Search PubMed⌕ Search

Biomedical subjects

H Nau

Publications and source records attributed to H Nau.

At least 199 records · Page 11Linked to original sources
PubMed1985

Pharmacological evaluation of various metabolites and analogues of valproic acid. Anticonvulsant and toxic potencies in mice.

Thirty-two metabolites and analogues of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) were tested for anticonvulsant and toxic effects in mice, in an attempt to find out if any of these compounds were superior to valproic acid. Valproic acid and ethosuximide, another clinically established antiepileptic drug, were included in these studies for comparison. After intraperitoneal administration, the anticonvulsant potency of the various drugs was determined in three seizure tests: the threshold for maximal electroconvulsions, the maximal electroshock seizure test and seizures induced by subcutaneous injection of pentylenetetrazol. For the most potent compounds, median minimal neurotoxic doses (TD50S) and LD50S (after i.p. and i.v. injection) were determined. Valpramide, the primary amide of valproic acid, proved to be the most potent compound in the three seizure tests, used, being 2-5 times as potent as valproic acid, but valpramide was also considerably more sedative and toxic than valproic acid or ethosuximide. Of the metabolites of valproic acid tested, the unsaturated compounds 4-en-valproic acid (4-en-VPA) and the trans-isomer of 2-en-valproic acid (2-en-VPA) were most potent and, depending on the seizure test used, reached 60-100% of the efficacy of the parent drug. Both metabolites had LD50 values which were similar or greater than those of valproic acid but they were more sedative than the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Nicotine and cotinine concentrations in serum and urine of infants exposed via passive smoking or milk from smoking mothers.

The exposure of infants to nicotine via milk of smoking mothers or via inhaled side-stream smoke ("passive smoking") was evaluated. Newborn infants nursed by smoking mothers and unexposed to passive smoking showed measurable serum concentrations of nicotine (0.2 to 1.6 ng/ml) and its main metabolite, cotinine (5 to 30 ng/ml), and also excreted measurable amounts of nicotine and cotinine in their urine: the ratio of nanograms of nicotine/milligrams of creatinine (N/C ratio) ranged from 5.0 to 110 (median 14), and the corresponding ratio of nanograms of cotinine/milligrams of creatinine (C/C ratio) from 10 to 555 (median 110). Infants of the same age nursed by nonsmoking mothers did not excrete measurable amounts of the two substances except in one case. Older and non-breast-fed infants exposed only to passive smoking had N/C ratios in the range of 4.7 to 218 (median 35) and C/C ratios in the range of 117 to 780 (median 327 ng/mg). Infants exposed to passive smoking and to smoke via breast milk had N/C ratios in the range of 3.0 to 42 (median 12) and C/C ratios in the range of 225 to 870 (median 550). The significant serum concentrations and urinary excretion rates of nicotine in the breast-fed infants of smoking mothers suggest that nursing contributes to the nicotine exposure of these neonates. In older infants, the wide variation of cotinine excretion values did not allow separate evaluation of the two exposure routes.

Breast Feeding↗
PubMed1985

Clinical pharmacokinetics in pregnancy and perinatology. I. Placental transfer and fetal side effects of local anaesthetic agents.

Local anaesthetic agents, both of the amide type (e.g., lidocaine, bupivacaine, etidocaine) and of the ester type (e.g., 2-chloroprocaine) are widely used to relieve pain in obstetric and gynaecological practice. The pharmacokinetics of these compounds are discussed in this review, with particular emphasis on the fetal exposure and its relationship to adverse effects on the fetus. 2-Chloroprocaine is rapidly hydrolyzed by esterases, and only traces of this compound reach the fetus, even following multiple injections, suggesting safety for the fetus. The main disadvantage of this compound is the short duration of action (0.5-1 h). The amide-type agents are active for longer time periods (up to several hours). The fetal/maternal total concentration ratios were approximately 0.3 for bupivacaine and etidocaine, 0.5 for lidocaine, 0.7 for mepivacaine, and 1 for prilocaine. The low ratios of bupivacaine and etidocaine result from extensive binding (90%) of these drugs to maternal alpha1-acid glycoprotein which exceeds corresponding fetal protein binding (50%). These low fetal/maternal total concentration ratios cannot be equated with fetal safety, because fetal side effects are better related to the free drug levels. Since the amide-type anaesthetics are weak bases, fetal acidosis will increase the maternal/fetal pH gradient and will result in accumulation of free drug in the fetus and possible fetal side effects. Addition of epinephrine to the injection solution reduces the maternal blood levels of the amide-type compounds, but apparently not the fetal levels to the same extent. Because of possible unwanted effects of epinephrine (decreased uterine blood flow), the addition of this compound is not generally accepted to be of advantage. Paracervical blockade may result in elevated fetal blood levels (possibly by transarterial diffusion into uterine arteries) and possibly fetal bradycardia.

