Biomedical subjects

H Nau

Publications and source records attributed to H Nau.

263 records · Page 15Linked to original sources

PubMedDate not supplied

[Valproate-associated hepatotoxicity--pathogenesis, clinical aspects, therapy and prevention].

The potential hepatotoxicity resulting in fatal liver failure is of major concern in treating patients with valproate (VPA). Until now there is no relevant laboratory parameter allowing early detection of impending liver failure. The major routes of VPA biotransformation are glucuronidation and beta-oxidation. There are several other pathways of degradation with formation of mono- und di-unsaturated derivates. VPA dose, patients age, co-medication (anticonvulsants, aspirin), fasting and glucose supply influence the VPA metabolism. The clinical spectrum of VPA-associated hepatotoxicity reaches from slight increases of liver enzymes without clinical manifestations over reversible slight to severe liver dysfunction to fatal liver failure. With respect to pathogenesis attention has focused on depletion of beta-oxidation and change of biotransformation to other pathways with increased synthesis of toxic unsaturated VPA derivates. Several inborn errors of metabolism, acute infections and status epilepticus seem to predispose to liver failure. Another hypothesis lies in the possible VPA-induced depression of free radical scavenging enzyme activities. On this basis N-acetylcysteine has been used successfully in treating children with severe hepatotoxicity. In the presence of certain risk factors VPA should be avoided.

Ammonia↗

PubMedDate not supplied

Penetration of valproate and its active metabolites into cerebrospinal fluid of children with epilepsy.

Levels of the antiepileptic drug valproate (VPA) and five of its active metabolites (2-en-VPA, 3-keto-VPA, and 3-,4-, and 5-hydroxy-VPA) were determined by gas chromatography-mass spectrometry in cerebrospinal fluid (CSF) of 15 epileptic children undergoing chronic treatment with VPA. In eight of these children, total and free drug and metabolite concentrations in plasma were also measured. All VPA metabolites present in plasma could also be detected in CSF, although concentrations were substantially lower than those of the parent compound. CSF concentrations of VPA and most of its metabolites were positively correlated with total and free concentrations in plasma. However, concentrations in CSF were always significantly lower than free plasma concentrations, which may be explained by asymmetric transport at the blood-CSF barrier. The data on low CSF levels of VPA metabolites do not exclude the possibility that accumulation of active metabolite(s) may occur in certain brain areas during chronic treatment of epileptic patients with VPA.

Child↗

PubMedDate not supplied

Therapy of infantile spasms with valproate: results of a prospective study.

In a prospective study, 22 children with recently manifested infantile spasms (18 patients with symptomatic and 4 with idiopathic infantile spasms) were treated with sodium valproate (VPA). Before VPA was instituted, a loading test was performed to exclude abnormal patterns of VPA metabolites by gas chromatography and mass spectroscopy of serum and urine. This test was repeated during VPA therapy; an abnormal pattern of VPA metabolites was not observed. VPA was started in increasing dosage until infantile spasms were controlled or a maximum dose of 100 mg/kg/day was reached. If VPA did not control seizures or at least reduce frequency significantly after a trial of 4-6 weeks, dexamathasone was added to VPA. If focal seizures occurred in association with localized epileptogenic EEG discharges, carbamazepine (CBZ) was added to VPA. After 4 weeks of VPA monotherapy, infantile spasms were controlled in 11 children. After 3 months of therapy, 16 children were free of seizures (14 patients VPA monotherapy), and 4 children had reduction of seizure frequency to less than 25%. VPA doses varied between 40 and 100 mg/kg/day (mean 74). The mean plasma concentration was 113 micrograms/ml (range 46-177). After 6 months of therapy, total seizure control was achieved in 20 of 22 patients (16 children VPA monotherapy). The mean observation time was 16 1/2 months (range 6-36 months). There were seven relapses in six children during the first 7 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Alterations in the renal excretion of valproate and its metabolites after chronic treatment.

