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H Helge

Publications and source records attributed to H Helge.

At least 19 recordsLinked to original sources
PubMed1992

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 4. Effects of multiple-dose treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral lymphocyte subpopulations of a non-human primate (Callithrix jacchus).

Non-human primates (Callithrix jacchus) were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) over a period of 30 weeks, and lymphocyte subpopulations of venous blood were monitored using monoclonal antibodies and flow cytometry (FACScan). There was no clear-cut change in the total lymphocyte population during this study. In the first part of the study the new-world monkeys (marmosets) were treated for 24 weeks with a weekly dose of 0.3 ng TCDD/kg body wt. At the end of this treatment period a level corresponding to an actual cumulative dose of about 2.5-2.7 ng TCDD/kg body wt was expected. The percentage and the absolute number of the CD4+CDw29+ cells ("helper inducer" or "memory" cells) surmounted the physiologically occurring increase. Concomitantly the percentage of the CD4+CD45RA+ cells ("suppressor-inducer" or "naive" cells) decreased. There was, at the same period, no change in the total T cell population (CD2+ cells) or in the cells carrying the CD8 or the CD4 epitope. When increasing the weekly dose to 1.5 ng TCDD/kg body wt, a transient increase in the percentage and the absolute number of the CD8+CD56+ cell population ("cytotoxic T cells") was observed 3 weeks after the increase in dosing. At this time the expected decrease in the percentage or the absolute number of CD4+CDw29+ cells was just detectable and this decline was at its maximum 6 weeks after switching to the higher weekly doses. The reduction in the percentage and the absolute number of CD4+CDw29+ cells persisted 5 weeks after discontinuation of the dosing, but this cell population was again within normal limits 7 weeks later. Because the two subpopulations are changed in opposite directions, the ratio CD4+CDw29+/CD4+CD45RA+ is a very sensitive measure of the effect induced by TCDD. There was a pronounced decrease in the percentage of the CD20+ cells (B1 cells), but their percentage and number rapidly normalized, in contrast to the CD4+CDw29+ cells, when the dosing was discontinued. At the end of the treatment period the apparent body burden was calculated to correspond to an actual dose of about 9-10 ng TCDD/kg body wt. Such an actual dose level might be assumed to be reached under steady-state conditions in chronic experiments with daily doses of about 135 pg TCDD/kg body wt (assuming a half-life for TCDD in the marmoset of 6-8 weeks). Extrapolations of the results obtained at higher doses to very low exposures is not justified with respect to the effects induced by TCDD on the immune system of marmosets. At lower doses the effect is clearly reversed.

Animals↗
PubMed1992

Increase of cytochrome P450IA2 activity by omeprazole: evidence by the 13C-[N-3-methyl]-caffeine breath test in poor and extensive metabolizers of S-mephenytoin.

Omeprazole has been shown to induce cytochrome P450IA1 and P450IA2 activity in vitro. To reflect cytochrome P450IA2 (CYP1A2) activity in vivo, the 13C-[N-3-methyl]-caffeine breath test was conducted in 18 volunteers: 12 extensive metabolizers, one intermediate metabolizer, and five poor metabolizers of S-mephenytoin. Breath tests were performed before treatment with an oral dose of 40 mg omeprazole, on the seventh day of treatment, and after a 7-day washout period. The mean percentage exhalation of the 13C test dose, as determined by 13CO2 in breath during 8 hours, was 23.0% +/- 8.0% (n = 18) before treatment. The largest increases in exhalation rate of 13CO2 were observed in the poor metabolizers and the intermediate metabolizers (range, 12.8% to 62.9%; median, 38.9%); median area under the plasma concentration-time curves (AUC) of omeprazole was four times higher than in the extensive metabolizers. The change after omeprazole treatment in extensive metabolizers ranged from -9.8% to +47.7% (median, 12.3%; n = 12) of pretreatment values. In both groups exhalation rates of 13CO2 returned to near pretreatment values within the 7-day washout period (24.2% +/- 7.8%; n = 17). Changes in the 13C-caffeine breath test correlated well with both the pretreatment value (R = -0.67, p = 0.003; n = 18) and the plasma AUC of omeprazole (R = 0.61, p = 0.007; n = 18). Therapeutic doses of omeprazole seem to induce CYP1A2 activity in poor metabolizers, whereas they exert minor inducing effects in extensive metabolizers of S-mephenytoin.

