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Biomedical subjects

D Neubert

Publications and source records attributed to D Neubert.

At least 91 records · Page 5Linked to original sources
PubMed1988

Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1. Dose-dependent tissue distribution and induction of hepatic ethoxyresorufin O-deethylase in rats following a single injection.

Concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver and adipose tissue, and hepatic ethoxyresorufin O-deethylase (EROD) activity were studied subsequent to a single subcutaneous injection of TCDD. Two types of experiments were performed to study: (a) time-dependent changes following a single injection of 300 ng TCDD/kg body wt (points 1-4), and (b) dose-dependent changes measurable after 7 days following a single injection (points 5-7). 1. Absorption of TCDD following a single subcutaneous injection was about 90% after 3 days and 98% after 5 days. 2. Following a single dose of 300 ng TCDD/kg body wt peak concentrations were: liver (after 3 days): 4.7 +/- 0.9 ng/g wet wt, and adipose tissue (after 7 days): 0.82 +/- 0.07 ng/g wet wt. 3. T1/2 of TCDD in liver was 13.6 days over the total experimental period (from day 10 to 91 of the study), apparently with an initial faster phase: 11.5 days (from day 10 to 49), and a slower period at the end of the experiment: 16.9 days (from day 49 to 91); in adipose tissue the t1/2 was 24.5 days (from day 14 to 91 of the study). 4. Maximum induction of EROD in the liver was observed (14-fold at 300 ng TCDD/kg body wt) 3-7 days following the injection; the activity was decreased to about one third of the maximum 3 weeks after the injection; increase in total cytochrome P-450 at this dose was only about 1.4-fold at the induction maximum. 5. The ratio of the TCDD concentrations in liver and adipose tissue increased considerably between doses of 3 ng TCDD/kg body wt (ratio: about 0.74) and 3000 ng TCDD/kg body wt (ratio: about 7.7). 6. The extent of EROD induction in the liver increased dose dependently. A significant effect was first observed with a dose of 3 ng TCDD/kg body wt (activity about +32% above control activity). The corresponding tissue concentration was about 10 pg TCDD/g liver wet wt. 7. An almost perfect linear relationship exists (when using a double-log plot) between the hepatic TCDD concentration and the EROD activity for tissue concentrations ranging from 40 to 30,000 pg TCDD/g wet wt.

Adipose Tissue↗
PubMed1988

Activation of cyclophosphamide in mouse limb bud cultures using a reconstituted cytochrome P-450 system.

Purified phenobarbital-induced rat liver cytochrome P-450 was incorporated in a reconstituted system containing NADPH-cytochrome P-450 reductase, dilauroyl phosphatidyl choline and sodium cholate. This system was added to organ cultures of limb buds from mouse embryos on day 11 of gestation. Cyclophosphamide (100 micrograms per ml) was used as a "pre-teratogen" and activation was initiated by adding an NADPH-regenerating system. Due to extensive purification, toxicity of the enzyme preparations and residual solubilisation detergents could be greatly reduced. A reconstituted system containing 10-100 pmol cytochrome P-450 per ml without cyclophosphamide caused no noticeable interference with limb development. The same assay containing cyclophosphamide, however, resulted in a pronounced impairment of cartilage differentiation and in the formation of clearly abnormal structures, especially at the paw skeleton. The activity of the reconstituted system declined under the experimental conditions used, but some activating capacity towards cyclophosphamide was still demonstrable after about 2 h of incubation.

Animals↗
PubMed1988

Prenatal toxicity of acyclovir in rats.

Pregnant rats were treated during organogenesis with s.c. injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown-rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crown-rump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 we found a similar but slightly more pronounced outcome. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively we measured maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 microM). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (+/- SD) of 60.3 +/- 14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6 +/- 16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. We conclude that acyclovir, at doses leading to plasma concentrations well above the therapeutic level in the dam, interferes with the embryonic development in the rat. Acyclovir induces typical gross structural abnormalities which have been first observed using a whole embryo culture system.

Acyclovir↗
PubMed1988

Gross-structural defects in rats after acyclovir application on day 10 of gestation.

