--were found to drop within the first month of pregnancy in two cases. The plasma concentrations remained low until birth and rose sharply thereafter. The phenobarbital/primidone ratio (mean 0.84) and PEMA/primidone ratio (mean 0.56) in pregnant patients were found to be lower than in non-pregnant patients, except when primidone was given in combination with phenytoin in which case the expected phenobarbital/primidone (mean 2.5) and PEMA/primidone (mean 1.5) ratios were found. A ventricular septal defect was found in one of the offspring of the fourteen mothers and five children had microcephaly. There was a high incidence of poor somatic development with dystrophy (n=3) and short stature (n=2). Head circumferences (n=8), lengths (n=4) and/or weights (n=8) were below the 10th percentile in a number of children. Four children showed marked facial dysmorphy. Our preliminary data suggest that primidone intake during pregnancy may be important in the pathogenesis of minor anomalies and in the induction of poor somatic development.

Abnormalities, Drug-Induced↗
PubMed1982

Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gamma-aminobutyric acid (GABA) metabolism in the mouse.

The slow onset and carry-over effect of valproic acid (VPA) therapy observed in some clinical as well as experimental animal studies have been examined by parallel pharmacokinetic and pharmacological investigations in a mouse model. VPA was rapidly transferred into brain and was cleared from that tissue with rates which exceeded plasma clearance rates. Of several VPA metabolites present in plasma, only one could be found in the brain: 2-propyl-2-pentenoic acid. This metabolite was cleared from plasma and from brain slower than the parent drug. gamma-Aminobutyric acid (GABA) concentrations were increased within 15 min after VPA injection and remained significantly elevated for at least 8 h. A similar time course was found in regard to the increase of the electroconvulsive threshold (maximal seizures) induced by VPA administration. The activity of glutamic acid decarboxylase rose parallel to the elevation of brain GABA levels, whereas the activity of GABA aminotransferase was not affected. Whereas the rapid onset of the effect on electroconvulsive threshold and on GABA metabolism can be explained by the rapid entrance of VPA into brain, the carry-over effects observed correlated with the kinetics of the metabolite 2-propyl-2-pentenoic acid better than with those of VPA due to the persistence of this metabolite in brain.

4-Aminobutyrate Transaminase↗
PubMed1982

Valproic acid: metabolite concentrations in plasma and brain, anticonvulsant activity, and effects on GABA metabolism during subacute treatment in mice.

Mice were continuously treated with valproic acid (VPA) via the drinking water for period from 1 to 12 days. The daily drug intake varied between 500 and 580 mg/kg. However, due to the rapid elimination of VPA in this species average plasma concentrations of only 3-4 micrograms/ml VPA were present at 8:30 a.m., the time chosen for determinations. In the brain, VPA levels were about 10% of those in plasma. In regard to VPA metabolism the products of beta-oxidation 2-en-VPA 2-propyl-2-pentenoic acid) and 3-keto-VPA (2-propyl-3-oxopentanoic acid) proved to be the main metabolites in plasma although other (minor) metabolites of VPA were also present. The only metabolite of VPA detected in the brain was 2-en-VPA. VPA medication caused a significant increase in the threshold for electroconvulsions which was associated with a slight increment of brain GABA levels. The activity of glutamic acid decarboxylase was significantly elevated whereas GABA aminotransferase was not affected. After withdrawal of VPA, a delayed effect on seizure threshold was observed which extended to time periods where VPA could no longer be detected in the brain, but 2-en-VPA was still present.

4-Aminobutyrate Transaminase↗
PubMed1981

Valproic acid and several metabolites: quantitative determination in serum, urine, breast milk and tissues by gas chromatography-mass spectrometry using selected ion monitoring.

A method has been developed for the simultaneous quantitative determination of valproic acid (2-propylpentanoic acid) and its metabolites 2-propyl-2-pentenoic acid (trans), 2-propyl-3-pentenoic acid (trans), 2-propyl-4-pentenoic acid, 3-hydroxy-2-propylpentanoic acid, 4-hydroxy-2-propylpentanoic acid, 5-hydroxy-2-propylpentanoic acid, 3-oxo-2-propyl-pentanoic acid, and and 2-propylglutaric acid. All compounds were extracted at pH 5.0 with ethyl acetate. The concentrated extracts were trimethylsilylated and the resulting mixtures analyzed by a gas chromatography-mass spectrometry-computer system operated in the selected ion monitoring mode. Linear calibration curves were obtained in the concentration ranges studied (0.1-20 microgram/ml for metabolites, 0.1-150 microgram/ml for valproic acid. The recoveries of the drugs were between 92 and 97%. The relative standard deviations were between 3.9 and 8.1% (analysis of multiple 10-microliter samples of patient urine). The lower detection limits were found to be between 2.8 and 18 ng/ml using 200-microliter serum samples. The derivatized extracts were stable for at least one week. Applications of the method described include studies of placental transfer for valproic acid and metabolites in the human, the elimination of these substances by the neonate, their transfer via mother's milk, and their levels in mouse brain.

Adult↗
PubMed1981

Placental transfer of thiamphenicol in the rat.

Measurement of thiamphenicol transfer to the rat embryo during organogenesis was performed as one step of the determination of possible drug embryotoxicity in man. Extrapolation of data on animal embryotoxicity to man will only become possible when data on the toxicokinetic properties of the substance under investigation are available for both animal and man. 1) Thiamphenicol, given between day 11.5 and 14 of rat gestation, rapidly reached the embryo; 4--6 h after single i.v. or s.c. injection, embryonic and maternal thiamphenicol levels became equal and decreased from that time on at the same rate. 2) No evidence was found for development of a placenta barrier with increasing placental function. The same dose applied at different developmental stages yielded the same embryonic drug concentrations. 3) Elimination via kidney (unchanged) or bile (glucuronide), may become rate-limiting for thiamphenicol excretion. Doses exceeding 50 mg/kg (i.v.) or approx. 100 mg/kg (s.c.) yielded thiamphenicol levels higher than those expected from linear dose-concentration relationships. 4) Drug concentrations (greater than 3--5 micrograms/g wet weight) obtained with dosing regimens (greater than 100 mg/kg/day) used for experimental induction of embryolethality in rats are equal to those necessary for inhibition of mitochondrial protein synthesis in vitro and to those necessary for treatment of bacterial infections in man.

Animals↗