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Biomedical subjects

G Ostermann

Publications and source records attributed to G Ostermann.

At least 19 recordsLinked to original sources
PubMed1992

[PAF-antagonists with phospholipid structure. 4. Alkylcarbamoylphospholipids with heteroarene and heterocyclase head groups and variation of the P-N-distance; synthesis, characterization and structure-activity relationship].

A series of 11 PAF-analogues, structurally modified in position 1 (alkylcarbamoyloxy), position 2 (n-propyl), and position 3 (polar head group) were synthesized, and the inhibitory potencies on human blood platelets in vitro was evaluated. Investigations of structure-activity relationships revealed, that the PAF antagonist activity is strongly influenced by the chain length of the alkylcarbamoyl residue and the structure of the polar head group. Derivatives with pentadecyl and octadecylcarbamoyl structure emerged effective inhibitors. The best activity was observed by dimethylaminopyridinium, analogues with a P-N distance of 3 or 4 methylene groups and pentadecyl or octadecylcarbamoyl structure (IC50 = 1.0-1.6 mumol/l).

Blood Platelets↗
PubMed1991

Inhibition of PAF-induced human platelet responses by newly synthesized ether phospholipids.

A series of 10 analogues of platelet-activating factor (PAF) was evaluated for proaggregatory and inhibitory behaviour on human blood platelets in vitro. Most of the compounds did not activate platelets but inhibited the PAF-induced aggregation. The inhibition was concentration-dependent and selective for PAF. Platelet responses to ADP and collagen were not suppressed. Schild analysis of the aggregation data was consistent with a simple competitive antagonism. The pA2 of the most effective antagonist (1-O-hexadecyl-2-O-ethylglycero-3-phosphoric acid-6'-(1-chinuclidinium)-hexylester) was 5.96. There is also evidence for its ability to inhibit the high affinity binding of [3H]PAF to the platelet receptors.

Adenosine Diphosphate↗
PubMed1991

Synthesis and proaggregatory activity of 1-O-(2-methyloctadecyl)-2-O-acetyl-rac-glycero-3-phosphocholine.

Racemic 1-O-(2-methyloctadecyl)-2-O-acetyl-glycero-3-phosphocholine, a branched chain PAF species, was prepared by chemical synthesis and investigated for biological activity on human blood platelets in vitro. The synthesis started from 2-O-benzylglycerol and 2-methyloctadecyl-1-methyl sulfonate and was accomplished in five reaction steps. A comparison with 'octadecyl-rich' PAF showed that the PAF species described here exerts a 22-fold weaker proaggregatory activity. Based on [3H]PAF-binding studies, an obstruction of PAF-binding or the signal transduction by the branched alkyl chain in C-1 position of the glycerol backbone is suggested.

Humans↗
PubMed1991

Effects of the synthetic ether phospholipid KO-286011 on cells and components of rabbit blood.

The ether phospholipid KO-286011, which is related to platelet-activating factor (PAF), was examined for PAF-antagonistic action on rabbit platelets both in vitro and ex vivo. It inhibited the aggregation of washed platelets induced by PAF (5 nmol/l) concentration dependently (IC50 = 6.5 X 10(-7) mol/l). After injecting 0.5 mg/kg to rabbits, the ex vivo PAF-mediated aggregation in heparinized platelet-rich plasma was influenced selectively. The inhibition was short and maximal after 5 min. In contrast, hematocrit, counts of peripheral platelets and leukocytes, hemoglobin content, partial thromboplastin time, prothrombin time, and fibrinolytic activity in plasma were not affected. However, the therapeutic range of KO-286011 is limited because of membranolytic activity at higher dosages, leading to hemolysis and drop of circulating platelet counts.

Animals↗
PubMed1991

Species-dependent differences of high affinity [3H]PAF-binding to platelets from humans and pigs and its inhibition by selected antagonists.

The sensitivity of blood platelets towards PAF (1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine) strongly varies with species and is primarily responsible for different pathophysiological effects after its administration to experimental animals. Platelets from domestic pigs were shown to possess one single class of high-affinity PAF-binding sites. Receptor density and sensitivity of pig platelets towards PAF were distinctly higher than those from humans. Preincubation of platelets from both species with PAF-specific antagonists diminished the high affinity [3H]PAF-binding concentration-dependently. Eight PAF-related antagonists, the ginkgolide BN 52021, as well as the hetrazepine WEB 2086 were included and mean inhibitory concentrations (IC50) between 0.09 and 124 mumol/l ascertained. Comparing the rank order of inhibitory potency considerable differences became evident between both species. The quotients of the IC50 values obtained with human and pig platelets differed for about two orders of magnitude. Moreover, the inhibitory profile of the PAF-related antagonists was found to be highly sensitive to small structural changes. Based on these findings a species-dependent difference at the PAF receptor level of platelets from pigs and humans is suggested.