Anesthesia, Obstetrical↗
PubMed1985

Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers.

Nicotine and cotinine concentrations were measured in placental tissue during the first trimester, in amniotic fluid during the second trimester and in placental tissue and fetal serum at birth. These values were compared to the corresponding serum concentrations of the smoking mothers. Nicotine concentrations in the placentas (range 3.3-28 ng/g), in amniotic fluid (range 1.5-23 ng/ml) and in fetal serum (range 0.5-25 ng/ml) were all higher than the corresponding maternal serum values: amniotic fluid/maternal vein serum concentration ratio 1.54 +/- (SD) 0.27 (n = 23; week 16-24 of gestation), umbilical vein serum/maternal vein serum ratio 1.12 +/- 0.30 (n = 26; at birth); placental tissue/maternal vein serum ratio 2.58 +/- 1.30 (n = 17; at birth); these ratios were between 1.2 and 5 during week 10 of gestation (n = 3). The ratios did not depend on the time between the last cigarette smoked and sampling. Significant correlations were found between nicotine concentrations in amniotic fluid and maternal serum (r = 0.88), between fetal and maternal serum levels (r = 0.88) and between placental and maternal serum levels (r = 0.52). Cotinine concentrations in placental tissue (range 10-131 ng/g), amniotic fluid (range 5-188 ng/ml) and fetal serum (range 15-233 ng/ml) were lower than or similar to corresponding maternal serum levels. Our results indicate that the human fetus is exposed to higher nicotine concentrations that the smoking mothers.

Adolescent↗
PubMed1985

Neonatal behaviour disturbances in infants of epileptic women treated during pregnancy.

Infants exposed in utero to antiepileptic drugs showed significantly more behaviour disturbances such as sedation (p less than 0.05) and hyperexcitability (p less than 0.01) than infants of a control group. The presence of these clinical symptoms and the time of their appearance did not seem to be dependent on the type of maternal medication, nor on the drug serum concentration in cord blood nor on the rate of drug disappearance from the infant's plasma.

Akathisia, Drug-Induced↗
PubMed1984

Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy.

The anticonvulsant potency of 2-propyl-2-pentenoic acid (2-en-VPA; trans isomer), a major metabolite of the antiepileptic valproic acid (VPA), was evaluated in different animal models of epilepsy and compared with the respective data for VPA. Four models were used: the maximal electroshock seizure (MES) test in mice, the pentylenetetrazol seizure test in mice, gerbils with 'major' (generalized tonic-clonic) seizures in response to specific sensory stimulation, and rats with chronically recurring, spontaneous 'petit mal' seizures. The overall anticonvulsant profile of 2-en-VPA in these models compared favourably with that of VPA. Both drugs were considerably more potent to block seizures in epileptic rats and gerbils than in the traditional MES and pentylenetetrazol mouse models. As regards toxicity, no side-effects were observed with effective doses of 2-en-VPA in rats and gerbils, whereas in the doses necessary to block MES and pentylenetetrazol seizures in mice (200-300 mg/kg i.p.) 2-en-VPA was more sedative than VPA. LD50 values determined for both drugs were comparable. A major difference between 2-en-VPA and VPA was found with respect to embryotoxicity. Single doses of VPA administered to pregnant mice gave rise to significant teratogenic effects (exencephaly, embryolethality , growth retardation), whereas 2-en-VPA was not embryotoxic, even at extremely high doses (600 mg/kg). The data suggest that 2-en-VPA may be a valuable alternative antiepileptic drug.

Animals↗
PubMed1984

Mutagenic activities of cyclophosphamide (NSC-26271) and its main metabolites in Salmonella typhimurium, human peripheral lymphocytes and Chinese hamster ovary cells.

Cyclophosphamide (CPA) and its main metabolites were analyzed with respect to their mutagenic activities in Salmonella, human peripheral lymphocytes (PL), and Chinese hamster ovary (CHO) cells. In Salmonella, the compounds were activated with S9 mix from rat livers, which were unstimulated or stimulated with Aroclor 1254 or phenobarbital. For the enzyme inducers the following order of efficiency was found for all test compounds except carboxyphosphamide: phenobarbital greater than Aroclor 1254 greater than non-induced. The most potent mutagens in all 3 test systems were 4-OH-CPA, PAM and nor-HN2. S9 mix transforms 4-OH-CPA to strong mutagenic compounds in the Salmonella assay. All metabolites tested in the Salmonella assay were activated by S9 mix to higher mutagenic potential.

Animals↗
PubMed1984

Valproic acid in the perinatal period: decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and some metabolites.

