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Biomedical subjects

A Kistler

Publications and source records attributed to A Kistler.

At least 55 records · Page 3Linked to original sources
PubMed1984

Ro 15-1570, a new sulfur-containing retinoid devoid of bone toxicity in rats.

Repeated ingestion of high doses of retinoids cause the so-called hypervitaminosis A syndrome. In rats the main symptoms are weight loss, alopecia, erythema, desquamation of the skin, and alterations of the skeletal system, including bone fractures. In the present study, three retinoids (Ro 15-1570, arotinoid ethylsulfone, 6 mg/kg; retinoic acid, 100 mg/kg and etretinate, 50 mg/kg) were administered orally to rats for 1 and 2 weeks, respectively, to six male and six female rats/group. All the above changes were induced by all three retinoids, with the exception that the arotinoid ethylsulfone Ro 15-1570 did not cause bone alterations. The absence of toxic effects on the bones by Ro 15-1570 was confirmed by X-ray-film examinations, densitometry of the X-rayed femora and tibiae, examination of the thickness of the femoral and tibial compacta in histological slides plus the determination of the femoral ash weight and its main inorganic constituents (calcium, magnesium, sodium, and potassium). The present demonstration that the arotinoid ethylsulfone Ro 15-1570 was devoid of bone toxicity constitutes major progress in the pharmacologic development of retinoids with a better balance between therapeutic and adverse effects.

Animals↗
PubMed1984

Preclinical safety evaluation of intravenously administered mixed micelles.

Mixed micelles, with their main constituents lecithin and glycocholic acid, form a new principle for the parenteral administration of compounds which are poorly water-soluble. Their composition of mainly physiological substances as well as their comparatively good stability substantiate their attractivity in comparison to existing solvents. A decomposition due to physical influences such as heat or storage for several years will almost exclusively affect the lecithin component in the form of hydrolysis into free fatty acids and lysolecithin. Their toxicity was examined experimentally in various studies using both undecomposed and artificially decomposed mixed micelles. In these studies the mixed micelles were locally and systemically well tolerated and proved to be neither embryotoxic, teratogenic nor mutagenic. Only when comparatively high doses of the undecomposed mixed micelles were administered, corresponding to approximately 30 to 50 times the anticipated clinical injection volume (of e.g. diazepam mixed micelles), did some vomitus (dogs), slight liver enzyme elevation (rats and dogs), and slightly increased liver weights (dogs) occur. After repeated injections of the artificially decomposed formulation (approximately 25% of lecithin hydrolyzed to free fatty acids and lysolecithin) effects such as intravascular haemolysis, liver enzyme elevations and intrahepatic cholestasis (dogs only) were observed but only when doses exceeding a threshold of approximately 40 to 60 mg lysolecithin/kg body weight were administered. All alterations were reversible after cessation of treatment.

Alkaline Phosphatase↗
PubMed1982

Histological changes during regression induced by retinoic acid in a transplantable rat chondrosarcoma.

Daily oral treatment with retinoic acid (100 mg/kg bodyweight) induced regression of a transplantable rat chondrosarcoma. In a previous biochemical investigation we have shown that the tissue breakdown is preceded by the loss of proteoglycan. The present study describes the histological changes induced by retinoic acid. A decrease in the intensity of metachromatic staining with toluidine blue was noted already after 1 day and the discoloration was almost complete after 4 days correlating with the loss of proteoglycan. Especially in the perichondrium there was a rapid proliferation of fibroblasts and monocytes. Osteoclast-like cells were missing, but tumor nodules were eroded and split up by penetrating perichondrium. After 4 days of treatment larger necrotic areas were found, initially in the center of tumor nodules only. In other areas the majority of tumorous chondroblasts survived. Tumor nodules appeared partly mesenchyma-like with some fibroblast-like cells suggesting a dedifferentiation of chondroblasts by retinoic acid. we believe that tumor regression induced by retinoic acid involved proteoglycan degradation by chondroblasts themselves and chondroclast-like activity of monocytes and fibroblasts.

