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We performed demographic and molecular investigations on woodland populations of the clonal herb Viola riviniana in central Germany. We investigated the pattern of seedling recruitment, the amount of genotypic (clonal) variation and the partitioning of genetic variation among and within populations. Our demographic study was carried out in six violet populations of different ages and habitat conditions. It revealed that repeated seedling recruitment takes place in all of these populations, and that clonal propagation is accompanied by high ramet mortality. Our molecular investigations were performed on a subset of three of these six violet populations. Random amplified polymorphic DNA analyses using six primers yielded 45 scorable bands that were used to identify multilocus genotypes, i.e. putative clones. Consistent with our demographic results and independent of population age, we found a large genotypic diversity with a mean proportion of distinguishable genotypes of 0.93 and a mean Simpson's diversity index of 0.99. Using AMOVA we found a strong genetic differentiation among these violet populations with a PhiST value of 0.41. We suggest that a high selfing rate, limited gene flow due to short seed dispersal distances and drift due to founder effects are responsible for this pattern. Although Viola riviniana is a clonal plant, traits associated with sexual reproduction rather than clonality per se are moulding the pattern of genetic variation in this species.

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We have investigated the effect of inhibitors of lipoxygenase (LOX), cyclooxygenase (COX) and dual inhibitors of both enzymes on the degranulation of peritoneal rat mast cells (pRMC) activated by different mechanisms. COX inhibitors weakly affected histamine secretion induced by A23187 and did not influence the histamine secretion induced by protamine in an isotonic medium but blocked protamine-induced release in a hypertonic medium. LOX- and dual-inhibitors inhibited secretion induced by A23187 and protamine under all conditions. As A23187 activates pRMC in an isotonic medium by Ca influx, and protamine acts in a hypertonic medium by mobilization of intracellular Ca and in an isotonic medium by both processes (this paper), LOX but not COX inhibitors, may block Ca influx, and both prevent Ca mobilization.

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The effects of PAF antagonists, of substances which influence the arachidonic acid metabolism, and of dexamethasone and ketotifen were evaluated in an acute PAF-induced mortality model in female NMRI mice. We established a dependence of sensitivity to PAF on strain (AB mice showed no dose dependence) and on sex of the animals as well as on the PAF charges used in our experiments. PAF produced resistance in surviving animals against the PAF-induced death on repeated application. The PAF antagonists, WEB 2170 and WEB 2086, provided the best dose-dependent protection against PAF toxicity, followed by dexamethasone, by the COX/LOX synthetase inhibitor X 86 (a BW 755 C-analogue) and by the PAF receptor antagonist BN 52021. Particularly remarkable was the excellent prevention by aspirin. Aspirin may not only inhibit the cyclooxygenase pathway but also endogenous PAF synthesis. Other drugs, i.e. indomethacin, the thromboxane receptor antagonist, BM 13177, the thromboxane synthetase inhibitor, HOE 944, as well as the lipoxygenase inhibitors (NDGA, esculetin, SHAM and phenidone) exerted a dose-dependent protection only at high doses.

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A series of 10 PAF-analogues, structurally modified in position C-2 (n-propyl) and position C-3 (polar head group) were synthesized, and the PAF-inhibitory potencies was evaluated using PAF-induced aggregation of human blood platelets in vitro. Structure-activity relationships revealed, that the PAF-inhibitory activity is strongly influenced by the distance between phosphate and onium center and the structure of the substituted heterocyclus. The best activity was observed by 3,5-dimethylpyridinium- and 4-ethylpyridinium derivative with a P-N-distance of 6 methylene groups (IC50 = 1.9 x 10(-6) mol/l and 2.7 x 10(-6) mol/l).

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The phospholipase (PL)A2 inhibitor p-bromophenacyl bromide (p-BPB), the antagonists of the platelet activating factor (PAF) 3-(4-(2-chlorophenyl)-9-methyl-6H-thieno(3,2-f)-(1,2,4)triazolo(4, 3-a)(1,4)diazepine-2-yl)-1-(4-morpholinyl)-1-propanone (a thieno-triazolo-diazepine, WEB 2086) and terpene-ginkgolide B and the antihistamine with PAF antagonistic qualities 4,9-dihydro-4-(1-methyl-4-piperidinylidene)-10H-benzo[2,5]cyclo hep ta[1,2-b]thiophen-10-one (ketotifen) inhibit in the order p-BPB greater than terpene-ginkgolide B greater than ketotifen greater than WEB 2086 with decreasing activity the protamine sulphate activated histamine release from peritoneal rat mast cells (pRMC) in vitro. All compounds also inhibit the PAF induced aggregation of human platelets. The order of inhibition of the histamine release by these compounds does not agree with the order of their inhibitory activity on PAF induced aggregation of human platelets, indicating that the inhibition of the mast cell degranulation caused by PAF antagonists does not occur via PAF receptors. A generally membrane stabilizing quality of terpene-ginkgolide B and WEB 2086 may be ruled out as the cause of degranulation inhibition because none of the compounds suppresses the cytotoxic, triton X-100 induced release of histamine from pRMC. The mechanism of mast cell degranulation inhibition by PAF antagonists is unclear. An inhibition of PLA2 and/or inhibition of the Ca(2+)-activation are suggested.

