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Biomedical subjects

K Jaschonek

Publications and source records attributed to K Jaschonek.

At least 37 records · Page 2Linked to original sources
PubMed1989

5-Lipoxygenase inhibition by antifungal azole derivatives: new tools for immunosuppression?

The effect of novel azole derivatives (itraconazole and fluconazole) on 5-lipoxygenase activity was examined using human polymorphonuclear leukocytes (PMNL) as the enzyme source. The novel imidazole derivative itraconazole proved to be a potent inhibitor (IC50 2 X 10(-6) M) of 5-lipoxygenase activity. In contrast, fluconazole, an antifungal agent with bistriazole structure, had no effect on the Ca2+ ionophore A 23187-induced formation of 5-lipoxygenase metabolites in PMNL.

Antifungal Agents↗
PubMed1988

Desensitization of platelets to iloprost. Loss of specific binding sites and heterologous desensitization of adenylate cyclase.

The binding characteristics of [3H]prostacyclin and [3H]iloprost ([3H]5-[(E)-(1S,5S,6R,7R)-7-hydroxy-6-[(E)-(3S,4RS) -3-hydroxy-4-methyl-1-octen-6-inyl]-bicyclo[3.3.0]octan-3-yl idene] -pentanoic acid) and platelet adenylate cyclase activities were investigated in platelet-rich plasma preincubated with iloprost. The exposure of platelets to 0.1 microM iloprost (12 h, 20 degrees C) caused a significant loss of iloprost binding sites (P less than 0.01) without causing changes in binding affinity. This loss of specific [3H]iloprost binding was time- and dose-dependent. The reduction of iloprost receptor density was accompanied by an impaired responsiveness of platelet adenylate cyclase to iloprost, prostaglandin D2 and forskolin. In contrast, basal adenylate cyclase activity was not affected by iloprost pretreatment. The diminished response of the enzyme to GTP and NaF pointed to an involvement of the stimulatory guanyl nucleotide-binding protein (Gs) in iloprost-induced heterologous desensitization. Consequently, [32P]NAD+ and cholera toxin were used for the direct labelling of Gs. Platelet membranes desensitized to iloprost incorporated less label into the 45 kD subunit of Gs. These data suggest that the site of action of iloprost for heterologous desensitization of human platelet adenylate cyclase is located on Gs.

Adenosine Diphosphate↗
PubMed1988

Correlation between low CSA plasma concentration and severity of acute GvHD in bone marrow transplantation.

Between 1982 and 1986 51 patients were treated with ciclosporin a (CSA) to prevent graft versus host disease (GvHD) after bone marrow transplantation (BMT). Major side effects of the drug were tremor, hypertension, hepatotoxicity and nephrotoxicity. Acute GvHD 0 degree to II degree occurred in 80% of our patients, and GvHD III degree and IV degree in 20% despite the use of CSA. Two to four days before the onset of GvHD, CSA serum levels were significantly lower on the average in patients who developed GvHD III degree and IV degree compared to the others. Our data indicate that plasma CSA concentrations higher than 250 ng/ml should be achieved to reduce the severity of GvHD after BMT.

Acute Disease↗
PubMed1988

Platelet and vessel associated prostacyclin and thromboxane A2/prostaglandin endoperoxide receptors.

Synthetic stable analogues of thromboxane A2 (TXA2), cyclic endoperoxides (PGH2) and prostacyclin (PGI2) opened up new opportunities for investigating the mechanisms of action of these compounds. They proved to be useful pharmacological probes for characterizing PGI2 and TXA2/PGH2 receptors. Over the past few years, new synthetic antagonists with high specificity allowed the modulation of biological responses to endogenous eicosanoids. These compounds will, therefore, considerably promote our understanding of the biological function and significance of arachidonate metabolites. The present review summarizes current concepts that have arisen concerning platelet and vascular PGI2 and TXA2/PGH2 receptors, their transmembrane signal transduction, as well as their possible implications in the pathophysiology of cardiovascular disease.

Adenylyl Cyclases↗
PubMed1986

Effects of heparin on prostacyclin binding and platelet adenylate cyclase activity stimulated by iloprost and forskolin.

