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R Müller-Peddinghaus

Publications and source records attributed to R Müller-Peddinghaus.

At least 37 records · Page 2Linked to original sources
PubMed1991

Effects of tiflucarbine as a dual protein kinase C/calmodulin antagonist on proliferation of human keratinocytes and release of reactive oxygen species from human leukocytes.

Various studies have suggested that calmodulin (CaM) is involved in the pathophysiology of psoriasis. Protein kinase C (PKC) is also accepted as playing a regulatory role in cell proliferation as well as in inflammatory processes. Therefore, we investigated the effects of the known CaM antagonist tiflucarbine (BAY/TVX P 4495) on two cellular systems related to the major clinical symptoms of psoriasis: proliferation of cultured human keratinocytes (HaCa T cell line) and release of reactive oxygen species (ROS) from human polymorphonuclear leukocytes (PMNL). Tiflucarbine inhibited both cellular responses in a dose dependent manner. Furthermore, tiflucarbine directly affected PKC, and may thus be considered to be a dual PKC/CaM antagonist with putative antipsoriatic activity. The effects of tiflucarbine on the different parameters were compared with those of the structurally unrelated dual PKC/CaM inhibitor W-7 and those of the potent PKC inhibitor staurosporine. The potencies of all three compounds were found to be in the same range as their PKC-inhibiting potency. Our data indicate that PKC, rather than CaM, may play a regulatory role in the release of ROS as well as in keratinocyte proliferation. Therefore, inhibition of PKC in general might have a therapeutic benefit in psoriasis.

Alkaloids↗
PubMed1989

Bradykinin and thrombin effects on polyphosphoinositide hydrolysis and prostacyclin production in endothelial cells.

Prostacyclin (PGI2) production by thrombin- and bradykinin-stimulated bovine aortic endothelial cells (BAEC) and human umbilical vein endothelial cells (HUVEC) was related to the receptor-linked activation of inositide hydrolysis. Bradykinin caused a rapid and transient 3-fold increase in the formation of inositol polyphosphates in BAEC. The increase in InsP3 reflected changes mainly in the Ins(1,4,5)P3 isomer. Thrombin was less effective than bradykinin in increasing InsP3 levels and appeared to only minimally stimulate the production of PGI2 in BAEC. In HUVEC, thrombin caused a 5-fold elevation of Ins(1,4,5)P3, closely related to a rise in PGI2 production. However, bradykinin did not affect inositol phosphates and PGI2 production in HUVEC. Other inositol phosphates were also assessed to obtain information on putative metabolism of Ins(1,4,5)P3. The present study supports the notion that formation of Ins(1,4,5)P3 is linked to an increase in PGI2 production in endothelial cells and furthermore provides evidence for a large degree of heterogeneity in the responses of BAEC and HUVEC to thrombin and bradykinin.

Animals↗
PubMed1989

[Reactive oxygen species and inflammation].

Reactive oxygen species (ROS) are generated in significant amounts by inflammatory phagocytes. ROS facilitate protection against infections. Yet they are also tissue damaging and doing so act synergistically with catabolic events. Direct evidence of ROS and oxidative tissue alteration is methodologically difficult. Protection against ROS-mediated tissue damage by pharmacological means is still unsolved.

Animals↗
PubMed1987

The amplified chemiluminescence test to characterize antirheumatic drugs as oxygen radical scavengers.

High levels of reactive oxygen species (ROS) are generated by phagocytes involved in host defence and inflammation. Thus, it appears highly desirable to learn more about the potential of antirheumatic drugs to scavenge ROS or to inhibit their enzymatic generation. Amplified chemiluminescence (CL) allows detection of O-2 using lucigenin (LgCL) or H2O2 using luminol (LuCL). A total of 43 compounds have been tested quantitatively in vitro (10(-6) to 10(-4) mol/l) with respect to three test parameters; varying cell-activity, and incubation-time employing two different phagocyte populations (neutrophils/macrophages). The most active compounds with LgCL were the known radical scavengers nordihydroguaiaretic acid (NDGA), N-propyl gallate, superoxide dismutase and chloroquine, the non-steroidal anti-inflammatory drugs (NSAID) benzydamine, timegadine, carprofen, enolicam, the known lipoxygenase inhibitors (e.g. CBS 1108/1114, BW 755C) and glucosaminoglucan polysulfate. Inactive in this system were corticosteroids (prednisolone, dexamethasone) most of the tested NSAID (N = 16/20), most disease modifying drugs (D-penicillamine, levamisole, gold-TM) and the anti-gout drugs (sulfinpyrazone, allopurinol, colchicine). Therefore amplified CL with lucigenin appears to be a rapid, kinetic, reproducible means of pharmacological profiling in vitro new anti-inflammatory drugs for radical scavenger activity.