The total concentrations of valproic acid were higher in cord serum than in the serum of epileptic mothers given this drug (fetal/maternal total concentration ratios 1.7 +/- 0.5). The maternal free fractions of VPA correlated with the fetal accumulation of the drug. The fetal/maternal free fraction ratios (0.47 +/- 0.24) correlated inversely with the fetal/maternal total concentration ratios. The free concentrations of VPA in fetal blood were similar to those in maternal blood. These results obtained in vivo were confirmed by an in vitro study in which the drug had been added to drug-free serum samples. The free fractions (x100) of VPA in the maternal serum at birth (27.3 +/- 6.3) were significantly higher than in the serum of adult controls (8.0 +/- 2.4) and in cord serum (11.8 +/- 1.3). The pattern of VPA metabolite binding in the three groups was similar to that of VPA, although an unsaturated metabolite (2-en) was bound to a much higher degree than VPA (greater than 98%). The high total drug load in the fetus was partially displaced from binding sites during the first few postnatal days. The free fractions of the drug and metabolites in the neonates were almost twice as high as those in the fetus at birth. The decreased protein binding of VPA in the mothers at birth and in the neonates during the first postnatal week was related to increased free fatty acid levels. VPA concentrations in mother's milk were much lower than the free concentrations in plasma milk/plasma ratios 0.025 +/- 0.01). In neonates, half-lives for VPA were prolonged (43 +/- 14 hours). Our results indicate that increased free fatty acid concentrations in the maternal blood at the time of birth result in partial displacement of VPA from maternal binding sites, additional placental transfer, and thus fetal accumulation of the drug. The high drug load in the fetus is subsequently partially displaced after birth, resulting in increased free fractions and free concentrations of VPA in the neonate.

Blood Proteins↗
PubMed1984

Automated high-pressure liquid chromatographic assay for antiepileptic drugs and their major metabolites by direct injection of serum samples.

We present a fully automated high-pressure liquid chromatographic (HPLC) assay for simultaneous quantitation of five antiepileptic drugs [ethosuximide (ES), primidone, phenobarbital, phenytoin, and carbamazepine] and their major metabolites [phenylethylmalondiamide (PEMA), carbamazepine-10,11-dihydro-10,11-diol (CBZD), and carbamazepine-10,11-epoxide (CBZE)] in serum samples without sample pretreatment. Two other metabolites, p-hydroxyphenobarbital (HPB) and 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), can be separated as well. Interference with serum constituents prevents a quantitative determination. Serum samples are injected onto a pre-column, the biological matrix is eluted with water, and the compounds of interest are subsequently separated on an analytical column. The anticonvulsants are eluted at 60 degrees C with a mobile phase containing acetonitrile:water (21:80 by vol) at a flow rate of 1.0-2.0 ml/min (flow-step gradient). The eluted compounds are monitored at 200 nm. Each analysis requires about 30 min. Analytical recoveries varied from 90 to 98%. Within-day coefficients of variation (CVs) ranged from 0.9 to 4.9%, between-day CVs from 2.8 to 7.6%. The lower limit of detection for all drugs is 0.2 microgram/ml serum, with a sample size of 100 microliters. At therapeutic concentrations we achieved baseline separation for all eight compounds, and there was no interference from other drugs.

Acetonitriles↗
PubMed1984

Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status.

A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. At birth foetal/maternal serum concentration ratios were 0.97 +/- 0.02 (n = 7) and ES half-lives in three neonates were 32, 37 and 38 h. The breast milk concentrations of ES were similar to those in maternal serum (milk/serum: 0.86 +/- 0.08, n = 12) and the nursed infants maintained serum levels between 15 and 40 micrograms/ml. Two major malformations (bilateral clefting, hare-lip) were observed in two neonates whose mothers received either ES/PB or ES/PMD comedication. The number of minor anomalies was higher in the ES group (6.2, n = 12) than in the pair-matched control group of infants born to non-epileptic mothers (2.1, n = 10). Neonatal behaviour complications occurred in seven infants, two of them were severely affected.

Abnormalities, Drug-Induced↗
PubMed1984

Decreased serum protein binding of diazepam and its major metabolite in the neonate during the first postnatal week relate to increased free fatty acid levels.

The protein binding of diazepam (D) and its major active metabolite N-desmethyl diazepam (DD) was investigated in vitro in the serum of 14 mothers at birth, 21 foetuses at birth, in 100 neonates between 1 and 11 days of age and in 16 control subjects. The free (unbound) fractions of D and DD in the foetus were similar to those in the controls, but lower than those in the mothers. During the first day of life the free fractions of D and DD doubled in the neonates and subsequently declined slowly to reach near control levels at 1 week of age. The sharp increase and slow decrease of the free fractions of D and DD during the first postnatal week was closely paralleled by sharply increasing and decreasing free fatty acid (FFA) concentrations. Bilirubin and albumin levels were of lower importance in regard to the protein binding of D and DD. These results indicate that the greatly increased FFA levels shortly after birth result in increased free fractions of D and DD. Because of the known immaturity of the neonatal hepatic elimination capacity, these elevated free fractions may result in elevated free concentrations of the two compounds, which may help to explain the adverse effects observed clinically in some D-exposed neonates.

