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K U Weithmann

Publications and source records attributed to K U Weithmann.

17 recordsLinked to original sources
PubMed1990

Annexin proteins PP4 and PP4-X. Comparative characterization of biological activities of placental and recombinant proteins.

The human placental proteins PP4 and PP4-X, belonging to the annexin protein family, were expressed in Escherichia coli at high yield. The proteins were purified to homogeneity. The physicochemical parameters of the recombinant proteins were determined and compared with those of their natural placental counterparts. Except for a minor change in the pI, the proteins appeared to be indistinguishable by several criteria. Both recombinant PP4 and recombinant PP4-X were biologically active in a thromboplastin inhibition test and in a phospholipase A2 inhibition test.

Annexin A5↗
PubMed1989

Incorporation of arachidonic, dihomogamma linolenic and eicosapentaenoic acids into cultured V79 cells.

The uptake and distribution of three common dietary polyunsaturated fatty acids was studied using Chinese hamster lung fibroblasts (V79 cells). Treatment of V79 cells with arachidonic (20:4), eicosapentaenoic (20:5) and dihomogammalinolenic (20.3) acids for 24 hr produced a marked uptake of 20:3 and 20:4, both of which were assimilated to a considerably greater degree than 20:5. All polyunsaturated fatty acids were incorporated primarily into phospholipids; however, there were considerable differences in their distribution into individual phospholipid species. Although 20:4 was incorporated primarily into phosphatidylcholine, 20:3 entered largely into phosphatidylethanolamine and phosphatidylglycerol, and 20:5 was distributed about equally between phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol. A marked conversion of 20:3 to 20:4 was found after 24 hr and, in several phospholipids, there was as much derived-radiolabeled 20:4 as there was radiolabeled 20:3. There was little evidence of 20:4 and 20:5 metabolism. V79 cells undergo substantial changes in phospholipid fatty acid composition following supplementation with these polyunsaturated fatty acids; however, these fatty acids are assimilated to different degrees and their distribution among cellular phospholipids is distinct, suggesting incorporation via independent mechanisms.

8,11,14-Eicosatrienoic Acid↗
PubMed1989

Stimulatory effects of vascular prostaglandins on the antiaggregatory activities of pentoxifylline acetylsalicylic acid combinations in vitro.

Pentoxifylline, Acetylsalicylic acid (ASA) and particularly both drugs in combination are known as active platelet inhibitors in pharmacological models in vivo. However, rather high amounts of these drugs are necessary to demonstrate inhibitory effects on the aggregation of human platelets in vitro, where no vessel walls are present. Surprisingly, these weak effects could be enhanced by the addition of external prostaglandins (prostacyclin (PGI2) and prostaglandin E1 (PGE1] into the in vitro system. Ternary combinations consisting of pentoxifylline, ASA and PGI2 exhibited the most impressive synergistic effects. Thus our study highlights the contribution of prostaglandins, especially of the natural vascular platelet inhibitor PGI2, for the display of the antiaggregatory potency of such drug combinations.

Alprostadil↗
PubMed1989

Substituted 3-phenyl-7H-thiazolo(3,2-b)(1,2,4)triazin-7-ones as antiinflammatory agents with immunomodulating properties.

After structure-activity relationship studies (SAR) on a novel class of substituted thiazolo(3,2-b)(1,2,4)triazin-7-ones, HWA-131 (3-(3,5-di-tert.butyl-4-hydroxyphenyl)-7H-thiazolo(3,2-b)(1,2,4)triaz in-7-one) was selected for incremental pharmacological investigations. This compound was effective in not only preventing, but also curing established arthritic disorders of rats such as adjuvant and type II collagen arthritis as well as those of mice such as chronic graft-versus-host (CGVH) disease, a model for systemic lupus erythematosus (SLE). Further, this non-immunosuppressive drug effectively inhibited the carrageenan-induced paw oedema, attenuated the active Arthus reaction, and demonstrated antierythema as well as antipyretic activity. Part of the antiinflammatory effects of this new compound is most probably related to its antioxidative activity, as well as inhibition of lipoxygenase metabolites. HWA-131's good gastric tolerance may have to do with its limited ability to inhibit the production of cyclooxygenase metabolites. Based on our data, we are sure that HWA-131 will be an effective nonsteroidal antiinflammatory agent, with immunomodulating properties, to combat human autoimmune disorders.