Adolescent↗
PubMed1992

Major and minor birth malformations and antiepileptic drugs.

In a study of infants of parents with epilepsy, malformations were twice as prevalent in these children as in controls. Children of mothers with epilepsy had more minor anomalies than those of fathers with epilepsy or controls. At 1 year of age, a greater number of minor anomalies was seen in children of mothers with epilepsy who had received treatment with antiepileptic drugs (AEDs) during pregnancy, whereas at 4 years, no difference was observed. Type of epilepsy, seizures during pregnancy, plasma levels of phenytoin or phenobarbital in the medium range, and fetal intrauterine growth did not correlate with the number of minor anomalies. We suggest that the special genetic background that predisposes to epilepsy also renders the fetus more vulnerable to major and minor anomalies. Although linkage between epilepsy and malformation is stronger than between AEDs and malformations, valproate, phenytoin, and phenobarbital show specific teratogenic effects. In addition, all AEDs unspecifically increase the number of minor anomalies. Under therapeutic conditions, valproate may be regarded as considerably teratogenic and all other observed AEDs as weakly teratogenic.

Abnormalities, Drug-Induced↗
PubMed1991

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 2. In vitro effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on lymphocytes of venous blood from man and a non-human primate (Callithrix jacchus).

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on poke weed mitogen-stimulated proliferation and differentiation of peripheral lymphocytes was studied in vitro with cells from a non-human primate (marmoset monkey, Callithrix jacchus) and from man. Monoclonal antibodies and flow cytometry (FACScan) were used for analysis. The extent of the overall mitogen-stimulated proliferation of isolated lymphocytes in vitro from marmoset blood was only slightly reduced in the presence of TCDD compared to the solvent control (0.01% DMSO). However, incubation with TCDD in the culture medium together with the mitogen led to a pronounced decrease in the percentage of the lymphocyte subset with the surface marker CD4, and a concomitant increase in the percentage of CD8+ cells. The lowest concentration found to be effective in vitro was 1 x 10(-13) M TCDD (25 fg TCDD/ml). When culturing lymphocytes from human blood of different donors under identical conditions in the presence of TCDD and the mitogen, corresponding effects were observed to those seen with marmoset cells. A closer analysis of the T lymphocyte subsets affected revealed the CD4+ CDw29+ (helper-inducer cells) to be the main target for the action of TCDD. A clear-cut change in the percentage of this subpopulation was induced at concentrations as low as 1 x 10(-13) M TCDD. The development of the IL-2-marker in culture was only slightly affected by TCDD, and concentrations of 1 x 10(-12) M were required to slightly reduce the number of CD2+CD25+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

CO2 breath tests using 14C-caffeine, 14C-methacetin and 14C-phenacetin for assessing postnatal development of monooxygenase activities in rats and marmosets.

The time course in which the activities of cytochrome P450-dependent drug-metabolizing enzymes develop during the perinatal period differs for various types of monooxygenases as well as for various animal species. Using [3-methyl14C]-, [7-methyl14C]-caffeine, [14CH3]-methacetin and [14C2H5]-phenacetin as substrates in breath tests, the developmental changes in the rates of 14CO2 formation, due to changes in the activity of monooxygenases, were studied in rats and marmoset monkeys (Callithrix jacchus). In rats a rate of 0.006% of the dose administered/min was found to be exhaled as 14CO2 in the caffeine breath tests on the 1st day of life. This value increased gradually reaching adult rates of 14CO2 exhalation after 21 days for [3-methyl14C]-caffeine and after 25 days for [7-methyl14C]-caffeine. In marmosets the rate of 14CO2 exhalation for [3-methyl14C]- and [7-methyl14C]-caffeine was also low at birth and developed gradually reaching adult values of 14CO2 exhalation within 120-200 days. In rats the capacity for dealkylation of methacetin and phenacetin developed much faster compared with caffeine: 9 days postnatally, the exhalation of 14CO2 reached adult values. Offspring of marmosets reached adult values of 14CO2 exhalation at 8 days postnatally when using [14CO2]-methacetin as substrate and at 30 days postnatally using [14C2H5]-phenacetin in the breath test. The results suggest that the monooxygenases for the N-demethylation of caffeine, the O-demethylation of methacetin and the O-deethylation are rather substrate specific in the two species studied. The breath tests used are sensitive methods for assessing the development of different monooxygenases in vivo in rats and marmosets, and they may well (using 13C-labelled substrates) be applicable for studies in children to monitor effects of certain environmental pollutants.