Animals↗
PubMed1982

Retinoic acid-induced cartilage resorption: induction of specific changes in protein synthesis and inhibition by tunicamycin.

The addition of retinoic acid to fetal rat bones in culture induces the release of proteoglycans followed by cartilage resorption. In this system retinoic acid markedly suppressed 3H-leucine and 3H-mannose incorporation into acid-precipitable macromolecules, and specifically changed the 3H-leucine incorporation pattern as revealed by gel electrophoresis. Tunicamycin, which selectively inhibits glycosylation of the asparagine residues in proteins, prevented the cartilage cell degradation in response to retinoic acid. Inhibitors of DNA synthesis did not affect the retinoic acid-induced changes indicating that cell division was not required for the cartilage degradation processes induced by retinoic acid. In consideration of our previous and present demonstrations that retinoic acid-induced cartilage resorption required RNA, protein, and glycoprotein synthesis and specifically changed the protein synthesis pattern, we suggest that retinoic acid may exert its action by altering gene expression.

Animals↗
PubMed1981

Teratogenesis of retinoic acid in rats: susceptible stages and suppression of retinoic acid-induced limb malformations by cycloheximide.

The susceptible stages and the malformation pattern produced by excess retinoic acid were investigated in rat fetuses. Retinoic acid (120 mg/kg body weight, suspended in rape oil) was administered orally to pregnant females on one of the first 20 days of gestation. Fetuses were examined for external and, after visualization of the skeleton with alizarin red, for skeletal malformations on the 21st day of gestation. Retinoic acid was highly embryolethal when administered on days 9 and 10 of gestation (96.2 and 100% resorptions). The earliest teratogenic effect of retinoic acid was noted on the 9th day of gestation. Severe multiple defects were produced by retinoic acid administration on days 9 and 11 of gestation, but more specific malformations involving the axial skeleton, the fore- and hindlimbs, and cleft palate resulted from treatment on days 12-18 of gestation. Cycloheximide, and inhibitor of protein synthesis, reduced the incidence of limb defects induced by retinoic acid. This result indicates that the teratogenic effect of retinoic acid on limb morphogenesis may be dependent upon continuous protein synthesis and is compatible with the view that vitamin A may act like a hormone.

Abnormalities, Drug-Induced↗
PubMed1981

Effect of retinoic acid upon the chick embryonic morphogenetic systems. I. The embryotoxicity dose range.

The effects of all-trans-beta-retinoic acid upon the developing chick embryo were investigated using the Chick Embryotoxicity Screening Test (CHEST). A dose of 0.3 microgram, injected subgerminally in stages HH 10--11, arrested the neural tube development, disturbed extraembryonic vasculogenesis, and induced formation of haemorrhagic blisters in the caudal region. Single administration of retinoic acid on days 2, 3, and 4 revealed a stage-specific effect. Being high, due to the abundant mortality of embryos injected on day 2, the effect drops conspicuously on day 3, and rises once again on day 4 when a remarkable proportion of the surviving fetuses suffer from serious morphological damage comprising cardiovascular lesions, maldevelopment of the central face, and dysmelia. The target tissues are similar to those of vitamin A in developing mammals. The increased sensitivity of chick embryo morphogenetic systems between days 3 and 4 supports the hypothesis that the deleterious action of retinoic acid is due to the development of specific binding sites in the target cell populations.

Animals↗
PubMed1981

Structure-activity relationship of retinoids in fetal rat bone cultures.