Adjuvants, Immunologic↗
PubMed1987

Surprising effects of the sequential administration of pentoxifylline and low dose acetylsalicylic acid on thrombus formation.

The effect of the combined oral administration of pentoxifylline (pof) and low dose acetylsalicylic acid (ASA) was evaluated with the help of the laser-induced thrombosis in rat mesenteric arterioles. Laser-induced thrombosis is inhibited in a dose-dependent way by both drugs. The administration of ASA, either simultaneously with or 1 hour prior to pof, does not show any effects in the laser model. On the contrary, the administration of pof followed 1 h later by ASA not only exhibited a significant effect but also produced a supraadditive inhibition of the laser-induced thrombus formation. Specific investigations concerning the time interval between the administration of both drugs determined that a significant effect can be achieved only after an interval of 30 to 90 minutes (principle of HWA 5112). The striking results could also be shown in diseased animals after sequential chronic administration of pof 1 h prior to ASA. HWA 5112 exhibits significant effects on laser-induced thrombus formation in the following chronic animal models: 1. adjuvant arthritic rats, 10----1 mg/kg for 21 days; 2. spontaneously hypertensive stroke-prone rats, 10----1 mg/kg three times within 24 h; 3. cholesterol-induced atherosclerosis in rabbits, 10----1 mg/kg for 14 days. The reported data clearly demonstrate that the sequential drug administration of first pentoxifylline followed 30 to 90 min later by ASA exhibits a supraadditive antithrombotic effect.

Administration, Oral↗
PubMed1986

Topographic aspects of prostacyclin-like and fibrinolytic activity and of biogenic amines in the arterial system of the mini-pig.

Although arteriosclerosis is a systemic disease, it nevertheless exhibits noticeable topographical preference and particularities. The reason for this could be lie with certain biochemical features of the arterial wall. We therefore examined prostacyclin-like and fibrinolytic activity in mini-pigs, as well as the concentration of various biogenic amines in the thoracic and abdominal aorta, in coronary arteries and in the carotid and femoral artery. There was a similar behaviour between PG I2-like release and biogenic amines in the different arteries, whereas fibrinolytic activity behaved differently in some cases. In the femoral artery particularly low fibrinolytic activity was confronted by a particularly high level of PG I2-like activity and biogenic amines, while the reverse was the case in the abdominal aorta. In older animals PG I2-like activity considerably decreased.

Animals↗
PubMed1985

Biochemical and pharmacological effects of dipyrone and its metabolites in model systems related to arachidonic acid cascade.

The metabolites of dipyrone (metamizol, Novalgin) were compared with appropriate standard drugs for their influences on the pathways of the arachidonic acid metabolism. The drugs in this study had no significant effects on the lipoxygenase pathway in human neutrophils in vitro. The dipyrone metabolites 4-methylaminoantipyrine (MAAP) and 4-aminoantipyrine (AAP) inhibited prostaglandin synthesis in the 10(-3) to 10(-4) mol/l range thus being comparable to acetylsalicylic acid (ASA), whereas the two additional metabolites 4-acetylaminoantipyrine (AAAP) and 4-formylaminoantipyrine (FAAP) were practically inactive. This result is in accordance with the effects of the metabolites on the formation of oedema in the arthritis rat model, and supports published data showing that MAAP and AAP are the metabolites responsible for the clinical effects of dipyrone. Further systems in our study depending at least partially on the prostaglandin pathway were the release of antiaggregatory activity from rat aortae in vitro and the aggregation of human platelets induced by arachidonic acid in vitro. MAAP exhibits antiaggregatory activity (IC50 5 x 10(-6) mol/l), whereas the inhibitory effect on the vascular antiaggregatory release is much weaker. Compared to normals platelet aggregability ex vivo is enhanced in arthritic rats, but could significantly be lowered again by treatment of the rats with MAAP. A further system studied was the release of 6-keto-PGF1 alpha from rat mucosa in vitro and ex vivo. In vitro there is inhibition to be found with MAAP as well as with ASA. Ex vivo, however, dipyrone or MAAP slightly stimulates mucosal 6-keto-PGF1 alpha rather than inhibiting it, whereas ASA exerts inhibition, as expected.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Reduced platelet aggregation by effects of pentoxifylline on vascular prostacyclin isomerase and platelet cyclic AMP.