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Biliary excretion of bendamustin (Cytostasan, 5-[bis(2-chloroethyl)amino]-i-methylbenzimidazole-2-butyric acid; 1) and its metabolites was studied in rats after i.v. administration of 14C-1. The most significant finding was the rapid excretion of 1 related radioactivity in the bile occurring shortly after injection. While radioactivity eliminated by bile within 2 h was 41.8%, in the course of subsequent 22 h it amounted only to 3.2%. Bile samples analyzed by TLC indicated that the total amount of radioactivity was excreted in the form of conjugates and two hydroxy metabolites. A significant amount of radioactivity was excreted in urine. The diversion of bile by cannulation of the bile duct led to a significant decrease of elimination by feces.

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The cyclization of ethyl 2-benzoylthioureidothiophen-3-carboxylates under basic conditions is known to give 2-thioxothieno[2,3-d]pyrimidin-4(1H, 3H)-ones. On the other hand, we have found that ethyl 2-benzoylthioureidothiophen-3-carboxylates 10-16 on treatment with concentrated sulphuric acid or polyphosphoric acid/ethanol undergo cyclization to give the new 2-aminothieno[2,3-d][1,3]thiazin-4-ones 17-23, in some cases 5,6-anellated. Reaction of 10-16, which are readily available from ethyl 2-aminothiophen-3-carboxylates 3-9 and benzoyl isothiocyante affords the title compounds 17-23 in good yields. Mass spectral fragmentation of 17-23 is discussed. A series of 2-aminothieno[2,3-d][1,3]thiazin-4-ones, which contain a free or substituted amino group was evaluated in the rat active cutaneous anaphylaxis test for anti-allergy activity. One compound, 23 had weak activity in the range of theophylline. Only high concentrations of this compound inhibited weakly the histamine release from rat peritoneal mast cells activated by protamine sulfate.

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Different types of anti-allergic agents have been compared for their ability to inhibit the antigen-induced contraction of isolated lung parenchymal strips and ilea of guinea pigs. Extremely low concentrations of the lipoxygenase inhibitor NDGA inhibit the contraction of the lung parenchymal strips and higher concentrations block the ileal phase II-contraction (both predominantly caused by the developing SRS-A), but do not inhibit ileal phase I-contraction (caused by released histamine). The H1-antihistamine clemastine predominantly antagonizes phase I of the ileum contraction, and the anti-allergic drug oxatomide reduces all three types of contraction. The degranulation inhibitor DSCG does not influence the contraction of the lung strip, but produces a slight inhibition of both ileal contractions. The PAF-antagonist BN 52021 influences these three contractions in the opposite way to DSCG. As these various types of anti-allergic agents influence these three contractions in a different manner, the models can be used for judging the mechanism of action of a new anti-allergic compound.

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In this study the stability of 14C-Cytostasan (1, bendamustine), in water solutions was investigated. In distilled water a rapid degradation of carrier-free 14C-1 occurred. The degradation products of 14C-1 are 14C-monohydroxy-1 and 14C-dihydroxy-1 (evidence with the TLC). The degradation rate of 14C-1 was reduced by addition of nonlabelled 1 to the 14C-1 stock solution. The possibility of using distribution coefficient as a stability indicator of 14C-1 solutions was investigated. A number of organic solvents ranging from polar to nonpolar were used for extraction of 14C-1 from water solution. Only ethyl acetate was slightly effective. The distribution coefficient of 14C-1 was dramatically enhanced in presence of dicarbolide of cobalt (DC-H+) in benzene at extraction from HClO4 (0.5 mol.l-1).

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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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This article investigates the effects of di-n-octyl tin dichloride (DOTC) on some morphologic changes in spleen and thymus as well as on the immune reaction of rats. One i.v. injection of DOTC in a dose of 4 mg/kg led in female rats to an atrophy which was reversible within six weeks, and to cell depletion of the thymus. The time needed for the regeneration (the thymus indicated a dose-dependency of the action of DOTC (4-12 mg/kg) on these morphologic changes, which was established by examining immunostimulated rats. Changes in the spleen were observed only with extremely high doses of DOTC. The action of DOTC after one or repeated immunization of rats erythrocytes taken from sheep, on the daughter-cell-dependent production of antibodies was examined by means of an immuno-rosette-test and by determining the hemagglutination titre. The number of lymphocytes in the spleen which form rosettes was reduced after one intravenous administration (4 mg/kg) of DOTC 1, 2, 3, or 8 d prior to antigenic stimulation. The time needed to form rosettes was dependent on the dose. The immunoglobulin-G-immunoglobulin-M antibody titre remained unaffected if DOTC was given once by i.v. injection 7 or 8 d prior to immunostimulation, the doses ranging from 4 to 12 mg/kg. DOTC-treatment carried out twice with 4 mg/kg led to a complete suppression of the immunoglobulin-G/immunoglobulin-M antibody production against erythrocytes taken from sheep, if DOTC had been applied on eight consecutive d and on d 0 (the d of the primary immunization).(ABSTRACT TRUNCATED AT 250 WORDS)

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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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