Acetamides↗
PubMed1991

[The significance of PCDD's/PCDF's (dioxins) in pediatrics].

No epidemiological data are available up to now which reveal adverse effects induced by dioxins during an exposure through breast milk. Furthermore, very few data on the concentration of PCDDs/PCDFs in the newborn and during the first year of life have been published. Of all PCDDs/PCDFs, the substance with the highest toxicity is 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, in the environment this congener is often only a minor component. A sensitive biological effect triggered by TCDD is the enzyme induction of hepatic monooxygenases. Using a 14CO2-breath-test the apparent enzyme induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) of the metabolic conversion of [3-methyl14C]-caffeine was studied during the perinatal period in Wistar rats and in a non-human-primate (marmoset, Callithrix jacchus). It could be shown that the apparent induction of monooxygenase activity by TCDD in rat offspring as measured with the breath-test, is dose-dependent and mainly achieved by postnatal exposure via mothers' milk. Our data indicate that caffeine is a convenient substrate for studying monooxygenase activities (probably P450 IA-dependent) to be induced by TCDD, and very likely also by other congeners. These results, therefore, may provide the rationale for applying a [13C]-caffeine breath-test in human newborn and infants to analyse possible biological effects induced by TCDD and similar pollutants in breast-fed children. Since PCDDs/PCDFs are pollutants without any benefit, strong efforts should be continued to further reduce the output of dioxins, the human exposure, and thereby also concentrations in human milk.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 1. Effects on peripheral lymphocyte subpopulations of a non-human primate (Callithrix jacchus) after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Monoclonal antibodies were used to analyse the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral lymphocytes from marmosets (Callithrix jacchus) following injections of single low doses of TCDD. A reduction of the percentage and the total number of lymphocytes among the white blood cells was seen 3 weeks after a single administration of 300 ng TCDD/kg body wt, but not following 167 ng TCDD/kg or less. After treatment of marmosets with the single subcutaneous dose of 10 ng TCDD/kg body wt. we observed an average decrease of about 20% in the percentage of CD4+ cells in the venous blood of treated animals. This change was not seen at the time of maximum absorption (2 weeks after the injection), but was demonstrable after 4 weeks and reached its maximum 15 weeks after the injection. The time course of the changes suggests an indirect effect (possibly via the thymus). Due to the considerable inter- and intra-individual variability in the number of peripheral lymphocytes the effect was less convincing on the basis of the total CD4+ cells per microliter blood. There was a significant concomitant increase in the percentage of cells with the CD8+ marker. A closer analysis of the lymphocyte subpopulation involved revealed a predominant effect on the cells with the CD4CDw29 ("leu 3a+4B4+") surface marker ("helper-inducer cells"). Subsequent to a dose of 10 ng TCDD/kg body wt the percentage of these cells was reduced by 50% or more when compared with the (24) controls. On an absolute basis (number of cell/microliter blood) these CD4+CDw29+ cells were clearly reduced in only two out of four marmosets. There was no significant effect on the percentage of the CD4+CD45R+ ("leu3a+2H4+") subpopulation ("suppressor-inducer cells"). The ratios: CD4+CDw29+/CD4+CD45R+, or CD4+CDw29+/CD8+ appear to be convenient measures for monitoring the effect described. Since the difference between the percentage of CD2+ cells minus the sum of CD4+ plus CD8+ cells was found to be increased following rather high doses (167 ng TCDD/kg body wt or more), this suggests that immature cells (CD2+ CD4-CD8-) are released into the periphery as a result of the exposure to TCDD. Furthermore, a decrease in the percentage of CD20+ (B1+) cells (about 50% when compared with controls) was observed in the treated animals following a single dose of 10 ng TCDD/kg body wt or higher. Subsequent to a dose of 10 ng TCDD/kg body wt the percentage of CD56+ (NKH1+) cells seemed to be slightly increased. The dose-response for the effects observed was rather poor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Transfer of various polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) via placenta and through milk in a marmoset monkey.