Animals↗
PubMed1987

[The effect of benzydamine on the generation and interaction of reactive oxygen species and cyclo- and lipoxygenase].

Pharmacological mechanisms of benzydamine (Tantum) are studied which are of relevance for the antiinflammatory properties of this non-steroidal antiinflammatory drug (NSAID). Benzydamine most effectively inhibits the generation of reactive oxygen species by murine neutrophils (IC50 1.7 X 10(-5) mol/l). Piroxicam, indomethacin and acetylsalicylic acid are ineffective. Benzydamine, however, does not interfere with xanthine oxidase-dependent superoxide anion radical formation or epinephrine oxidation. The other tested NSAID are as well inactive. The findings confirm the missing cyclooxygenase inhibition of benzydamine (IC50 greater than 10(-3) mol/l), contrary to the other NSAID which are strong (indomethacin IC50 6 X 10(-8) mol/l; piroxicam IC50 2 X 10(-7) mol/l) or moderate cyclooxygenase inhibitors (acetylsalicylic acid IC50 10(-5) mol/l). LTB4 generation via the lipoxygenase is only inhibited by indomethacin (EC50 3.6 X 10(-5) mol/l). Benzydamine appears unique among other NSAID by its relatively strong interference with the generation of reactive oxygen radicals and the lack of cyclooxygenase inhibition.

Animals↗
PubMed1987

[Effects of benzydamine on leukocyte aggregation].

The effect of benzydamine (Tantum) on the aggregation of rat leukocytes was compared to some commonly used nonsteroidal antiinflammatory drugs (NSAID). The aggregation response was induced by various activators such as the tumour promoter phorbol myristate acetate, the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), arachidonic acid, sodium arachidonate, platelet activating factor (PAF) and a combination of cytochalasin B and Ca++-ionophore A 23187. As compared to indomethacin, piroxicam and acetylsalicylic acid benzydamine was inhibitory against most of the activators, i.e. the receptor-mediated induction of the aggregation by FMLP, the phorbol ester and sodium arachidonate. No effect could be observed against PAF induced aggregation. Under the assay conditions benzydamine exerted cytolytic effects at 2 X 10(-4) mol/l. Cytolysis reached 100% at 5 X 10(-4) mol/l benzydamine, as could be shown microscopically and by measurement of free cytosolic lactate dehydrogenase. Thus benzydamine exerted a broad spectrum inhibitory activity against rat leukocyte aggregation, possibly explained by its unspecific membrane affinity.

Animals↗
PubMed1987

[New pharmacologic and biochemical findings on the mechanism of action of the non-steroidal antiphlogistic, benzydamine. A synopsis].

Benzydamine (Tantum) is an indolic non-steroidal antiinflammatory drug (NSAID) for systemic use in acute traumatic lesions and locally as mouth gargle wash. Benzydamine is lipophilic at pH 7.2, has an affinity for membranes and shows membrane stabilizing properties with local anaesthetic effects. Contrary to other NSAID, benzydamine does not inhibit the cyclo- nor the lipoxygenase (10(-4) mol/l) and is also not ulcerogenic in the rat. Phospholipase A2 is slightly inhibited as well as the lysophosphatide-acyltransferase (greater than 10(-4) mol/l). Macrophage PGE2 synthesis is enhanced at 10(-4) mol/l. The production of reactive oxygen species by phagocytes is effectively inhibited (10(-5)-10(-4) mol/l). Phagocyte degranulation and aggregation are also inhibited (10(-4) mol/l). The strongest in vitro effect is the inhibition of leukocyte adhesion to vascular endothelium (3-4 X 10(-6) mol/l). Benzydamine is also antithrombotic in the rat (ED35 8.5 mg/kg p.o.) and reduces PAF (platelet activating factor)-induced mortality in the mouse (50 mg/kg p.o.; p less than 0.05). It is concluded that benzydamine is antiinflammatory by preventing vessel wall damage from activated, adhering and emigrating leukocytes i.e. being vasoprotective.

