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Amalgam fillings are still widely used in dentistry. Based on toxicological data, patient's and medical staff's risk of mercury poisoning is evaluated; pharmaco-prophylaxis against chronic poisoning is discussed.

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The analgesic action of D-phenylalanine (D-Phe) is well known. It has been demonstrated in hot-plate tests on mice that combining D-Phe with narcotic analgesics already with doses inactive on separate application. In combination with D-Phe, a dose of morphine less by half compared to its unique use does not reduce analgesic activity in rats, but after six weeks of treatment some undesirable side effects like dependence, behavioural disorders and growth retardation are markedly lowered. These results suggest the possibility to design a combined drug similarly effective as well-introduced narcotic analgesics, but better tolerated.

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AWD 23-15 (6-Methyl-1,2,3,4-tetrahydro-pyrimidin-2,4 dion) which is known to improve learning and memory processes in laboratory animals, was investigated in several hypoxia models. The following results were obtained: 1. Increase of survival rate, 2. change in hypoxia-induced decrease of cerebral post-mortem adenylic energy charge and in concentrations of metabolic products in the brain and 3. antagonism of the hypoxia-induced decrease of dopamine release. However in the general behavioral test the drug was ineffective. These results support the idea that AWD 23-15 is a potential nootropic drug.

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Experiments were carried out to lower the mortality (LD70-90) of rats in ovalbumin-induced anaphylactic (DA) shock and in endotoxin-induced (ET) shock, and of mice after injection of Platelet-activating Factor (PAF shock) comparing the effects of the cyclooxygenase (COX)-inhibitors aspirin (ASA), indomethacin, of the COX-/lipoxygenase (LOX)-inhibitors nordihydroguajaretic acid (NDGA), phenidone and X 86 (analogue of BW 755c), of the inhibitor of thromboxane (TX) synthesis HOE 944, of the TX-antagonist BM 13177, of the PAF-antagonist BN 52021 and of ketotifen. Ketotifen was strongly effective in DA shock, COX- and LOX-inhibitors only slightly. Combined COX- and LOX-inhibitors and BN 52021 showed good effects in the ET shock. Ketotifen was inefficacious. All the used substances influenced the PAF shock. The shock syndromes were biochemically characterized by determination of isocitratedehydrogenase (ICDH) activity, lactate, glucose, haematocrit, numbers of thrombocytes and leucocytes, TXB2 and 6-keto-Prostaglandin(PG)F1 alpha.

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Lipoxygenase inhibitors block the release of histamine from protaminesulfate-stimulated peritoneal mast cells of the rat in vitro. The order of this inhibitory activity of the agents does not correlate with the order of this inhibitory activity of the agents does not correlate with the order of their inhibitory activity against lipoxygenases from reticulocytes and peas. Antioxidants/radical scavengers, which do not inhibit lipoxygenase activity (mannitol, hydrochinone) block the protaminesulfate-activated degranulation of peritoneal rat mast cells, too. Therefore we assume that activated oxygen radicals are generated by stimulation of pRMZ with protaminesulfate. These oxygen radicals could be promotors for the histamine secretion of the peritoneal mast cells. Consequently, lipoxygenase inhibitors with radical scavenging properties may influence degranulation of peritoneal mast cells of the rat by two mechanisms, namely by reduction of the synthesis of 5-LOX-products (promotors of the histamine release) and by reduction of the toxic effects of activated oxygen radicals.

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In this article we use the linear regression model to compare the values of IC50 and LD50 p.o. (mice and rats) taken from the literature and estimated in our laboratory. By this analysis it was found that for different substance classes a similar relationship exists between IC50 and LD50, even if different cell types or cellular activities were used for estimating the IC50 on the one hand and different modes of substance application in animal toxicity tests on the other hand. The minimum and maximum values of the measured LD50 (LD50G) registered in animal experiments deviated from the theoretical LD50 values (LD50T) on the (log transformed) regression line in approximately 77 per cent of the cases by the factor FG less than or equal to log 5 only. The linear correlation between IC50 and LD50 is to be expected only for such substances which do not act specifically via higher levels of integration, cell type specific reactions or metabolites, respectively. These and previously reported results indicate a certain general validity not only for the positive linear correlation between IC50 and LD50 but also for the predicting the LD50 in a relatively narrow dosage range on the basis of in vitro estimated IC50 values. With these results new possibilities were opened for reducing animal experiments to estimate LD50.

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Alternative approaches to toxicity tests with animals-more precisely defined as complementary methods-serve for reducing the number of animal experiments. The determination of cytotoxicity with cell cultures could be an important complementary method to get more information about a general basal toxicity of a substance in an organism during the course of an acute toxicity experiment. We employed the endothelial cell line BKEz-7 in a general (i.e. nonspecific) cytotoxicity test. As a quantitative marker of cytotoxic effects we determined the inhibition concentration for a fifty per cent reduction of the cell number per culture (IC50). the IC50 values of 28 compounds were compared with the corresponding LD50 values in the acute toxicity experiments. In these comparisons we included the determination of the lethality index (LI = IC50/LD50), the correlation analyses and the application of a single linear regression model. The following results were obtained. Between the IC50 and LD50 values a positive correlation exists at the significance level 1 - alpha = 0.95. After plotting the regression line in a coordinate system, a novel graphic prediction of LD50 estimations is possible with a relatively high accuracy. On the basis of tenfold steps of concentrations a new scale of cytotoxicity was attributed to the internationally employed classification of LD50. In the cytotoxicity test with the cell line BKEz-7 a broad spectrum of substance classes can be tested. The cytotoxicity test and the comparison of IC50 and LD50 p.o. as described here contribute to reduce the number of animals in the acute toxicity experiments.