A defined mixture of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) was subcutaneously administered to a pregnant marmoset monkey (Callithrix jacchus) 11 weeks prior to delivery. Transfer of PCDDs and PCDFs via placenta and mother's milk was investigated by measurement of concentrations in a newborn 1 day after birth and in an infant of the same litter after a lactation period of 33 days. Furthermore, comparative measurements were performed in different tissues of the mother at the end of the lactation period, and in addition, in two groups of four adult monkeys each 1 and 6 weeks after treatment. Deposition of the PCDDs and PCDFs into fetal liver was very low for most of the 2,3,7,8-substituted congeners. Highest deposition was observed for 2,3,7,8-T4CDD and 1,2,3,7,8-P5CDD. For all other compounds concentrations in the hepatic tissue of newborn shortly after birth were lower than one tenth of corresponding concentrations in adults. Especially for PCDFs, prenatal deposition in fetal liver was extremely low. Fetal liver is apparently largely unable to accumulate PCDDs/PCDFs. In contrast to liver, concentrations of 2,3,7,8-substituted PCDDs/PCDFs in adipose tissue of the newborn were at least one third of the levels in adults. However, concentrations of OCDD and OCDF were about three times higher in the newborn than in adult adipose tissue. Transfer of some of the 2,3,7,8-substituted PCDDs and PCDFs to the offspring via mother's milk was considerable, leading to hepatic concentrations in the suckled infant at the end of the 33-day nursing period well above corresponding concentrations in the dam. When hepatic concentrations in the infant and dam were compared 2- to 4-fold higher concentrations were found in the infant's liver for 2,3,7,8-T4CDD/F and for 1,2,3,7,8-P5CDD. In the case of the 2,3,7,8-substituted H6CDDs, P5CDFs, and most of the H6CDFs, hepatic concentrations in the infant and dam were in the same range at the end of the suckling period. In contrast to this, less than one tenth the concentration of OCDD was found in the infant's liver when compared with adult liver. A corresponding phenomenon was observed for PCDFs. At the maximum absorption, 1 week after injection, for almost all 2,3,7,8-substituted congeners highest concentrations were measured in hepatic tissue of adult monkeys. This is especially true for those substances with six and more chlorine atoms. Besides adipose tissue, comparatively high levels were found in thymus and also in lung tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Effect of different oestrogen doses on final height reduction in girls with constitutional tall stature.

The effects of different doses of oestrogens in constitutionally tall girls were evaluated in two centres for paediatric endocrinology. In one centre, 38 girls were treated with a high oestrogen dose of 0.3 to 0.5 mg ethinyloestradiol (EE) daily. In the other, 44 girls received a comparably low dose of 0.1 mg EE per day. Height prediction (HP), chronological age (CA), and height at the onset of treatment were comparable in both groups. Although the duration of treatment was significantly longer in those receiving the low dose, the cumulative oestrogen dose was still significantly lower. The dose of EE had no effect on final height reduction (high dose group: 4.9 +/- 2.6 cm, low dose group: 5.1 +/- 2.4 cm). Final height was more reduced in both groups when treatment was started at an early bone age (BA) (less than or equal to 13 years). No serious side effects were observed in either group, however weight gain was more pronounced in girls receiving the higher dose. We conclude that treatment of constitutionally tall girls with low doses of oestrogens is equally effective in reducing the final height as the usually administered high doses. The lowest effective dose has to be determined in a randomized, prospective clinical trial.

Adolescent↗
PubMed1989

Cytotoxic antibodies in congenital hypothyroidism.

