Histopathologic findings and energy dispersive X-ray spectroscopic analysis of experimentally induced foreign-body pneumonias in rats.

To document the diagnostic features of foreign-body pneumonias, four commonly used orally administered medicaments were instilled into the lungs of Sprague-Dawley rats. Rats in each group received a single 0.4 ml dose of either barium sulfate suspension (BaSO4), mineral oil, Pepto-bismol, or Kaopectate inoculated into a lung via a mainstem bronchus. The other lung served as a non-inoculated control. Rats were euthanatized on post-inoculation day 2 or 7 in order to document fully-developed acute pulmonary lesions and developing, chronic pulmonary lesions, respectively. Light microscopic features of BaSO4-inoculated lungs were distinctive from changes in mineral oil-inoculated lungs at both post-inoculation days. On post-inoculation day 2, rats inoculated with BaSO4 had pneumonia characterized by large numbers of alveolar macrophages containing green-to-brown granular material. There was minimal interstitial involvement. On post-inoculation day 2, mineral oil caused pneumonia characterized by giant cells and alveolar macrophages that had cytoplasms distended with variably-sized clear vacuoles. Lungs inoculated with BaSO4 or mineral oil had changed little on post-inoculation day 7 compared to the light microscopic features observed on day 2. On post-inoculation day 2, rats inoculated with either Pepto-bismol or Kaopectate had broncho-interstitial pneumonia with areas of necrosis and hemorrhage. On post-inoculation day 7, lungs inoculated with Pepto-bismol or Kaopectate had extensive fibrosis within alveolar lumens. Energy dispersive spectroscopy performed on sections of lung from rats given BaSO4, Pepto-bismol, and Kaopectate yielded a unique elemental spectrum for each compound in situ on post-inoculation days 2 and 7.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dietary iron supplementation on the toxicity of piroctone olamine in the growing rat.

Weanling Charles River CD rats of both sexes were fed 300 mg/kg/day of Piroctone Olamine, an anti-bacterial agent, and were supplemented with 0, 50, 100 or 200 ppm dietary iron as FeSO4.7H2O for six weeks. However, analytical data indicated that Piroctone was degraded in the diet so that the rats received only 225 mg/kg/day. The rats given Piroctone Olamine without iron gained significantly less body weight and ate significantly less feed than controls, with the effect being more pronounced in the males. They also developed severe microcytic, hypochromic anemia. The rats supplemented with all three levels of dietary iron grew at a rate similar to controls. The rats supplemented with 50 ppm dietary iron had anemia with all of the hematological iron-associated factors being significantly depressed. The 100 ppm supplement restored all hematologic factors to normal in the females, but slight reductions remained in the males. The 200 ppm supplement of iron restored all parameters to values similar to the controls in both sexes. These results suggest that the mechanism of the toxicity of Piroctone Olamine is the prevention of dietary iron absorption by in situ chelation.

Mediastinal fibrin glue: hemostatic effect and tissue response in calves.

There is continued controversy regarding the effectiveness and potential adverse effects of fibrin glue. Thus, we chose to evaluate it in a model of experimental calf aortic valve replacement that has been previously well established. Concentrated fibrinogen and topical thrombin were sprayed to form a thin layer of fibrin glue over the mediastinal tissues of 20 consecutive calves undergoing aortic valve replacement. Chest tube outputs of these animals were compared with those of the preceding 20 consecutive calves undergoing aortic valve replacement without fibrin glue. All procedures were performed by the same surgeon, and no other technical changes were made between the two series. Total postoperative chest tube output (mean +/- standard error) was 553 +/- 50 mL for the calves treated with fibrin glue and 1,155 +/- 103 mL for the control calves (p less than 0.001). On histological examination of mediastinal tissues from 5 treated calves killed 6 weeks after operation, there was no evidence of inflammation, fibrosis, or residual fibrin. To our knowledge, this is the first controlled laboratory study to show that fibrin glue spray is an effective hemostatic agent and that it produces no long-term tissue reaction.

[Comparative morphological characteristics of the pulp reaction to direct coating with therapeutic packings]. / Sravnitel'naia morfologicheskaia kharakteristika reaktsii pul'py na priamoe pokrytie razlichnymi lechebnymi prokladkami.