Following three s.c. injections of acyclovir (100 mg acyclovir/kg) into rats on day 10 of pregnancy 19 litters were evaluated on day 21 of gestation and the effects were compared to the results obtained from controls (nine litters) which received the vehicle (0.1 N NaOH) only. The following results were obtained (treated group versus control group): 1) Implantations/litter: 11.2 +/- 1.3 versus 10.2 +/- 1.1; 2) resorptions/implantations: 27.7% versus 2.2%; 3) number of viable fetuses evaluated: 154 versus 90; 4) fetuses with anomalies of the skull: 78% versus 12%; 5) fetuses with anomalies of the vertebral column: 38% versus 13%; 6) gross-structural anomalies predominantly affected the skull and tail. The most frequently registered defects were: os tympanicum (smaller): 23%, os tympanicum (missing): 23%; missing tail: 7%; protruding tongue (15%); none of these defects were seen in the control fetuses. Postnatally we observed a high mortality rate among the offspring. From a total of 85 newborn (nine litters) we obtained 73 viable offspring (9.1 +/- 3.4); 81% of them had tail alterations. In the control group of eight litters (9.4 +/- 2.3) no tail alterations occurred. On day 21 postnatally 40 viable offspring were alive (mortality rate: 38.8%). Nearly all of these animals had visible alterations at multiple sites of their bodies; most frequently observed were: tail impairment, closed eyes, dragging hind-limbs, and urogenital alterations (e.g. testicular atrophy). These studies how for the first time that prenatal treatment with acyclovir induces gross-structural defects which persist postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1988

Embryotoxic effects of thalidomide-derivatives in the non-human primate Callithrix jacchus. I. Effects of 3-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine (EM12) on skeletal development.

The response of pregnant marmosets (Callithrix jacchus) to the thalidomide derivative EM 12 was evaluated. EM 12 was selected for these studies because it is more active than thalidomide and is much more stable for hydrolysis. Skeletal gross structural abnormalities were observed when EM 12 was given to marmosets for 3-7 days during the period between days 49 and 60 post ovulation. Using the treatment schedule finally adapted in our laboratory, i.e. treatment during days 51-57 post ovulation, doses of 5 (or 10) mg EM 12/kg body wt induced the typical limb abnormalities known from man with an 80-100% certainty. In some animals we could observe the typical pattern of abnormalities even with doses as low as 1 mg EM 12/kg body wt. Abnormalities of the skeleton induced during this sensitive period are described. None of these (except some bifurcations of ribs) were seen in any of the ten litters (23 fetuses) serving as controls during the period of the study.

Abnormalities, Drug-Induced↗
PubMed1988

Hypertension and nephrotoxic lesions in rats 1 year after prenatal exposure to gentamicin.

Using the aminoglycoside antibiotic gentamicin persistent functional and morphological changes were induced prenatally in the rat kidney. After 6 days of s.c. treatment (110 mg gentamicin/kg body wt) from day 10 to 15 of pregnancy complete resorption was noticed in 8 of the 14 treated animals. Fifty-three newborn were obtained from six dams. One year later only 26 rats (16 male, 10 female) were still alive. The systolic arterial pressure of the female offspring was significantly increased (139 +/- 15 mm Hg versus 112 +/- 9 mmHg) compared with controls. No statistically significant effect could be noticed in the male offspring (128 +/- 15 mm Hg versus 118 +/- 21 mm Hg). Corresponding results were obtained from analysis of urea plasma concentrations. Another cohort of pregnant rats received daily injections of gentamicin from day 15 to 20 of pregnancy (110 mg/kg body wt s.c.). In this group 59 newborn from a total of 109 died within the first 5 days after birth. Six litters were observed postnatally. One year after birth the following blood pressure values were determined: 122 +/- 14 mm Hg (male) and 132 +/- 17 mm Hg (female). Urea plasma concentrations were significantly higher in female, but not in male, offspring. Light and electron microscopic inspection revealed pathological changes in the kidneys of the female offspring only. The degree of maternal kidney damage - which shows considerable variations - was monitored during the treatment period. For this purpose the plasma gentamicin and urea concentrations were measured on 3 days of treatment in all of the pregnant animals. The postnatal data (mortality, blood pressure, and urea plasma concentrations) show a correlation to the degree of maternal kidney impairment.

Animals↗
PubMed1988

Prenatal induction of benzo(a)pyrene hydroxylases in mice.