Animals↗
PubMed1991

[PAF-antagonists with a phospholipid structure. 1. Phospholipids with hetero-arene head groups: synthesis, characterization and determination of the action of structural elements].

A series of analogues of platelet-activating factor (PAF) with heteroarene head groups have been synthesized, and tested for biological activities on blood platelets in vitro. In comparison with PAF most of the structural modifications exerted weak proaggregatory effects. The 4-(dimethylamino)pyridinium compound did not activate platelets but inhibited selectively PAF-induced platelet responses. These results point to a crucial role of the distance between the phosphoryl group and polar head for expression of PAF-antagonistic properties. Structural features of PAF-antagonist have been investigated by two-dimensional proton NMR spectroscopy, and proposed a model with three-dimensional structure.

Blood Platelets↗
PubMed1991

[PAF-antagonists with phospholipid structure. 2. Phospholipids with heteroarene head groups and variations of the phosphorus-nitrogen distance; synthesis, characterization and structure-activity relationships].

A series of 27 PAF-analogues with heteroarene head groups and variation of the P-N-distance on the C-3-position of the backbone were synthesized, and the PAF-antagonistic activity on human blood platelets in vitro was evaluated. Investigation of structure-activity relationships revealed that PAF-antagonistic activity is strongly influenced by the 4-(Dimethylamino)-pyridine as polar head base and the distance between phosphate group and onium center. Maximal activity was observed with a chain length of 3 or 4 methylene groups. Among the compounds tested, 1-O-Hexadecyl-2-n-propylpropan-1,3-diol-3-phosphoric acid-4'-[4-(dimethylamino)pyridinium]butylester was the most effective inhibitor in the in vitro assay (KB = 0.3 mumol/l).

Chromatography, Thin Layer↗
PubMed1991

[PAF-antagonists with phospholipid structure. 3. Phospholipids with heterocyclane head groups and variations of the phosphorus-nitrogen distance; synthesis, characterization and structure-activity relationship].

A series of 13 PAF-analogues with heterocyclane head groups and variation of the P-N-distance on the C-3-position of the backbone were synthesized. The proaggregatory and inhibitory potencies on rabbit and human blood platelets in vitro was evaluated. Investigations of structure-activity relationship revealed that the PAF-inhibitory potency is strongly influenced by the distance between phosphate and onium center and the structure of the heterocyclane. Derivatives with a P-N-distance of 4 or more methylene groups emerged effective inhibitors. The best activity was observed by chinuclidine- and N-methylpiperidine analogues with a chain length of 6 methylene groups (KB = 1.1 to 2.3 mumol/l).

Animals↗
PubMed1990

Platelet-activating factor (PAF) inhibitory profile of KO-286011 on blood platelets in vitro and in vivo.

A newly synthesised structural analogue of PAF, coded KO-286011 (1-O-hexadecyl-2-O-ethyl-rac-glycero-3-phosphoric acid 4-(N,N-dimethylamino)pyridinium butylester), was proved for its ability to inhibit PAF-mediated platelet responses in vitro and in vivo. The compound inhibited effectively the PAF-induced aggregation and secretion of human and rabbit platelets. In contrast, there was little influence on ADP-, collagen-, and arachidonic acid-triggered platelet responses. Schild-analysis of aggregation data ascertained in human platelet-rich plasma was consistent with a simple competitive antagonism and yielded a pA2 of 6.44. Proaggregatory activity of KO-286011 was excluded turbidimetrically as well as by means of a single cell counting technique. [3H]PAF binding studies provided evidence that KO-286011 exerts its inhibitory action at the PAF-receptor level. A significant inhibition of the ex vivo PAF-induced platelet aggregation was found after i.v. administration of 0.5 mg/kg KO-286011 to rabbits. The effect was most pronounced 5 min after dosing the inhibitor and detectable over a period of 30 min. Intravenous administration of 10 and 25 micrograms/kg KO-286011 to guinea pigs prevented dose-dependently the PAF-induced formation of thromboxane A2. The PAF-inhibitory action of KO-286011 was more potent than that of the ginkgolide BN 52021.

Animals↗
PubMed1990

[Aggregative behavior and calcium content of platelets in thrombocythemia and thrombocytosis].

Patients with thrombocythaemia due to myeloproliferative disorders (n = 21), with secondary thrombocytosis of various origin (n = 16), and a control group of healthy donors (n = 20) were investigated with respect to the aggregation behaviour and the total calcium content of blood platelets. The calcium content was significantly lower in both groups of patients as compared to controls (2 p less than 0.001). In 16 of 21 patients with myeloproliferative disorders platelet rich plasma did not respond to epinephrine (15 mumol/l), a concentration which induced at least weak aggregation in 14 of 16 patients with secondary thrombocytosis and also in healthy subjects. In patients with thrombocythaemia the mean extent of aggregation induced by epinephrine, collagen or adenosin diphosphate was significantly lower as compared to controls (2 p less than 0.001).