Antibody-dependent cell-mediated cytotoxicity was determined in serum samples from 61 patients with congenital hypothyroidism (CH) and 46 of their mothers, using a 51chromium release assay with human thyroid cells. Such cytotoxic antibodies were found in 31% of the children and 24% of their mothers. In the 12 (of 37) newborn infants with hypothyroidism (group 1) who had positive tests, the median cell lysis was 20.1% compared to 4% in healthy newborns. In the 7 (of 29) mothers who had positive tests, the median lysis was 21.3%. In 24 older children with CH (group 2), cytotoxic activity was found in 6, and in them the median lysis was 19.7%; 4 of their mothers had increased lytic activity (median, 20.6%). In 96% of the mother-infant pairs concordance existed between the cytotoxic activity in mothers and their children. Increased thyroid cell lysis was found in 6 of 20 children with athyrosis (30%) and in 6 of 23 children with an ectopic gland (50%), but in only 1 of 14 children with a normal gland. Thyroglobulin antibodies were detected in 2 and antithyroid microsomal antibodies in 3 children-mother pairs. TSH receptor antibodies were present in 5 children and 3 of their mothers. The results indicate that intrauterine autoimmune thyroiditis could be involved in the pathogenesis of CH in some patients.

Autoantibodies↗
PubMed1989

Immuno-toxicology and -pharmacology.

1. The new field of immunotoxicology may be expected to gain considerable importance in the assessment of possible toxic risks of chemicals. It is an applied science based on the considerable experience gained in basic immunological research within the last decades. 2. Some possibilities are discussed and procedures suggested for evaluating toxic effects induced by chemicals (including drugs) in experimental animals and man. 3. Original data are presented on thymus atrophy induced in the offspring of rats treated on day 10 of pregnancy with the virostatic drug acyclovir. 4. Experimental data are presented on the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the distribution of lymphocyte populations (peripheral blood) in primates in vivo and in vitro, as determined with monoclonal antibodies as probes.

Acyclovir↗
PubMed1988

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↗
PubMed1988

Long-term monitoring of treatment with recombinant human growth hormone by serial determinations of type III procollagen-related antigens in serum.

Inasmuch as recombinant human growth hormone is now more generally available for the treatment of different types of short stature, there is a need for better short-term indicators of treatment success. In healthy children, serum concentrations of antigens related to the aminoterminal propeptide of type III procollagen (P-III-NP) closely follow the growth velocity curve. P-III-NP was measured longitudinally in 20 children with growth hormone deficiency during 6 months of human growth hormone substitution therapy. Two different radioimmunoassay systems were used; one recognizes predominantly the intact propeptide showing a lesser affinity to a smaller monomeric peptide (RIAgnost assay), while the other assay detects both forms equally (FAB assay). These results were compared to the growth response [median 5.6 (0.4 to 13.9) cm in 6 months] and to other established growth correlated parameters (somatomedin C, alkaline phosphatase). A relatively better growth response correlated significantly with high pretreatment P-III-NP (RIAgnost assay) values (r = 0.56) and delayed bone age (r = -0.70). A combination of these parameters in multiple regression analysis increased the cumulative prediction value to above 60% (r2 = 0.61). On the other hand, P-III-NP (FAB assay) values proved to be best in monitoring treatment, correlating with the individual growth rate during the first 3 months (r = 0.40; p less than 0.05), during the consecutive 3 months (r = 0.66; p less than 0.001), and during the total 6-month period (r = 0.46; p less than 0.05). All other parameters showed associations to growth only during some treatment periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

[Determination of the oxidation rate of medium-chain triglycerides in newborn infants with the 13C trioctanoin breath test].

Up to the present time medium chain triglycerides (MCT) have been applied solely for the enteral nutrition of newborn infants. Results of the oxidative utilization of parenterally applicated MCT have not yet been published. We therefore investigated the MCT oxidation with the 13C trioctanoin breath test in neonates. The patients received parenterally 10 mg/kg MCT (1-13C3 trioctanoin) enriched with the stable isotope 13C and emulsified with MCT/LCT 10%. The expired 13CO2 resulting from fat oxidation was determined by a ratio-mass-spectrometer. The 13C content of exhaled air represents the rate of fatty acid oxidation. Within the test period the fatty acid oxidation showed a clear dependency on the simultaneous carbohydrate supply. The oxidation rates of MCT were about twice als high as those of long chain triglycerides (LCT). On account of their high energetic level, MCT-containing emulsions are, in principle, also suitable for the parenteral nutrition of newborn infants.