Urinary excretion of valproate (VPA, administered as its sodium salt) and its various metabolites was studied in rats before and after 6 weeks of chronic treatment with intraperitoneal (i.p.) injection of 200 mg/kg VPA three times daily. Urinary excretion was determined after i.p. injection of a single dose of 200 mg/kg VPA, to which [14C]labeled VPA had been added to yield a dose of 1 microCi/kg body weight. Unlabeled VPA and metabolites were determined in urine by gas chromatography-mass spectrometry (GC-MS). After injection of a single dose of VPA before onset of chronic treatment, approximately 40-50% of the dose administered was excreted in the urine within 24 h, mainly in the form of conjugated VPA and omega-oxidation products, i.e., 5-hydroxy-VPA and 2-propyl-glutaric acid. After chronic treatment, urinary excretion of total radioactivity increased approximately 75% as compared with activity before chronic treatment, demonstrating a marked increase in elimination rate of VPA during prolonged administration. Determination of VPA and metabolites in urine by GC-MS indicated that this enhanced elimination resulted mainly from increases in glucuronidation and beta-oxidation of VPA, whereas omega-oxidation was apparently not altered or was even reduced. The data strongly indicate that at least in rats VPA produces induction of its own metabolism during prolonged treatment.

Animals↗

PubMedDate not supplied

Valproate metabolites in serum and urine during antiepileptic therapy in children with infantile spasms: abnormal metabolite pattern associated with reversible hepatotoxicity.

The purpose of this study was to identify abnormal metabolite patterns of valproate (VPA) as possible early indicators of VPA-induced liver toxicity. In a prospective study, we determined serum and urine levels of VPA metabolites by gas chromatography-mass spectrometry (GC-MS) during the course of therapy in 25 children treated for infantile spasms with high VPA doses (less than or equal to 100 mg/kg body weight/day). Most patients had similar metabolite profiles: The main metabolites in serum were the beta-oxidation products (2-en-VPA and 3-keto-VPA) and the major diunsaturated metabolite 2,3'-dien-VPA. Glucuronide conjugates and the oxidation products represent the most abundant metabolites in urine. Other metabolites, including the potential hepatotoxin 4-en-VPA, were detected only in low concentrations. Two children had transiently aberrant metabolite profiles, indicating altered beta-oxidation, (levels of 2-en-VPA, 2,3'-dien-VPA, and 3-en-VPA were markedly increased) in connection with hepatomegaly and increased liver enzyme activities at a time when both had febrile infections and were receiving dexamethasone comedication. At no time were increased levels of 4-en-VPA or its derivatives detected. Establishing the VPA metabolite profile may aid in evaluation of patients who show signs and symptoms of liver dysfunction during VPA therapy. The present study shows that initial stages of hepatotoxicity reactions to VPA may be accompanied by characteristic changes in VPA metabolism; early detection of such abnormal metabolite patterns might decrease the risk of severe hepatic injury.

Chemical and Drug Induced Liver Injury↗

PubMedDate not supplied

Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity.

Of a cohort of 470 epileptic patients in whom valproate (VPA) serum metabolites had been measured, 170 subjects without symptoms or signs of hepatic side effects were chosen as a reference group to establish the usual metabolic pattern. A wide interindividual variation of VPA metabolite concentrations was noted. Infants receiving VPA monotherapy and comedication with other antiepileptic drugs (AEDs) showed lower concentrations of the potential hepatotoxin 4-ene-VPA than did older children. In 11 patients with early symptoms and signs of possible fatal VPA-associated hepatotoxicity, the following spectrum of benign clinical conditions was observed: unusually severe side effect during initiation of VPA therapy (1 patient), high VPA dosage (2 patients), reversible impairment of coagulation with bleeding manifestations in association with a slight increase in transaminase levels (1 child), and reversible liver dysfunction associated with febrile illness (7 patients). Reversible or irreversible fulminant liver failure had occurred in 5 children. Three of the 4 children with a fatal outcome had massive lactic acidosis. In all patients with probable VPA-associated hepatotoxicity, some aspects of VPA metabolism differed distinctly from that of the reference group, but the inter-individual profile of metabolites varied considerably, even in the subgroup of 4 children who died. Impairment of VPA beta-oxidation and increase of metabolites of alternative metabolic pathways (omega- and omega 1-hydroxylation, dehydrogenation reactions) were the most frequent findings. Increased values of 2-n-propyl-4-pentenoic acid metabolite of VPA (4-ene-VPA), could be detected only in 1 of the 5 patients with fulminant liver failure and in one other child with a slight hepatic dysfunction, indicating that this VPA metabolite is not the decisive hepatotoxin or indicator of hepatotoxicity. Because we cannot distinguish between benign and life-threatening hepatic adverse reactions on the basis of VPA metabolites, all identified changes are considered secondary to an as-yet-unknown primary metabolic event. The most toxic compound could be VPA itself, which may unmask an inborn or an acquired metabolic defect in the processing of fatty acids.