In experiments performed on green monkeys the molar pulp response to direct coating with calmecin and polycarboxylate cement saturated with the potassium nitric solution. Compared, the results of morphological pulp investigation showed the polycarboxylate cement with saturated potassium nitrate solution coating to be most effective. It had a rather good odontotropic effect and increased the protective action of the pulp. Polycarboxylate cement with saturated potassium nitrate solution coating is recommended for clinical trials to treat occasional pulp denudation.

[Experimental study of the antitumor properties and mechanism of action of kortifen]. / Eksperimental'noe izuchenie protivoopukholevykh svoistv i mekhanizma deistviia kortifena.

Cortiphen, a newly developed hormonal cytostatic ester of 11-desoxy-17 alpha-hydroxycorticosterone and chlorophenacyl, is described. It was studied in transplantable, spontaneous and induced tumors of 7 sites: hemoblastosis (5), hepatoma (3), mammary gland (5), lung (2), gastrointestinal tract (3), sarcoma (2) and melanoma. Practically all the tumors were shown to respond to cortiphen action. Among the antitumor effects of the drug were: long-term inhibition of tumor growth or tumor regression, contribution to longer survival, antimetastatic action and sustained action during repeated courses of administration. Cortiphen was found to interact with glucocorticoid receptors in both animal and human tumors. The role of the hormonal component of the drug's molecule in the realization of its antitumor effect is discussed.

Developmental toxicity evaluation of Bendectin in CD rats.

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).

Lymphatics in the aorta of rats treated with a soy-bean oil extract (lipofundin).

Lipofundin-S 20% (a soy-bean oil extract) when administered intravenously to rats resulted in dilation of aortic lymphatics at the media-adventitia junction. Increased endothelial permeability as demonstrated by intraaortic colloidal iron uptake with dynamic insufficiency of lymphatic drainage is suggested as the basis for dilatation of intraaortic adventitial lymphatics.

Safety of ticarcillin disodium/potassium clavulanate.

Clavulanate potentiated ticarcillin contains two components with an established safety record. Ticarcillin used clinically alone and with clavulanate, a component of clavulanate potentiated amoxycillin, given orally or intravenously. No pharmacokinetic interaction occurs between the two components when given together in man or animals in which metabolism is qualitatively similar to man. Safety evaluation studies carried out in the animals established as suitable for studying the toxicology of ticarcillin have shown no unexpected synergistic or antagonistic toxic effects of Timentin not predicted from the toxicological evaluation of clavulanate alone. Reproductive mutagenic, cardiovascular and general pharmacological studies have shown no significant hazard from Timentin. Clinical experience with ticarcillin has been reviewed, and impairment of platelet function, seen at supratherapeutic doses, has been shown in an animal model not to be influenced by clavulanate. The assessment of the safety of ticarcillin and clavulanate for therapeutic use in man is thus comprised of the clinical experience with ticarcillin and parenteral clavulanate in clavulanate potentiated amoxycillin, animal safety evaluation studies, and the clinical experience with Timentin reported in this symposium.

[Effect of diucifon and its structural precursors on inflammatory and pain reactions]. / Vliianie diutsifona i ego strukturnykh predshestvennikov na vospalitel'nuiu i bolevuiu reaktsii.

The anti-inflammatory and analgesic action of diucifon, methyluracil and 4,4'-diaminodiphenylsulfone (DDS) was studied in comparison with some nonsteroid preparations. In three traditional models of agar, kaolin and carrageenan paw edema and in the models of analgesia (convulsions, induced by intraabdominal administration of acetic acid to mice and hyperalgesia according to Randall-Selitto's test in rats), diucifon proved more active than its precursors. In Randall-Selitto's test the efficiency of diucifon was 1.5 times less than that of butadione but 24 times higher than that of methyluracil; DDS had no analgetic activity. Diucifon, methyluracil and DDS did not exert any ulcerogenic action.

Evaluation of bendectin embryotoxicity in nonhuman primates: II. Double-blind study in term cynomolgus monkeys.

