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Biomedical subjects

R Stahlmann

Publications and source records attributed to R Stahlmann.

At least 73 records · Page 4Linked to original sources
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

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

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↗
PubMed1985

Effects of the cyclophosphamide metabolite acrolein in mammalian limb bud cultures.

Cyclophosphamide must be metabolized by drug-oxidating systems in order to become biologically active. Up to now, it is not known exactly which metabolite is responsible for the teratogenic effects of the drug. Besides aldophosphamide and phosphoramide mustard, the metabolite acrolein must be considered as a possible candidate. We tested this unsaturated aldehyde in a mouse limb bud culture system, since results from in vivo studies are controversial and inconclusive. The following results were obtained: Concentrations of acrolein between 3 and 10 mg/l induce a significant impairment of limb bud differentiation with explants from 12-day-old mouse embryos. Scapula and paw skeleton were more affected than ulna and radius. With limbs from 11-day-old embryos we found similar effects, even at lower concentrations. A contact time of 20-40 min is sufficient to induce abnormal development. It is possible to antagonize the teratogenic effect of acrolein by addition of mesna (300 mg/l) to the culture medium. The abnormalities observed with acrolein under these experimental conditions are clearly different from those seen with hydroperoxy-cyclophosphamide.

Acrolein↗
PubMed1985

Enzyme cytochemistry combined with electron microscopy, pharmacokinetics, and clinical chemistry for the evaluation of the effects of steady-state valproic acid concentrations on the mouse.

A number of organs from adult female mice were investigated after continuous application of the anticonvulsant drug valproic acid (VPA) by enzyme cytochemistry, light and electron microscopy, pharmacokinetics and clinical chemistry. VPA plasma levels were maintained between 55 micrograms/ml and 67 micrograms/ml for three days following subcutaneous implantation of drug reservoirs. Effects detectable by enzyme cytochemical or electron microscopical means were mainly observed in liver, kidney, thymus and spleen. A strict concentration-dependency of drug effects could not be found. In the liver, the activities of some surface-membrane hydrolases were increased at the biliary pole; the activities of other hydrolases were decreased or unchanged. Electron microscopically, number and length of microvilli of hepatocytes were increased and many of them showed fat inclusions, mitochondrial swellings and autophagic vacuoles. In some of the proximal convoluted tubules of the kidney, the reaction product originating from microvillous and lysosomal hydrolases was diffusely distributed and its amount lowered. This was paralleled by tubular cells with an increased number of fat droplets and swollen mitochondria or destroyed tubular cells, as demonstrated by electron microscopy. Additionally, peritubular endothelial cells were arranged in a garland-like pattern. Alkaline phosphatase was activated in the straight portion of the proximal tubules. Increased glucose, creatinine and total protein concentrations and increased gamma-glutamyl transpeptidase and alkaline phosphatase activities in the urine reflected well the damage of the proximal renal tubules. Cortical and medullary morphology varied considerably in the thymus. In extreme cases, the cortical zone was either reduced in size or the medulla showed a cortex-like structure or vice versa (inverted type of thymus). The thymic cortical reticular cells showed increased aminopeptidase A activity accompanied by a generalized aminopeptidase M and alkaline phosphatase reaction. Our data indicate that--in addition to the liver--also the kidney, thymus and spleen are target organs of VPA-induced toxicity in the mouse.

Alkaline Phosphatase↗
PubMed1983

Interference of acetoxyalkyl-nitrosamines with limb bud differentiation in organ culture.

alpha-acetoxynitrosamines have been used as model compounds to study biological activity of N-nitrosamines. After hydrolytic cleavage they yield an "active intermediate" (the hydroxynitrosamine) which presumably also arises as metabolite of N-nitrosamines. We tested eight N-nitrosamines mono-substituted at the alpha-carbon with an acetoxy group for their teratogenic potential in a mouse limb bud culture system. The following results were obtained: 1. The methyl compound (MOAc-MNA) - a derivative of dimethynitrosamine - proved to be the strongest teratogen in this group of chemicals. 2. The tertiary-butyl derivative - releasing a carbonium ion of low chemical reactivity - possessed the lowest activity in our test system. 3. The primary alpha-acetates with unbranched side chains (POAc-MNA or BOAc-MNA) were more active than the corresponding derivatives with branched side chains. 4. The secondary alpha-acetate (EOAc-ENA) was clearly less active than the primary alpha-acetate (EOAc-MNA). 5. A teratogenic potential could also be demonstrated in the organ culture system with the cyclic derivative: N-nitroso-alpha-acetoxy-pyrrolidine (NAPYR). 6. With the use of limb buds from 12-day-old mouse embryos the explants showed the highest susceptibility to the teratogens on the first day of culture. No effect could be produced if the substances were added to the culture medium at the third day of culture or later. 7. When initiating the culture with limb buds from 11-day-old mouse embryos the concentrations needed to induce typical effects were lower than those tested with 12-day-old explants. 8. Typical and pronounced impairment with morphogenetic differentiation could be induced by MOAc-MNA if the substance was present in the medium for less than 60 min - the shortest period tested was 15 min. 9. A different abnormality pattern could be induced with the various substances tested. This may partly be explained by a quite different stability of the compounds in the test system. 10. N-Nitrosamines must be expected to be highly teratogenic if they can be "activated" in embryonic tissues. Such an activation into potent electrophilic agents does not occur in rodents under normal conditions. It will be interesting to study if such activity can be "induced" in embryonic tissues of rodents or if it is already present in embryonic tissues of primates.