1. Benzo(a)pyrene hydroxylase (BPH) activity was measured in homogenates of fetal liver (day 18) or of whole-embryos of mice on day 9, 10 or 12 of gestation after maternal pretreatment with B(a)P on 3 consecutive days. A 3H-liberation assay with 3H-B(a)P labelled either generally or at the 6-position was used. The values obtained with the embryonic/fetal tissues were compared with those found in maternal liver. 2. Three oral doses of 17.5 mg B(a)P/kg body wt were found to just significantly induce BPH in maternal liver. An induction was observed after pretreatment with 24 mg B(a)P/kg body wt in 9-, 10- or 12-day-old whole-embryos, but the Vmax reached was only 10-20% (1% on day 9) of that of adult non-induced liver. The Km (6-hydroxylation) for all tissues tested were in the same range (600-900 nM). The induction was demonstrable in embryos at tissue levels about one order of magnitude lower than those required for induction in maternal liver. 3. Treatment with 25 mg B(a)P/kg body wt on 3 consecutive days was required to induce BPH in fetal liver on day 18 of gestation. The required B(a)P tissue concentrations were about one half of those necessary for induction in maternal liver. 4. Among a variety of other polycyclic hydrocarbons only chrysene showed an inducing potency similar to that of B(a)P in adult and fetal liver. For all compounds tested there was no correlation found in the inducing potency between adult and fetal liver (e.g. coronene).(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants↗
PubMed1988

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↗
PubMed1988

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↗
PubMed1988

Gentamicin plasma concentrations in pregnant and non-pregnant rats and fetuses after single and multiple injections.

As part of our studies on the prenatal induction of renal dysfunctions in rats by gentamicin we measured maternal plasma levels of the drug. Additionally, the gentamicin concentrations in the plasma of rat fetuses after single s.c. injections of gentamicin were measured. The following results were obtained: 1) Non-pregnant rats excrete the drug faster than pregnant rats; 2) after a single s.c. injection of 110 mg gentamicin/kg body wt to six pregnant rats on day 21 of gestation the following pharmacokinetic variables were calculated: t1/2(inv): 27.0 +/- 6.1 min, t1/2(elim): 54.7 +/- 3.8 min, Cmax: 166.2 +/- 22.7 mg/l, tmax: 53 +/- 6.7 min, AUC: 431.7 +/- 53.4 mg/l x h; 3) plasma concentrations increase with the duration of pregnancy; 4) fetal plasma concentrations were determined between 45 and 660 min after single injections of 150 mg/kg to the dams. The concentrations showed minimum variation over this time period. Thus, the ratio of maternal to fetal plasma levels decreases drastically during this period; 5) 8 h after s.c. injection of 110 mg/kg to six dams (day 21 of gestation) individual plasma concentrations in the plasma of mother animals and in the plasma of 65 fetuses were determined. All fetal plasma samples showed higher concentrations than the corresponding maternal ones; 6) after multiple injections a significant increase in plasma concentrations can be seen. A considerable individual variance is obvious at all times and with both doses investigated; 7) since maternal plasma concentrations vary considerably in individual animals, especially after multiple injections, fetal exposure must also be variable in different litters. This would also affect the extent of postnatal dysfunction in various litters.

Animals↗
PubMed1988

Transfer of benzo(a)pyrene into mouse embryos and fetuses.

The distribution of radioactive material within maternal and embryonic/fetal mouse tissue was studied over a period of 2 days following a single dose of 14C-benzo(a)pyrene (B(a)P) orally on days 11, 12, 13 or 18 of pregnancy. B(a)P poorly penetrated into the embryo/fetus, and 14C-radioactivity was found in embryonic tissues at concentrations one to two orders of magnitude lower than in maternal organs. If the compound was administered for 3 consecutive days at the same dose the expected cumulation was compensated for by an accelerated elimination of the substance, which is probably due to enzyme induction.

Animals↗
PubMed1988

Identification of the main gestagen metabolite in marmoset (Callithrix jacchus) urine by NMR and MS spectroscopy.

Hydroxypregnanolone is the most abundant progesterone metabolite in the urine of marmoset monkeys (Callithrix jacchus). The substance is excreted as conjugate. The concentration of this steroid may be monitored by high performance, thin layer chromatography and postchromatographic derivatization. Hydroxypregnanolone was purified and subsequently identified by NMR spectroscopy and gas chromatography/mass spectroscopy. The exact chemical structure is 5 alpha-pregnane-3 alpha, 7 alpha-diol-20-one.