The embryotoxic and teratogenic potential of Bendectin was assessed in this double-blind study in the cynomolgus monkey (Macaca fascicularis). Bendectin was administered orally at doses approximately two, five, and 20 times the human dose equivalent from 22 +/- 2 through 50 days of gestation. Fetuses were delivered by cesarean section near term and examined for malformations. There was no maternal toxicity as evidenced by maternal weights and physical signs. There was no correlation between dosage and the number of prenatal deaths. No significant abnormalities related to treatment were observed in postdelivery physical examinations, placental evaluations, external and internal gross examinations, or from radiographs of the neonates. Under the conditions of this study the treatment of pregnant cynomolgus monkeys with Bendectin produced no evidence of teratogenicity or embryo-, or fetal-, or maternal toxicity.

Contrast media induced pulmonary edema. Comparison of ionic and nonionic agents in an animal model.

High intravenous doses of diatrizoate are known to induce pulmonary edema in the rat. The newer generation of contrast media--nonionics and monovalent dimers--are considered less toxic than diatrizoate. In this study we evaluated the degree of pulmonary edema induced by a high dose (6 g I/kg) of these new agents and found that Ioxaglate produced higher lung weights than Renografin 60 and Iopamidol. Iohexol and Amipaque did not induce a significant degree of edema. The model used in this study demonstrates distinct differences in pulmonary toxicity among these new agents, when given in doses exceedingly higher than given in clinical practice.

[Trial of trimedin action on chickens]. / Izpitvane deistvieto na trimedina pri pileta.

Investigations were carried out with a total of 421 broiler birds (four-line Cornish X Plymouth Rock hydbrids) within the age range of 2 days to 5 weeks. Determined was the acute toxicity of the combination sulfadimidine (SDM) + trimetoprim (TMP)--5 + 1 and the water-soluble formula of trimedin following the intraingluvial introduction with week-old birds. LD50 of the combinations SDM+TMP (5+1) was 3980 mg/kg (2780: 5690), and that of trimedin was 2038 mg/kg body mass. The biologic half-life of SDM ranged from 4.77 to 5.34 h, and that of TMP--from 4.81 to 5.71 h at the intraingluvial introduction of the combination SDM+TMP (5+1) at the rate of 0.06 g/kg. Demonstrated were the therapeutic levels of SDM and TMP during the whole period (10 days) of treatment with the combination SDM+TMP (5+1) given with the feed in conc. 500 ppm or at the application of trimedin alone via the drinking water in conc. 0.05%. It was found that trimedin used for 10 days with the drinking water in conc. 0.05 per cent with broilers at the experimental infection with Salmonella gallinarum-pullorum protected about 40 per cent of the birds, the latter remaining, however, carriers of the infection.

[Pharmacological and clinico-pharmacological studies of a combination preparation for calves having antianemia and general tonic action]. / Kombiniran preparat za teleta s protivoanemichno i obshtoukrepvashto deistvie--farmakologichni i kliniko-farmakologichni izsledvaniia.

A combined preparation, biofer, was studied, defining its clinical and pharmacological capacity. Featuring in its composition are: normal bovine gammaglobulin, 8.0 g; ferridextran (dextrofer-100), 32 cm2 (= 3.2 g Fe); cuprum sulfuricum, 0.32 g (= 0.08 Cu); Co chloride, 0.18 g (= 0.08 Co); cyancobalamin, 0.0032 g; and protein hydrolysate up to 100 cm3, at pH = 7.0-7.2. The local and total tolerance of animals for biofer was studied along with the acute toxicity, absorption, and retention in the body of test animals and calves as well as the antianemic action in albino mice and calves. It was found that at 4 degrees C to 8 degrees C the shelf life of biofer was 2 years. Its LD50 at subcutaneous injection to albino rats was 11.7 cm3/kg body mass. At the rate of 0.6 cm3/kg (i/m) rabbits did not manifest local and total intolerance; at 1.8 cm3/kg there was no local inflammation, however, a transient drop of appetite was seen; at 3 cm3/kg rabbits manifested intoxication with exitus. At i/m introduction to rabbits and calves biofer was more slowly absorbed than dextrofer-100. The liver and spleen of animals injected with biofer showed higher values for copper. In i/m application to anemic albino rats biofer showed a better antianemic effect than dextrofer-100. In calves it activated to a better extent both erythropoiesis and leukopoiesis.