Animals↗
PubMed1980

[Comparative pharmacokinetics of oral cephalosporins: cephalexin, cefaclor and cefadroxil (author's transl)].

In a randomized crossover study, the pharmacokinetics of two new cephalosporin antibiotics, cefaclor (CCL), and cefadroxil (CDX), were determined after oral administration of 1000 mg (capsules) on an empty stomach in 12 normal subjects in comparison to cephalexin (CEX). Serum concentrations were measured during a period of 8 h and urine recovery during 24 h. The significant parameters of bioavailability of an orally administered substance were determined. The maximum serum concentrations (ymax) were 38.8 +/- 8.1 mg/l (CEX), 34.6 +/0 7.8 mg/l (CCL), 33.0 +/- 5.4 mg/l (CDX); the areas under the curve were 93.0 +/- 14.8 h . mg/l (CEX), 74.5 +/- 9.9 h . mg/l (CCL), and 108.5 +/- 18.4 h . mg/l (CDX). In a further crossover study with 6 subjects, 1000 mg CEX and CDX were given during a standard breakfast. The ymax of CEX decreased to 23.1 +/- 6.6 mg/l in contrast to CDX with an unchanged ymax of 32.7 +/- 3.4 mg/l.

Adult↗
PubMed1979

[Pharmacokinetics of cefaclor and initial therapeutical experience (author's transl)].

Twelve normal volunteers in the fasting state were given 1000 mg cefaclor, and the serum and urine concentrations over 8 h and 24 h respectively were measured. The average peak serum concentration was 34.6 +/- 7.8 mg/l, this value being reached after 65.2 +/- 11.1 min; the half-life was 42.5 +/- 8.3 min. In another six volunteers the absorption of 500 mg of 'cefaclor following administration in the fasting state and after a test breakfast was studied. The peak serum concentrations after administration in the fasting state were 16.1 +/- 3.2 mg/l, and after a meal 12.5 +/- 1.9 mg/l; the areas under the curve did not differ. The low recovery rate of cefaclor in urine observed in this series of investigations could be partly explained by the inactivation of the substance in urine. Cefaclor was administered therapeutically to 23 patients, most of whom were suffering from bronchopulmonary infections and chronic pyelonephritis. The results of therapy were good in four patients, satisfactory in 13 patients and unsatisfactory in three patients. Intolerance was rare.

Cefaclor↗
PubMed1979

Comparative pharmacokinetics of cephalexin, cefaclor, cefadroxil, and CGP 9000.

In a randomized crossover study, the pharmacokinetics of three new cephalosporin antibiotics, cefaclor, cefadroxil, and CGP 9000, in comparison to cephalexin, were determined after oral administration, by capsules, of 1,000 mg on an empty stomach in 12 normal subjects. Serum concentrations were measured during a period of 8 h, and urine recovery was measured during 24 h. The significant parameters of bioavailability of an orally administered substance were determined. The maximal serum concentrations (y(max)) for cephalexin, cefaclor, cefadroxil, and CGP 9000 (in milligrams per liter) were: 38.8 +/- 8.1; 34.6 +/- 7.8; 33.0 +/- 5.4; and 23.3 +/- 7.3, respectively. The areas under the curve (in hours x milligrams per liter) were: 93.0 +/- 14.8; 74.5 +/- 9.9; 70.1 +/- 9.0; and 108.5 +/- 18.4, respectively. In a further crossover study with six subjects, 1,000 mg of cephalexin and of cefadroxil were given during a standard breakfast. The y(max) of cephalexin decreased to 23.1 +/- 6.6 mg/liter, in contrast to cefadroxil, with an unchanged y(max) of 32.7 +/- 3.4 mg/liter.

Administration, Oral↗