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D Neubert

Publications and source records attributed to D Neubert.

At least 73 records · Page 4Linked to original sources
PubMed1990

Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations.

Arthropathia in juvenile animals is the most important toxic effect induced by quinolones. We conducted pharmacokinetic and morphological studies with ofloxacin on non-human primates (Callithrix jacchus, Marmosets) and rats. In the marmoset, electron microscopy and the application of immuno-morphological methods proved to be suitable for the detection of specific alterations in cartilage (e.g. loss of proteoglycans and altered chondrocytes). Subsequently performed electron microscopic examinations in rats showed similar specific alterations of the femur cartilage surface after multiple oral applications of 600 mg ofloxacin/kg body wt. These results were correlated with pharmacokinetic data obtained for the same species. After single oral application of 100, 300 or 600 mg ofloxacin/kg body wt to 5 week-old rats peak plasma levels were achieved 15-45 min after administration indicating a rapid absorption of the drug. The following peak concentrations were measured for the three doses applied (mean +/- SD): 8.9 +/- 2.1, 22.6 +/- 7.5 mg/l and 33.5 +/- 9.8 mg/l, respectively. After 360 min the concentrations were 1.1 +/- 0.4, 5.9 +/- 2.5 and 15.9 +/- 5.1 mg/l, respectively. After subcutaneous injection of 100 mg ofloxacin/kg body wt the mean peak concentration was 27.7 +/- 2.6 mg/l after 45 min (0.5 +/- 0.2 mg/l after 360 min). In the marmoset higher plasma concentrations were measured with comparable doses. One, 3, and 6 h after the last of nine administrations of 200 mg ofloxacin/kg body wt, the mean (+/- SD) plasma concentrations were: 42.7 +/- 16.7, 40.6 +/- 9.5, and 26.5 +/- 3.6 mg ofloxacin/l plasma. Typical alterations of the joint cartilage of juvenile rats (e.g. opened chondrocyte cavities, swelling of rough endoplasmic reticulum and mitochondrial swelling in the chondrocytes) were induced by oral administration of ofloxacin at doses that were approximately 100 times higher than therapeutic ones, but led to peak plasma concentrations which were only approximately 10 times above the therapeutic level.

Administration, Oral↗
PubMed1990

Development of the fetal mouse palate in suspension organ culture.

Explanted palates of day 12 and day 13 mouse fetuses were cultured in a chemically defined serumless medium for 48-72 h by a suspension culture technique. The palate of day 12 fetuses closed successfully within 72 h and that of day 13 fetuses within 48 h. Both macroscopically and histologically, the in vitro fusion of palatal shelves simulated the palatogenetic process in vivo. This novel technique for culturing the fetal mouse palate may be of potential use for the study of palatogenesis and in developmental toxicology.

Animals↗
PubMed1990

Single dose toxicity study of beta-myrcene, a natural analgesic substance.

The present study was undertaken to provide data on acute toxicity of beta-myrcene, a peripheral analgesic substance found in the essential oils of several plants. Although myrcene has long been used in perfumes and as a food additive, there is almost no information on its toxicological hazards. The acute oral toxicity of myrcene was low in rodents, with approximate lethal doses (ALD) of 5.06 g/kg body weight for mice and greater than 11.39 g/kg body weight for rats. Necropsy data did not reveal any relevant alteration in rats but histopathology findings in mice suggested that the liver and stomach may be target organs for myrcene toxicity after oral administration. Myrcene is highly irritant to the peritoneum, and deaths after intraperitoneal injection of this monoterpene in rats (ALD 5.06 g/kg body weight) and in mice (ALD 2.25 g/kg body weight) were probably due to drug-induced chemical peritonitis.

Acute Disease↗
PubMed1990

Enzyme histochemical and histological changes in the adult rat kidney after prenatal gentamicin exposure.

Treatment of rats between day 15 and 20 of gestation with gentamicin caused histological as well as enzyme histochemical lesions in the kidney of the one year old offspring (F1 generation). Other organs were not significantly affected. Primarily in the female kidney dilated convoluted proximal tubulus with reduced or absent staining for brush border and lysosomal proteases, phosphatases and glycosidases and mitochondrial dehydrogenases were observed. In comparison, glomeruli were less frequently damaged and contained fewer capillary loops or irregularly arranged tissue elements with lowered or no activities for plasma membrane-associated proteases as well as specific and non-specific phosphatases. In addition, the activities of proteases and phosphatases in cortical and medullary endothelial cells of capillaries were reduced or even abolished in the kidney of the female and male F1 generation after treatment of their mothers with gentamicin.

Animals↗
PubMed1989

Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 2. Pharmacokinetics in rats using a loading-dose/maintenance-dose regime with high doses.