The structure-activity relationship of 29 retinoids was investigated in fetal rat bone organ cultures. Retinoids induced the release of proteoglycan followed by cartilage tissue breakdown. In this study the loss of RNA was used as a parameter for cartilage resorption. During 6 days of incubation RNA decreased up to 80% in presence of active retinoids. Thus the ED40 was determined from dose-response curves of the various retinoids. The new compounds, called arotinoids, which contained the retinoic acid carbon skeleton in a fixed cisoid geometric conformation, were up to 200 times more active than all-trans-beta-retinoic acid. The most active compound contained a tetramethylated tetralin ring and a second aromatic ring in the side chain. Several lines of evidence indicated that the carboxylic acid end group was essential for the activity of retinoids in fetal bone cultures. The new, highly active retinoids described here might be an excellent tool to investigate whether the retinoid action is mediated by specific cellular retinoid binding proteins.

Animals↗
PubMed1980

Effects of excess 1,25-dihydroxycholecalciferol in young rats.

The oral administration for 5 days of excess 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3] at doses of 1, 5, and 25 micrograms/kg to rats, beginning at the age of 2 or 10 days, produced dose-dependent reductions in weight development and additional calcification near the skeleton. Alizarin red S stained skeleton revealed calcific deposits near the bones of the head, near the neural arches, between the ribs, along the bones both of the fore limbs and, to a lesser extent, of the hind limbs. Histologically, the deposits appeared to be localized primarily in the sub-epithelial connective tissues. Starting treatment with 1,25(OH)2D3 (25 micrograms/kg for 5 days) at the age of 20 days produced additional calcification in 1 of 8 rats at only 1 location (lower jaw). Additional calcification as described above could no longer be induced by 1,25(OH)2D3 in 30-day-old rats using doses up to 25 micrograms/kg and 10 daily treatments. We conclude that the sensitivity of young rats to 1,25(OH)2D3-induced additional calcification, which differs in localization from that observed in adult rats, decreases with the maturation of the animals.

Aging↗
PubMed1980

Requirement of RNA and protein synthesis and inhibition by ethylenediaminetetraacetic acid of retinoic acid-induced proteoglycan release in a transplantable rat chondrosarcoma.

In in vitro cultures of prepared pieces of transplantable chondrosarcoma from F344 rats, retinoic acid enhanced the release of proteoglycan, with a lag between 6 and 14 hours. The retinoic acid-induced release of proteoglycan was inhibited in vivo and in vitro by cycloheximide, an inhibitor of protein synthesis, and in vitro by actinomycin D and cordycepin, inhibitors of RNA synthesis. These results suggested that the retinoic acid-induced release of proteoglycan depends on de novo RNA and protein synthesis. The proteoglycan release induced by retinoic acid in vitro was blocked by EDTA but not by other proteinase inhibitors (pepstatin, phenylmethylsulfonyl fluoride, and Trasylol) and was completely restored by Zn2+. The degradation of proteoglycan induced by retinoic acid may depend on newly synthesized metal-dependent proteinases.

Animals↗
PubMed1978

Inhibition of glycolysis by L-sorbose in dog erythrocytes.

We have demonstrated previously that in vitro L-sorbose acts directly on dog erythrocytes to induce hemolysis. Here we report that L-sorbose depresses lactate formation in dog hemolysates from glucose, mannose and fructose but not from glucose-6-phosphate and galactose, suggesting that L-sorbose interacts with glycolysis at the level of the hexokinase.

Animals↗
PubMed1977

Preferential binding of tri-substituted thyronine analogs by bullfrog tadpole tail fin cytosol.

The relative strength of binding of several triiodothyronine (T3) analogs by cytosol prepared from the tail fin of the bullfrog tadpole has been tested and compared with their thyromimetic activity in tail tissue. In competitive binding experiments, four tri-substituted analogs were bound much more strongly than two tetra-derivatives. Correlation between binding and relative thyromimetic activity was observed only for three triiodo-substituted compounds, triiodothyronine, its methylene bridge analog and the acetic acid analog. The affinity for T3 was 250 times that of T4, making it unlikely that the T3 binding sites in tadpole tail fin cytosol bind T4 under physiological conditions. The difference in binding by tadpole tail fin cytosol constitutes one of the largest differences observed between T3 and T4 in a potentially significant biological system.

Animals↗