Animals↗
PubMed1988

Significance of pharmacokinetic variables in reproductive and developmental toxicity.

1. As in other fields of toxicology, pharmacokinetic variables are of considerable significance for the assessment of reproductive or developmental toxicity. 2. When assessing the possibility of an adverse effect of a chemical on male or female fertility, in the majority of the cases no information on the concentration at the target is available. This may cause problems in the case of a 'negative' finding. 3. Prenatal toxicity takes place within a complex 'two-compartment' system (mother: conceptus); pharmacokinetic variables in both systems determine the concentration at the target (the conceptus). These variables may be expected to vary greatly during the different stages of development. While the contribution of maternal pharmacokinetics can easily be assessed, the pharmacokinetics within the embryo/foetus will remain largely unknown in man. 4. While it is quite feasible in animal experiments to study the transfer of a given chemical to the conceptus in vivo at various stages of pregnancy it is almost impossible to obtain such information for most developmental stages in man, except at the perinatal period (by sampling cord blood). For this reason during most risk assessments exposure of the embryo or fetus can only be roughly assumed from maternal plasma concentrations. 5. A significant capacity of foetal tissues (including liver) for metabolic transformation of many chemicals (e.g. via cytochrome-P-450-dependent monooxygenases) develops only perinatally in the usual rodent animal species. But in primates (including man) the activity of several such monooxygenases is substantial in liver already at early foetal stages. Much less information is available on the metabolic capacity for xenobiotics in extrahepatic tissues of primate embryos and foetuses. 6. Since pharmacokinetic variables (e.g. half-life) often differ considerably in laboratory rodents and in man a risk assessment for man on the basis of doses is often greatly misleading. It seems more justified to predict toxic effects on the basis of plasma levels. This aspect is of great significance and must be taken into consideration since the results of many routine studies are not suitable for risk assessments because pharmacokinetic variables were not considered when planning experimental studies. 7. Factors affecting the transfer of chemicals via mothers milk to the neonate are largely known today. But solid data on the pharmacokinetics of xenobiotics with respect to transfer to the milk and ensuing concentrations in the neonate are still lacking for the majority of relevant chemicals.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗
PubMed1988

[Correlation between some environmental, anamnestic and social markers of pregnant patients and the delivery of eutrophic premature and hypotrophic newborn infants].

12,577 single newborns of 19 hospitals of the northern districts of GDR were classified immediately after birth following the recommendations of WHO from 1971 and the Society of Perinatal Medicine of GDR for classification of newborns. In a prospective study the influence of some different parameters on the relative frequency of deliveries of preterm appropriate-for-gestational-age infants and term small-for-gestational-age infants was proved. To secure the statistical statements u-test was used. A sometimes different efficiency of the proved parameters on the tested groups demonstrated that preterm appropriate-for-gestational-age infants, term small-for-gestational-age infants and other groups of newborns of low birth-weight should'nt be collected as infants of low birth-weight up to 2,499 g in present time. With the provided introduction of new percentiles in GDR an exact classification of newborn infants should be realized all over the country.

Abortion, Induced↗
PubMed1987

Principles and problems in assessing prenatal toxicity.

The terminology to be used in reproductive (or in prenatal) toxicology has to be in accord with other fields and principles of toxicology; the reasons are briefly discussed. In addition it is essential to assess prenatal toxicity in comparison to adult (maternal) toxicity. Since pharmacokinetics in laboratory animals (e.g. rodents) usually differ considerably from that in man, this fact has to be considered when planning and evaluating studies on prenatal toxicity. Up till now this aspect has seldom been taken into account. A special problem in prenatal toxicity is the inter- and intralitter variability of the toxic manifestation (especially in polytocal animals). This problem has to be recognized by the investigators and means of dealing with it have to be developed. Like all other toxic effects, embryo-/fetotoxic manifestations occur dose dependently. Little information is available in the literature on clean dose-response-curves for teratogenic effects. Some data from our laboratory are presented. Risk assessment of teratogenic effects up till now represents a major problem. While qualitative risk assessment for man on the basis of animal data is possible, quantitative extrapolation from such data to the situation possibly existing in man is still difficult, because basic principles and strategies are largely lacking (e.g. may a "threshold" be assumed or not?). The results of some activities towards this goal are presented from our laboratory.

Animals↗