1. Inhibition of platelet aggregation in vitro by pentoxifylline is rather weak, requiring about 1 mM pentoxifylline. Ex vivo, however, 15 mg/kg p.o. pentoxifylline exerts an enhanced release of prostacyclin-(PGI2)-like antiaggregatory activity from rat aortas. 2. Rat aorta incubated in vitro with 1 microM pentoxifylline releases antiaggregatory activity in a similar manner. The conversion of prostaglandin H2 to PGI2-like activity which is catalyzed by vascular microsomes, also is drastically stimulated in vitro by addition of 1 microM pentoxifylline. 3. Despite its inhibitory effect on platelet cyclic AMP-phosphodiesterase pentoxifylline in vitro without PGI2 has no essential effect on cyclic AMP levels in human platelets. However, in presence of PGI2, release of which probably is increased by pentoxifylline cyclic AMP level as well as inhibition of aggregation are enhanced by pentoxifylline above the effects of PGI2 itself.

Animals↗
PubMed1982

HL 725, an extremely potent inhibitor of platelet phosphodiesterase and induced platelet aggregation in vitro.

The new pyrimido-isoquinoline compound HL 725 is an extremely potent inhibitor of the aggregation of human platelets induced in vitro by ADP, collagen, thrombin and epinephrine. The aggregation induced by 0,5 mM arachidonic acid is inhibited about 50% with 50 pM HL 725. Thus the potency of HL 725 is higher than that of prostacyclin, the most active natural inhibitor of aggregation. We hypothesize that HL 725 inhibits the enzymatic degradation of cyclic adenosine 3', 5'-monophosphate (cAMP) in the platelets. In accordance with this proposal is the strong inhibitory action on cAMP phosphodiesterase extracted from human platelets. About 250 pM HL 725 inhibited 50% of the activity of this enzyme at a substrate concentration of 0.5 microM. A marked elevation of cAMP levels in human platelets could be demonstrated after incubation in vitro with 100 nM HL 725.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1981

Drug stimulated prostacyclin release.

We suggest pentoxifylline (POF) to exert in vivo its offiaggregatory effect by enhancing prostacyclin (PGI2)-like activity from the vessel walls, which in turn stimulates platelet adenylate cyclase resulting in an elevated cyclic AMP level in the platelets. Despite its inhibitory effect on platelet cAMP phosphodiesterase, POF without PGI2 has almost no effect in vitro on cAMP levels in human platelets or on the inhibition of aggregation. However, a combination of POF together with PGI2 in these in vitro systems drastically stimulates cAMP-levels as well as inhibition of aggregation above that concerning to PGI2 itself. We therefore conclude that the intact vessel wall-platelet interaction is required for the anti-aggregatory action of POF in vivo.

Animals↗
PubMed1980

Stimulation of anti-aggregatory activity from rat aorta by hypolipidemic drugs.

The effect of clofibrate, clofibric acid and nicotinic acid on the ability of rat aortas to synthesize prostacyclin-like biological material is reported. Dissected and washed aortas of rats, treated with these drugs showed a markedly higher capacity to synthesize acid-labile prostacyclin-like activity than those of untreated controls. The investigated drugs may thus not only exert their influence on plasma lipid metabolism but also on the inhibition of platelet thrombi formation in the treatment of atherosclerotic diseases.

Animals↗
PubMed1978

A modified assay system for collagen glucosyltransferase.

A simplified assay procedure has been developed for the determination of collagen glucosyltransferase activity in tissue extracts. Using degraded gelatine as acceptor it was possible to isolate the reaction product by precipitation on to a glass fibre disc. Under our conditions degraded gelatine is glucosylated with a reaction rate which is 3--4 times lower compared with the glucosylation of basement membrane derived glycopeptides. Good reproducibility is demonstrated by the coefficient of variation of 4% in the same assay and an interassay variation coefficient below 8%. As the assay allows the testing of large numbers of samples in a few hours, it should prove a useful tool to determine the enzyme level in the tissue of diabetic animals. In humans the activity of the glucosyltransferase could provide a biochemical parameter related to diabetic microangiopathy.

Amino Acids↗