Chemical and Drug Induced Liver Injury↗

PubMedDate not supplied

Cigarette smoke exposure and development of infants throughout the first year of life: influence of passive smoking and nursing on cotinine levels in breast milk and infant's urine.

The effects of smoke exposure via mothers' milk and/or via passive smoking during the first year of life were investigated in a prospective longitudinal matched-pair study. The somatic and mental development of 69 infants whose mothers smoked more than five cigarettes per day throughout pregnancy and continued smoking after childbirth were compared with 69 children of non-smoking mothers. At birth, mean body weight of neonates from smoking mothers was significantly lower than the weight of neonates from non-smoking mothers. This weight difference between the two groups was no longer significant in infants at 12 months of age. With the methods employed by the authors, neither psychomotor nor mental development was affected by smoke exposure during pregnancy and early infancy. Infections of the lower respiratory tract were more frequent in the children of smoking mothers. These mothers weaned their babies earlier than non-smokers, but the different feeding behaviour did not influence any of the clinical parameters that were investigated in this study. In order to evaluate the extent of smoke exposure, cotinine was measured in children's urine and in breast milk once a month throughout the first year of life. Cotinine in the urine was significantly dependent on feeding behaviour: infants breast fed showed concentrations 10-fold higher than those who were bottle fed. Cotinine excretion in urine of infants from smoking mothers, who were not breast fed (nicotine exposure via passive smoking only) was even higher than that of adult passive smokers. If infants from smoking mothers were breast fed, their urinary cotinine excretion was in the range of adult smokers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics.

Few data are available on placental transfer of anticonvulsants during early pregnancy. Nevertheless, it has been demonstrated that at this early stage of gestation, considerable amounts of phenytoin, primidone/phenobarbitone and carbamazepine as well as some of their metabolites are already present in fetal tissues. Potentially reactive metabolites of anticonvulsants can be formed by the fetal liver and accumulate in some organs. At term, most anticonvulsants are present in neonatal plasma in concentrations similar to those in maternal plasma. Valproic acid, on the other hand, can accumulate in fetal blood, for still unknown reasons. Elimination by the neonate is variable and is dependent on several factors, such as clinical state, pre- or perinatal enzyme induction, absorption of the drugs and their plasma protein binding. Neonatal acquisition of anticonvulsants via breast-feeding does not seem to be harmful for the neonate. In the case of phenobarbitone, however, the drug may accumulate in nursing neonates to levels approaching or even exceeding those of their mothers. Significant drug levels can also build up in neonates and infants nursed by carbamazepine- and ethosuximide-treated mothers. This review contains relevant pharmacokinetic data on anticonvulsant drugs widely used during pregnancy and the neonatal period. The differences between pregnant and non-pregnant adults as well as between neonates and older age groups are emphasized. Some pharmacokinetic data are correlated with clinical manifestations, such as seizure frequency, neonatal depression and withdrawal symptoms.

Anticonvulsants↗

PubMedDate not supplied

Plasma pharmacokinetics and metabolism of 13-cis- and all-trans-retinoic acid in the cynomolgus monkey and the identification of 13-cis- and all-trans-retinoyl-beta-glucuronides. A comparison to one human case study with isotretinoin.