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Cordemcura has a dose-dependent inotropic effect in the Langendorff-perfused guinea pig heart, in the isolated spontaneously active atria of the guinea pig as well as in the isolated electrically stimulated rabbit papillary muscle. Tachyphylaxy symptoms and arrhythmogene side-effects have not been observed. The dose-dependent coronardilatory effect caused by Cordemcura as observed at the isolated heart of a guinea-pig appears intensely. The positive inotropic effect by Cordemcura on an isolated electrically stimulated papillary muscle of a rabbit is linked with a significant decrease of the relaxation time t2, whereas there is no change in the time to peak force t1. Both mean velocity of force development S1 as well as the mean velocity of relaxation S2 are increased by Cordemcura.

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Cordemcura causes a dose-dependent inhibition of noradrenaline contractions of isolated rabbit aorta as well as of isolated guinea pig ductus deferens. In both organ preparations analogous intensity of effect has been observed. In different intestinal isolated organs Cordemcura also produces a dose-dependent inhibition against different agonists. The Ba2+-induced contraction is inhibited to approximately the same extent as various receptor-induced contractions. Consequently a specific receptor function on smooth muscle has to be excluded with regard to Cordemcura. Furthermore Cordemcura has a bronchodilatory effect. This property could be proved by the protection effect as observed in the inhalative histamine-induced bronchoconstriction in guinea pig.

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Side-effects of Cordemcura were verified in a relatively extensive repertoire of methods. Investigations of blood pressure activity, effect on heart frequency as well as PQ and QT times after continuous infusion, influence on diuresis and antidiuresis and behaviour to achieve results of a possible activity of the central nerve system were given priority. The proved vasodilatory qualities of Cordemcura become also evident in the rat blood pressure reduction due to higher dose as a result of i.v. injection. No hypotensive effect could be observed after oral administration of the drug. Heart frequency as well as PQ and QT times after i.v. infusion of 1 X 10(-4) mol/kg/min Cordemcura over a period of 15 min remained unchanged. Doses going far beyond therapeutically applied doses indicate a reduction of diuresis after oral administration of Cordemcura for rats. Only due to these high doses unspecific changes in the behaviour of rats and mice occurred. No specific central nerve system activity could be observed.

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Acute and subacute toxicity studies were carried out on the positive inotrop substance Cordemcura in various species. No undesirable side effects were observed in rats and rabbits.

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The results of the subchronic toxicity studies gave in mini-LEWE-pigs no toxic effects for the substance Cordemcura.

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In comparison to well-established non-narcotic analgetics, the amino acid D-phenylalanine produces similar, dose-dependent analgesic effects in animal experiments, but acts significantly longer. Neither a tolerance of mice to D-Phe after administration for 10 d nor a development of drug dependence in rats following treatment for 6 weeks could be regarded.

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Derivatives substituted at position 2 of 4-oxochinazolin as well as derivates of oxochinazolin-3-yl-benzoic acid and 4-oxochinazolin-3-yl-acetic acid had been tested for their antianaphylactic activities in the passive (PCA) and/or active cutaneous anaphylaxis (ACA) in rats. At i.p. administration (ACA) or intracutaneous (i.c.) administration (PCA) most of the derivates displayed a moderate antianaphylactic activity which et best could be compared to the theophylline activity. Only the free acids of the 4-oxochinazolin-3-yl-acetic acid derivatives were active at i.c. administration. All compounds tested remained inactive at p.o. administration.

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2-Aryliminomethylquinolines were synthesized by the condensation of quinoline-2-carbaldehyde with the corresponding anilines. The compounds were evaluated for analgesic activity using the acetic acid writhing test. Some of them showed significant inhibition of the writhing syndrome. The most potent compound 3b was approximately as active as aminophenazone in the writhing and the hot-plate method.

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Aminoacetonitriles were synthetized from arylaldehyde, arylamine and cyanhydrogene. Their dehydrogenation led to the iminoderivatives. The compounds were evaluated for spasmolytic activity in vitro. Some aryl-arylaminoacetonitriles showed significant inhibition of the histamine-induced contraction in guinea-pig ileum and acetylcholine-induced contraction in rat ileum. Structure-activity relationships are discussed.

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The influence of smooth muscle contractility of (3,4-dichloranilino)phenyl-acetonitrile (H 74) was studied in comparison with the analogs (4-chloranilino)phenyl-acetonitrile (H 47) and (3,4,5-trichloranilino)phenyl-acetonitrile (H 84) and several standard pharmaca. H 74 and H 84 showed a spasmolytic action that was almost equal to that of methphenethamine and papaverine. Other investigations have revealed that H 74 was free from any side effect. It is concluded that chloranilino-phenyl-acetonitriles cause a nonspecific inhibition of smooth muscle contractility.

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