Wistar rats were treated initially with very high single doses of 14C-2,3,7,8-TCDD (either 75 or 25 micrograms/kg body wt) followed by weekly maintenance doses of 15 and 5 micrograms/kg body wt, respectively. 14C-radioactivity was measured in various organs over a period of 22 weeks. 1) 75 micrograms TCDD/kg body wt (followed by the maintenance doses) was lethal for all the rats within a period of 9 weeks. While the concentration of 14C-TCDD equivalents in liver and thymus stayed reasonably constant during this period in the surviving rats, the concentration in adipose tissue and kidneys clearly increased in the same animals. 2) The dose of 25 micrograms TCDD/kg body wt (followed by weekly doses of 5 micrograms/kg body wt) proved to be a just tolerable dose over a period of 22 weeks for our strain of rats. 3) Within the individual variabilities the TCDD concentrations in the investigated organs showed no clear-cut decline, indicating that the animals were exposed to fairly constant levels of TCDD throughout the study. Thus, this dosing regime is suitable for maintaining constant TCDD exposure during long-term studies.

Adipose Tissue↗
PubMed1989

Influence of 13-cis and all-trans retinoic acid on rat embryonic development in vitro: correlation with isomerisation and drug transfer to the embryo.

In vitro experiments using whole rat embryo cultures show that all-trans retinoic acid (all-trans RA) administered at low concentrations (30 ng/ml culture medium) is 10 times more active than 13-cis retinoic acid (13-cis RA) and 3 times more active when administered at high concentrations (1000 ng/ml culture medium). Morphological investigation of the embryos shows that both substances directly influence embryonic development in an identical manner. Isomerisation products of the administered compounds (all-trans RA from 13-cis RA and vice versa) were detected by HPLC both in the culture medium and the embryo. Correlation of embryonic retinoid concentration with the observed effects led us to suggest that the isomerisation to all-trans RA is crucial in regard to 13-cis RA-induced abnormal embryonic development. A 100% effect can be induced in vitro with very low amounts of all-trans RA (7.2 ng/g) in the embryo.

Animals↗
PubMed1989

Absorption and tissue distribution of various polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) in the rat.

A defined mixture of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) was parenterally administered to rats and absorption and tissue distribution were measured: 1) Toluene/DMSO (1 + 2; v/v) proved to be a convenient vehicle for the subcutaneous administration of the various PCDDs and PCDFs. Seven days after application the rate of absorption was 90% of the administered dose or even higher for almost all of the PCDDs/PCDFs in the mixture. In a few cases only (e.g. OCDD) the rate was found to be 84-89%; 2) Seven days after subcutaneous administration all 2378-substituted congeners were found in the liver, whereas only a few non-2378-substituted congeners could be measured in minor quantities. The 2378-substituted congeners also predominated in adipose tissue; however, most of the non-2378-substituted congeners were also detected; 3) The amount deposited within the liver as percentage of the administered dose differed for the various 2378-substituted PCDDs and PCDFs, ranging from less than 10% for OCDD or 2378-T4CDF, and between 60 and close to 100% for 12378-P5CDD or the H6CDDs. Therefore, the concentration ratio (liver/adipose tissue) was also found to be very different, ranging from less than 3 in the case of 2378-T4CDD or 2378-T4CDF to greater than 40 in the case of 1234678-H7CDD, 23478-P5CDF, 123678-H6CDF, or 1234678-H7CDF; 4) Studies performed at the time period of ongoing absorption (13-14 h after injection) provided the first evidence that some of the non-2378-substituted congeners do reach substantial concentrations in hepatic tissue shortly after administration; 5) Subsequent to intraperitoneal injection of the same PCDD/PCDF mixture the concentrations within the liver were found to be almost identical with that found after subcutaneous injection. In contrast, much higher concentrations of the congeners were found in (abdominal) adipose tissue; 6) In the liver of untreated rats of the same strain no T4CDDs/T4CDFs or P5CDDs/P5CDFs were detectable under our experimental conditions.

Animals↗
PubMed1989

Reproductive toxicity and pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1. Effects of high doses on the fertility of male rats.

A study on the reproductive toxicity of 14C-TCDD in male rats was performed. Two dose regimes were applied subcutaneously: TCDD-25 (initial dose: 25 micrograms/kg body wt; maintenance dose: 5 micrograms/kg body wt) and TCDD-75 (initial dose: 75 micrograms/kg body wt; maintenance dose: 15 micrograms/kg body wt); the maintenance dose was administered once weekly. The rats were treated for 10 weeks before they were mated and throughout the entire mating period. The dose regime TCDD-75 led to a mortality rate of 93% within a period of 16 weeks. The first animals died during 4 weeks, and an LD50 was reached after 8 weeks. The dose regime TCDD-25 did not cause any mortality over a period of 12 weeks; but an LD10 was reached within 13-20 weeks. The body weight was significantly decreased in both groups treated with TCDD after 1 week of treatment. It stabilized in the TCDD-25-group 4 weeks after treatment and stayed at this level until the end of the treatment period. The most significant finding is the delayed fertilization by the treated males; 15% of the males were found to be sterile. The mating index (84%) and fertility index (14 +/- 11 days) of the TCDD-25-group were lower when compared with controls (95%, 8 +/- 5), but the pregnancy index was not reduced. Application of the chosen TCDD doses led to clear-cut morphological changes of the testes. The Sertoli cells were changed (increased occurrence of vacuoles, swelling of endoplasmatic cavities), and the contact between the Sertoli cells and spermatogonia was disturbed, which might indicate an inhibited maturation of spermatozoa precursors.