Animals↗
PubMed1987

[Pathophysiology and pharmacology of reactive oxygen species in inflammation].

Free reactive oxygen species (ROS) are generated during cell respiration and by various metabolic processes, after reoxigenation of infarctions and to a large extent by activated phagocytes. In- and extracellular physiologic radical scavengers control the multiple reactions of ROS to prevent the generation of the highly damaging hydroxyl radical (OH). ROS damage after reoxigenation of an infarct can be reduced by employing the xanthine oxidase inhibitor allopurinol. ROS generated by activated phagocytes are both defensive and noxious. ROS reduction is achieved by applying physiologic radical scavengers as the superoxide dismutase, which are of therapeutic interest for the treatment of inflammatory joint and vascular diseases and the adult respiratory distress syndrome. Known drugs e.g. benzydamine (Tantum) are increasingly recognized to act via ROS mediated mechanisms and a ROS-targeted pharmacological research appears now possible.

Animals↗
PubMed1985

Glucocorticosteroid effects on dog and rat serum complement.

Inhibiting properties of glucocorticosteroids in vivo on the complement system are not fully recognized. Dexamethasone and prednisolone (10(-7)-10(-3)mol/l.) have no direct effects on serum complement of the dog, rat, human and guinea pig. Yet after subcutaneous application of dexamethasone (0.4 mg/kg) on two consecutive days to healthy beagle dogs the total functional complement is reduced to about 60% of the normal level within the next three days. This effect could be shown to be dose-dependent in male beagle dogs. Partial recovery of the depressed complement level (CH50 U/ml) occurs after the 6th day without treatment. In parallel a decrease in serum C3 is observed. The qualitative serum protein pattern documented by cellulose acetate film electrophoresis (CAF) reflects the decrease of C3 by a reduced beta 1-beta 2 level with a concomitant increase of the alpha 2 serum proteins. In contrast, serum complement, C3 and the serum CAF pattern in rats are not much altered by prednisolone (2 X 15 mg/kg s.c.) or dexamethasone (2 X 2 mg/kg s.c.). Thus the rat appears relatively insensitive to humoral changes induced by steroid alone. Altered liver protein synthesis of complement and other acute phase proteins appear responsible for the profound steroid effects observed in the dog.

Animals↗
PubMed1984

In vitro determination of phagocyte activity by luminol- and lucigenin-amplified chemiluminescence.

Amplified chemiluminescence (CL) detects most sensitively biologically important reactive oxygen species (ROS) which are generated by phagocytes by the respiratory burst permitting the determination of cell activity in vitro. Different murine phagocyte populations were used in combination with various ROS-catabolizing enzymes and some of their inhibitors to determine the possible advantages of one of the two main presently used amplifiers, i.e. luminol and lucigenin. Lucigenin appeared to react mainly with the first of the generated ROS the superoxide anion radical (O-.2) and thus records cell activity via the respiratory burst much more reliable than luminol. The more commonly employed luminol reacts mainly with hydrogen peroxide (H2O2) and probably the singlet oxygen (1O2) which result in photon emission. However, it seems not to react with the hydroxyl radical (OH.). The dependence of luminol-amplified CL upon the generation of the chain reaction intermediate H2O2 and its three main catalysts catalase, myeloperoxidase and glutathione makes this reaction prone to different artifacts if cell activity is to be determined. Lucigenin-amplified CL offers great advantages to study cell activating or inhibiting properties of drugs and kinetics in vitro because of the biological relevance of O-.2 determination, its sensitivity, reproducibility and ease in handling.

Acridines↗
PubMed1984

Protective effects of various compounds on lysis of antibody-coated sheep erythrocytes by hypotonic shock or complement.

The combination of the two well known in vitro methods of hypotonic shock and immune hemolysis employing sheep erythrocytes (E) were used to evaluate membrane stabilization. Direct drug-induced hemolysis of antibody-coated E (EA), protection against hypotonic shock and complement (C)-mediated hemolysis can be recorded from a consecutive preparative procedure to give information to irreversible drug effects. The most active probable working mechanisms are interference with binding sites of the complement membrane attack complex (MAC) and unspecific membrane stabilization. Protection against C-mediated erythrolysis appeared more sensitive than against hypotonic shock.

Animals↗