Heparin is known to impair the antiaggregatory effectiveness of prostacyclin (PGI2) for adenosine diphosphate-induced aggregation in citrated platelet rich plasma. Thus porcine mucosal heparin (PMH) from different commercial sources was investigated for its ability to compete with specific platelet prostacyclin binding. In concentrations up to 250 IU/ml PMH itself did not interfere with the binding of 3 X 10(-9) M 9-3H-PGI2-sodium salt to intact washed platelets. The displacement of specifically bound PGI2 observed by PMH (Ki 60 IU/ml) containing 4-chloro-m-cresol (4-CC) was caused by the preservative (Ki 4-CC 3.0 X 10(-4) M). Although 60 IU/ml PMH (free of 4-CC) have been shown to inhibit basal 3 X 10(-5) M forskolin-, and 10(-8)M Iloprost-stimulated adenylate cyclase in platelet membranes (-63%, -62%, -83% respectively), no effect of PMH on 3H-cyclic-AMP formation has been observed when intact platelets were studied by 3H-adenine prelabeling technique. There is also no evidence that the preincubation of PGI2 (5 X 10(-7) M) with 1000 IU/ml PMH might neutralize the effectiveness of this eicosanoid. In contrast, PGI2 preincubated with PMH (10 min, 37 degrees C) caused a more pronounced increase of platelet 3H-cyclic AMP (+65%) compared with PGI2 incubated in 5 X 10(-2) M Tris-HCl, pH 7.4. Thus our data provide no evidence that PMH interferes with i) specific platelet PGI2 binding, ii) PGI2-stimulated cyclic AMP synthesis or iii) neutralizes PGI2 by formation of a biologically less active PGI2-PMH complex.

Adenylyl Cyclases↗
PubMed1986

The binding of 6-oxo-prostaglandin E1 to platelet prostanoid receptors.

6-oxo-PGE1 has been shown to cause a dose dependent stimulation of platelet adenylate cyclase (Km 1.6 X 10(-7)M). Since this compound also displaced specifically bound 9-3H-PGI2 from intact washed platelets (Ki 1.6 X 10(-6)M), the coupling to platelet PGI2 receptors has been suggested to account for the observed platelet cyclase stimulation. However, the Ki/Km-ratio of 6-oxo-PGE1 appears to be high (10.3) as compared to PGI2, ZK 36 374, and PGE1 (1.9, 2.4 and 3.1, resp.). Thus, one might expect that 6-oxo-PGE1 interacts with a heterogeneous population of platelet receptors mediating the same biological response, eg cyclase activation. In this study, we present evidence supporting this concept and report that 6-oxo-PGE1 also displaces specifically bound 3H-PGD2 from its platelet receptor (Ki 1.6 X 10(-5)M).

Adenylyl Cyclases↗
PubMed1986

Platelet prostacyclin binding in coronary artery disease.

Reduced responsiveness of platelets to prostacyclin, reported in vitro in patients with coronary artery disease, has been thought to be a factor predisposing toward coronary thrombosis and vasospasm as a result of enhanced in vivo release of cyclic endoperoxides and thromboxane A2 by the platelets. In this study, specific binding of prostacyclin to intact platelets was determined in patients with coronary artery disease by direct binding studies using 9-3H-prostacyclin sodium salt. In addition, the inhibitory effect of prostacyclin on primary aggregation induced by adenosine diphosphate and cyclic adenosine monophosphate (cyclic AMP) accumulation stimulated by prostacyclin was examined. Twenty patients with angiographically documented coronary artery disease and stable angina, 8 patients with acute myocardial infarction, 14 healthy volunteers and 10 patients with normal angiograms were studied. In patients with stable angina, binding capacity and affinity of platelet prostacyclin binding sites and prostacyclin-induced cyclic AMP accumulation were not different from those of control subjects. In patients with acute myocardial infarction, however, binding capacity of platelet prostacyclin receptors was significantly reduced (0.69 +/- 0.45 versus 1.35 +/- 0.37 pmol/10(9) platelets, p = 0.001) and the postreceptor response, represented by platelet responsiveness to prostacyclin and prostacyclin-induced cyclic AMP synthesis, was impaired. Because all patients with myocardial infarction were receiving intravenous heparin and nitroglycerin, which might interfere with platelet prostacyclin binding, competition experiments were performed in vitro. Neither heparin (3 to 250 IU/ml) nor nitroglycerin (0.8 to 22 microM) displaced specifically bound 9-3H-prostacyclin. L-Epinephrine in concentrations up to 10 microM also exhibited no competition with specific platelet prostacyclin binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1986

Platelet prostacyclin binding in smokers.