Animals↗
PubMed1989

All-trans retinoic acid and 13-cis-retinoic acid in the rat whole-embryo culture: abnormal development due to the all-trans isomer.

9.5-day-old rat embryos were exposed to 3 micrograms 13-cis retinoic acid (13-cis-RA)/ml culture medium or 1 microgram all-trans retinoic acid (all-trans-RA)/ml culture medium for different time intervals of the culture period (test substance-exposure periods alternated with test substance-free periods). These studies were performed to confirm the hypothesis (Klug et al. 1989) that the effect of 13-cis-RA on embryonic development in vitro is predominantly caused by its isomerisation to all-trans-RA. A 12 h exposure of the rat embryos to 13-cis-RA during different periods of culture did not interfere with normal development. However, a 12 h exposure of the embryos to all-trans-RA in the first three quarters of the culture period significantly interfered with normal development and caused clear-cut and typical abnormalities. Embryonic exposure to 13-cis-RA, for periods of more than 12 h, caused severe interference with normal development and led to branchial effects very similar to those observed following to a 12 h exposure to all-trans-RA.

Animals↗
PubMed1989

Elimination of various polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) in rat faeces.

A defined mixture (of a composition characteristic of that present in incinerator fly ash) of polychlorinated dibenzo-p-dioxins and -furans (PCDDs and PCDFs) was subcutaneously administered to rats and the elimination of the unchanged congeners via faeces was measured. 1) All congeners administered could be found in faeces. 2) The rates of elimination via faeces were rather different for the different congeners. 3) The most toxic congeners, 2378-T4CDD and 12378-P5CDD, were present in unmetabolized form in faeces to less than 4% and less than 8% of the administered dose within the first week. Thus, parenteral administration clearly minimizes contamination of the animal quarters when compared with corresponding oral dosing. 4) The rate of unchanged elimination was apparently especially pronounced for the higher chlorinated PCDDs and PCDFs. The highest excretion rate was found for 1234678-H7CDD (up to 30% of administered dose). 5) No obvious differences were observed in the rates of elimination of the unchanged substances via faeces of the 2378-substituted or the non-2378-substituted isomers.

Animals↗
PubMed1989

Purification and properties of cytochrome P-450 from liver microsomes of phenobarbital-treated marmoset monkeys (Callithrix jacchus).

One form of cytochrome P-450 from phenobarbital-induced marmoset liver was purified to apparent electrophoretic homogeneity and compared with the major inducible form isolated from rat liver. Whereas spectral properties and molecular weights, as well as catalytic activities towards aminopyrine and ethylmorphine N-demethylation are quite similar, rates of O-dealkylation with enzymes from the two species are considerably different. While ethoxycoumarin deethylation for the marmoset cytochrome is about one-fortieth of that for the rat, ethoxyresorufin and even pentoxyresorufin dealkylations for the marmoset form are not detectable. By contrast, aldrin epoxidation as catalyzed by this cytochrome is about three times as high as that obtained from the rat.

Aldrin↗
PubMed1989

Device for monitoring locomotor activity of 120 animals: motility of offspring of dams exposed to haloperidol.

A device using four infra-red light photocells per cage which monitor simultaneously the motility of 120 individual rodents, was developed at our institute. The measuring interval can be chosen freely, the starting time may be set freely and the test may last several weeks. The motility of the offspring (day 35-39) of dams exposed to the neuroleptic haloperidol during lactation was investigated, because of the important stage of the brain development in the neonatal age and of the relatively high concentration of haloperidol in the milk. Mice dams were treated sc. with a single dose (1.5 mg/kg) of haloperidol postnatally on day 3 to 6. Compared to the controls the body weight gain of treated (via milk) pups was reduced (controls = 72%, haloperidol = 30%) and the mortality was higher (controls = 10%, haloperidol = 77%) during the treatment period. The quantitative and qualitative analysis of the locomotor activity from day 35 to day 39 shows a distinct shift in the kind of motility: the locomotor activity of haloperidol offspring is significantly reduced while the number of activity phases is increased. It appears that there is a persistent alteration in the central nervous system that leads to a higher frequency but a lower efficacy of activity.

Animals↗
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

Embryotoxicity induced by alkylating agents: 5. Dose-response relationships of teratogenic effects of methylnitrosourea in mice.

The teratogenic potency of the directly acting alkylating agent methylnitrosourea (MNU) was analysed in mice. Skeletal abnormalities were evaluated after treatment on either day 11 or 12 of pregnancy. Ectrodactyly was the predominant effect after treatment on day 11. Treatment on day 12 triggered especially double-sided microdactyly (method of analysis: measuring digit lengths). Litter variabilities were analysed using a new biometrical procedure. Using probit analysis, dose-response curves were computed from the experimental data obtained and the effective doses were calculated and compared with maternal toxicity. Low dose extrapolation was performed by use of various mathematical models which yielded very similar ED1/100 and ED1/1000 values.

Abnormalities, Drug-Induced↗
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↗