Adult↗
PubMed1984

Nicotine and cotinine concentrations in serum and milk of nursing smokers.

Analysis of 44 milk samples from 23 nursing smokers revealed that there was a linear correlation between nicotine concentrations in serum and in milk (r = 0.70). The nicotine concentrations in milk were considerably higher than the corresponding serum concentrations: milk/serum concentration ratio = 2.92 +/- 1.09; (n = 44). There was also a linear correlation between the cotinine concentrations in serum and in milk (r = 0.89). The cotinine concentrations in milk were lower than the corresponding serum concentrations: milk/serum concentration ratio = 0.78 +/- 0.19; (n = 44). The direct comparison between the half-lives of nicotine in serum and in milk was possible in five nursing smokers. The half-life of nicotine in milk was determined in four additional smoking mothers. The half-life of nicotine in milk t 1/2 = 97 +/- 20 min slightly exceeded the half-life of nicotine in serum t 1/2 = 81 +/- 9 min; the difference between these two values was not statistically significant (P greater than 0.05). Cotinine concentrations remained fairly consistent during a 4 h interval without smoking.

Breast Feeding↗
PubMed1984

Protein binding of carbamazepine and its epoxide in maternal and fetal plasma at delivery: comparison to other anticonvulsants.

A detailed investigation of the plasma protein binding of carbamazepine (CBZ) and its major metabolite carbamazepine epoxide (CBZE) revealed that both compounds are more extensively bound to plasma proteins in the mother (% free fraction CBZ, 28.4 +/- 3.0; CBZE, 55.1 +/- 5.0) than in the fetus (% free fraction CBZ, 31.5 +/- 2.2; CBZE, 61.5 +/- 3.1) at the time of birth. Fetal and maternal protein binding is reduced compared to controls (% free fraction CBZ, 26.5 +/- 2.1; CBZE, 49.1 +/- 5.7). A correlation of the unbound fraction with various biochemical parameters suggested that among other factors, high bilirubin concentrations in the fetus could be responsible for the relatively increased free fraction of CBZ and CBZE compared to maternal values. As free fraction values of CBZ and CBZE are either the same (CBZ) or slightly higher (CBZE) in women at term compared to nonpregnant controls, a regular monitoring of maternal free fraction values seems unnecessary. For other anticonvulsive drugs, however, like diazepam and valproic acid, monitoring of both total plasma concentrations and free fractions is strongly recommended.

Adult↗
PubMed1984

Microscale ultrafiltration technique for determining free drug in 50-microL serum samples.

This ultrafiltration technique allows determination of free drug in 50 microL of serum. We ultrafiltered sera containing the following drugs--valproic acid (and its major metabolites), phenobarbital, diazepam, indomethacin, phenytoin, furosemide, and chloramphenicol--using both the commercially available micropartition system (MPS-1, Amicon), which requires a 200-microL sample, and our modified micro system, which requires only 50 microL. The value for the free fraction of each drug obtained in the two experiments agreed well. The smaller sample requirement makes the micro method particularly suited for pediatric samples and studies on small laboratory animals.

Animals↗
PubMed1984

Comparative transfer of valproic acid and of an active metabolite into brain and liver: possible pharmacological and toxicological consequences.

The transfer of the antiepileptic drug valproic acid (2-propyl-pentenoic acid) and one of its active metabolites, 2-en (2-propyl-2-pentenoic acid) from plasma to brain and liver were studied in mice at low dose levels (0.1, 0.3, 0.7, and 1.0 mmole/kg). The liver concentrations of 2-en were found to be lower than those of VPA: the liver/plasma ratios of 2-en for the four doses were 0.1, 0.2, 0.3 and 0.8, respectively; for VPA the corresponding liver/plasma ratios were 3, 2, 1.2 and 1.0, respectively. Following doses of 0.1-0.7 mmole/kg, plasma protein binding of 2-en (free fractions 2-7%) was much more extensive than of VPA (free fractions 40-45%). Also in the rat the liver/plasma concentration ratios of 2-en (0.3) were much below those of VPA (0.6). In mice, brain concentrations of 2-en were approximately 1/2 of corresponding plasma levels. Our results indicate that the transfer of 2-en into liver is limited by extensive protein binding of this compound in plasma.

Animals↗