In order to compare the disposition and metabolism of 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (all-trans-RA) in the nonpregnant female cynomolgus monkey, the plasma concentrations of the parent compound, the oxidized metabolites 4-oxo-13-cis-retinoic acid and 4-oxo-all-trans-retinoic acid, and the conjugate metabolites 13-cis-retinoyl-beta-glucuronide (13-cis-RAG) and all trans-retinoyl-beta-glucuronide (all-trans-RAG), were determined on day 1 and day 10 after oral dosing of 2 and 10 mg 13-cis- and all-trans-RA/kg/day. Both 13-cis-RAG and all-trans-RAG have been identified as major plasma metabolites in these studies using thermospray/HPLC/mass-spectrometry of the intact conjugates. AUC comparisons from 0-24 hr after administration indicated that 13-cis-RA treatment resulted in primarily cis metabolites and all-trans-RA treatment resulted in primarily trans metabolites, although low levels of isomerization products were observed. Comparison of the two doses (2 and 10 mg/kg, po) revealed that the AUCs were proportional to the dose administered. Although qualitatively similar, elimination of 13-cis-RA in the monkey was more rapid than in the human, and approximately a 10-fold greater dose of 13-cis-RA was required in the monkey to produce the AUC values comparable to the human. The elimination of all-trans-RA in monkey was faster than that of 13-cis-RA and tended to increase with repeated dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Identification of 9,13-dicis-retinoic acid as a major plasma metabolite of 9-cis-retinoic acid and limited transfer of 9-cis-retinoic acid and 9,13-dicis-retinoic acid to the mouse and rat embryos.

9-Cis-retinoic acid (9-cis-RA) has been proposed to be the endogenous ligand of retinoid X receptors. We examined the plasma pharmacokinetics of 9-cis-RA and its metabolites in nonpregnant female NMRI mice after oral dosing with 50 mg 9-cis-RA/kg body weight. Furthermore, we studied the metabolism of 9-cis-RA and its transfer to the embryo following oral administration of the precursor 9-cis-retinaldehyde (9-cis-RAL; 100 mg/kg body weight) to pregnant mice and rats on gestational days 11 and 13, respectively. Following 9-cis-RA administration, plasma levels of 9-cis-RA reached their maximum within 40-60 min and then declined in a monoexponential manner with an apparent half-life of 64 +/- 32 min. A great variety of polar metabolites of 9-cis-RA was found; among them, the beta-glucuronides of 9-cis-RA (9-cis-RAG) and of 9-cis-4-oxo-RA (9-cis-4-oxo-RAG) could be identified. A further prominent polar metabolite of 9-cis-RA in mouse plasma was shown to be an additional RA isomer (distinct from 13-cis-RA and all-trans-RA) whose concentrations weeesimilarly high as those of 9-cis-RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Pharmacokinetics of 13-cis-, all-trans-, 13-cis-4-oxo-, and all-trans-4-oxo retinoic acid after intravenous administration in the cynomolgus monkey.

The intravenous pharmacokinetics of 13-cis-, all-trans-, 13-cis-4-oxo, and all-trans-4-oxo retinoic acid (RA) were determined in nonpregnant female cynomolgus monkeys. All-trans- and 13-cis-RA were injected at two doses (0.25 or 0.0125 mg/kg) and all-trans-4-oxo RA and 13-cis-4-oxo RA at 0.25 mg/kg. Total body clearance, volume of distribution, and volume of distribution at steady state of all-trans-RA were dose-dependent with greater values at the lower dose. Elimination half-life was longer for the cis-compounds and not dose-dependent (N = 1 for 13-cis-4-oxo RA, N = 3 for other compounds, harmonic mean +/- pseudostandard deviation, min): 13-cis-4-oxo RA (837) > or = 13-cis-RA (301 +/- 204) > all-trans-RA (38 +/- 3) > all-trans-4-oxo RA (11 +/- 2). Secondary plasma peaks were noted only after administration of 13-cis-4-oxo RA. The low area under the time concentration curves for observable metabolites after intravenous injection of the oxidated compounds suggests further metabolism plays a minimal role in the elimination of these compounds from the monkey. Plasma-time concentration curves were fitted to multicompartmental models and suggested < 30% of each compound was available in the central compartment for elimination in the postdistribution phase. A comparison of the kinetics of the isomers indicated oxidation of all-trans-RA to all-trans-4-oxo RA increased mean total body clearance values 4-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