Binding capacity (Bmax) and dissociation constant (KD) of platelet prostacyclin (PGI2) receptors in 23 male smokers and 14 nonsmokers have been determined by direct binding studies to investigate whether platelet prostacyclin binding is altered in smokers. In addition, the inhibitory effect of PGI2 (IC50) on adenosine diphosphate (ADP)-induced platelet aggregation was measured. As confirmed by discriminant analysis, 69% of the smokers had significantly different Bmax and KD. Binding capacity was increased in 12 smokers (Bmax + 74%), with a concomitant decrease in affinity (KD + 94%). In these volunteers, the postreceptor responses (PGI2-induced cyclic adenosine monophosphate [AMP] accumulation in platelet-rich plasma as well as IC50) did not differ from those of controls. In contrast, four smokers with considerably reduced PGI2 binding capacity (Bmax - 65%) exhibited a lower antiaggregatory effect (IC50 + 74%), although the affinity was slightly increased (KD - 61%). Nicotine, L-epinephrine, and prostaglandin E2 did not significantly compete with the binding of 9-3H-PGI2 sodium salt. The antiaggregatory effect of PGI2 on ADP-induced platelet aggregation, however, was inhibited by L-epinephrine (Ki 26 nmol/L) and prostaglandin E2 (Ki 230 nmol/L). Our data suggest that with respect to platelet PGI2 binding and in vitro responsiveness to PGI2, smokers are a heterogeneous population. Although increased binding capacity was observed in 50% of the smokers investigated, our data provide no evidence that a biologically relevant upregulation, for example with concomitant enhanced postreceptor reaction, occurs in smokers.

Adenosine Diphosphate↗
PubMed1980

Blood platelet cyclic AMP during long-term treatment of premature labor.

The mean platelet cyclic AMP (cAMP) value in normal pregnant women between 20 and 37 weeks of gestation was 8.2 +/- 0.4 (SEM) pmol cAMP/10(9) platelets (n = 100). From 35 patients with premature labor, 81 blood samples were obtained from measurement of the platelet cAMP before, during and after treatment with fenoterol/verapamil. During the first 4 days of therapy there was an increase of cAMP (p < 0.005); with long-term therapy the blood platelet cAMP was decreased (p < 0.005). Because platelet aggregation has a negative correlation with platelet cAMP, fenoterol should be used cautiously in patients with defective platelet function, in severe bleeding, and before surgery. With long-term treatment platelet aggregation may be increased and thus contribute to the formation of thrombi. Placental perfusion is not likely to be improved by increased platelet aggregation during long-term treatment with fenoterol.

Blood Platelets↗
PubMed1980

Plasma cAMP in normal and abnormal human pregnancy.

Plasma cAMP was determined using the method of Tovey et al. in normal pregnant women with a mean concentration of 18.9 +/- 0.8 pmol/ml (x- +/- SEM). Between weeks 9-12 and 33-36 of gestation, there were two peaks, with a mean cAMP of 22.5 +/- 2.4 which were significantly increased in comparison to the other weeks of pregnancy. Significantly decreased values were found in patients with threatened abortion (weeks 12-28) which terminated in abortion (11.6 +/- 2.4; p < 0.01). In premature labor no differences were found. During therapy with fenoterol there were highly significantly increased plasma cAMP levels (48.2 +/- 2.8; p < 0.0005). During thyroid hormone therapy in euthyroid goiter, cAMP was significantly decreased (14.0 +/- 1.4; p < 0.05). 1 week after cessation of therapy a highly significant increase of cAMP was observed (38.2 +/- 6.9; p < 0.0005). There was a negative linear regression between T3 and cAMP (2p < 0.01). In pregnancy with hypertension cAMP was significantly elevated (30.5 +/- 3.8 p < 0.0005), but nearly normal under antihypertensive therapy. In pregnancy with edema only, no difference was found. Induction of labor with PGE2 alpha was followed by a decrease of plasma cAMP.

Abortion, Threatened↗