Breath Tests↗
PubMed1987

[Effect of carbohydrate administration on leucine oxidation in newborn infants. Studies using the 13C leucine breath test].

The branched-chain amino acid leucine plays an important role in the protein metabolism of human beings. It not only inhibits protein degradation but also stimulates protein synthesis. The oxidation rate of leucine and the influence which nutritional conditions have on this amino acid can be measured with the intravenous 13C-leucine breath test. In order the apply the breath test on newborn infants, the required dosage of L-(1-13C)-leucine and the reproducibility of the test had, firstly, to be determined. Following this, the extent to which the leucine oxidation rate was influenced by a simultaneous carbohydrate intake was investigated. An evident discrimination between the 13CO2-exhalation and the 13CO2-baseline exhalation is demonstrated after a bolus injection of 1 mg L-(1-13C)-leucine/kg B.W. We were able to measure reproducible values of the leucine oxidation rate in newborn infants with a tracer dosage of 4 mg L-(1-13C)-leucine/kg B.W. We found that a higher intake of carbohydrate given at the same time produced a lower rate of leucine oxidation, which indicates increased utilization of leucine for the benefit of protein synthesis.

Breath Tests↗
PubMed1986

Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid.

The association of fetal and neonatal distress, birth measurements, major malformations, and minor anomalies was studied prospectively in 14 infants of women with epilepsy who were receiving valproic acid (VPA) monotherapy and in 12 infants of women with epilepsy who were receiving VPA in combination with other anticonvulsant drugs. Comparison was made with 26 matched-pair controls and 116 controls from a larger study of antiepileptic drugs. During the first trimester, total VPA serum concentrations were well above therapeutic levels (100 to 184 micrograms/ml) in two women receiving high VPA doses (2000 and 1500 mg daily). Although dosage remained the same, serum concentrations decreased during pregnancy to therapeutic levels (33.9 to 57.0 micrograms/ml). The VPA percent free fraction increased in the third trimester and was threefold higher at birth. Almost half of the infants exposed to VPA monotherapy were distressed during labor, and 28% had low Apgar scores. Fetal and neonatal distress may be caused by the high VPA percent free fraction during labor and at birth. Mean body measurements at birth after VPA monotherapy were comparable to those in the matched control group, but were reduced in the group of infants receiving VPA combination therapy. Four infants exposed to VPA monotherapy were born with major malformations. The median number of minor anomalies was four times higher in infants whose mothers received VPA alone or VPA combination therapy than in controls. Seven infants had a pattern of craniofacial and digital anomalies that was distinctly different from that observed after in utero exposure to other anticonvulsant medications. The occurrence of major malformations and the number of minor anomalies may be dose related.

Abnormalities, Drug-Induced↗
PubMed1985

[13C]Acetate oxidation in infants after oral versus rectal administration: a kinetic model.

To study the fate of volatile fatty acids (VFA) in the large bowel, we compared the rate of oxidation of 13C-labeled VFA administered rectally with that of the orally administered substrate. On two different days, 1-[13C]acetate was administered rectally or orally to five infants recovering from diarrhea. Breath samples were collected over 4 h and analyzed for 13C enrichment of breath CO2 by gas isotope ratio mass spectrometry. The percent dose recoveries of 13C in breath were fitted to multicompartmental models using the SAAM-27 program. Following model development procedures, the oral acetate breath test curves could be accounted for only by a compartmental model in which labeled acetate underwent absorption into and mixed with a systemic pool before oxidation took place. The rectal acetate breath test curves could be accounted for by a simpler model in which oxidation occurred directly in the compartment in which the rectal acetate was administered, and required no rate-limiting absorptive process. Our results indicate that the labeled acetate was oxidized more rapidly when the substrate was administered rectally than orally. This observation points to the direct utilization of volatile fatty acids within the colon.

Acetates↗