Adenosine Diphosphate↗
PubMed1989

[Megakaryocytic myelosis--clinical aspects, morphology and platelet function].

The study reviews 22 patients, aged between 19 to 73 years, with megakaryocytic myelosis. In the course of the disease 11 patients presented haemorrhagic manifestations, 12 patients thrombotic complications, and 6 patients the association of haemorrhage and thrombosis. The maximum platelet counts ranged from 524 to 2700 x 10(9)/l. The bone marrow showed a conspicuous megakaryocytic proliferation with polyploidy of the nuclei, giant forms and clusters. Marked alterations of erythro- and granulopoiesis were excluded. There was no evidence for a reactive thrombocytosis in any case. Patients with thrombocythaemia due to megakaryocytic myelosis (n = 14), with secondary thrombocytosis of various origin (n = 16), and a control group of healthy donors (n = 20) were investigated with respect to the aggregation behaviour and the total calcium content of blood platelets. In 9 of 14 patients with megakaryocytic myelosis platelet rich plasma did not respond to epinephrine (15 mumol/l), a concentration which induced at least weak aggregation in 14 of 16 patients with secondary thrombocytosis and also in healthy subjects. In patients with megakaryocytic myelosis the mean extent of aggregation induced by epinephrine, collagen or adenosine diphosphate was significant lower as compared to controls whereas in patients with secondary thrombocytosis in most cases this parameter did not differ significantly from that of controls. The total calcium content of platelets was significantly lower in both groups of patients as compared to controls. In 14 patients with megakaryocytic myelosis the concentration of the glycoprotein (GP) IIb-IIIa complex was estimated by crossed- and rocket-immunoelectrophoresis and found to be decreased in 8 of them.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Blood platelet behaviour in patients with a type I diabetes mellitus.

Platelets appear to be involved in the development of vascular diseases in diabetic patients. In a number of studies, platelet adhesion and aggregation has been found to be enhanced in diabetic patients indicating a platelet hyperreactivity. However, contradictory results on hyperreactivity of diabetic platelets towards agonists published in the literature leading to the problem of reliability of agonist-induced aggregation as a parameter which is able to reflect an altered platelet reactivity. Therefore, we introduced the quantification of actin filaments of platelets as an early indicator of platelet hyperreactivity. In 20 patients with type I diabetes mellitus agonist-induced aggregation, spontaneous aggregation, malondialdehyde (MDA)-formation, plasma lipid status and the ability of plasma to degrade platelet activating factor (PAF) as well as the G- to F-actin equilibrium of platelets were assayed. Compared to an age- and sex-matched control group F-actin values, spontaneous aggregation and PAF-hydrolase were significantly increased in diabetic patients.

Actin Cytoskeleton↗
PubMed1989

The contribution of individual lipoproteins to the degradation of platelet-activating factor in human serum.

Platelet-activating factor (PAF) is rapidly degraded in vivo by the action of a specific acetylhydrolase. Measuring the PAF-acetylhydrolase activity in serum from 12 healthy volunteers a maximum velocity of 67.2 +/- 11.8 nmol/min X ml and a Km value of 15.8 +/- 2.9 mumol/l were ascertained. More than 90% of the activity was found to be associated with lipoproteins. It was detected in isolated VLDL, LDL, Lp(a) as well as HDL2 but not in HDL3. The PAF-acetylhydrolase activities associated with the various lipoproteins were shown to behave like a unique enzyme with distinct kinetic properties. Because VLDL and LDL were found to take up about 5 and 2.5 times more PAF with respect to their mass than HDL, it is concluded that lipoproteins affect the PAF-acetylhydrolase activity at the level of substrate presentation. As a consequence of the distinct kinetic properties, the lipoprotein-associated PAF-acetylhydrolase activities do not contribute proportionately to the degradation of PAF in serum. The latter is shown to depend primarily on the amount of PAF-acetylhydrolase bound to the apoprotein B-containing lipoproteins.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1989

Enhanced degradation of platelet-activating factor in serum from diabetic patients.

The degradation of platelet-activating factor (PAF) and lipid concentrations were measured in sera from 20 patients with insulin-dependent diabetes mellitus and from 20 age- and sex-matched healthy volunteers. The PAF-degrading capacity as well as triglycerides and total and very low density and low-density lipoprotein cholesterol were found to be significantly increased in the patients group, whereas the difference observed in high-density lipoprotein cholesterol was statistically nonsignificant. There were also a series of close relationships between the degradation of PAF and some lipid variables in the control group. These results confirm the parallel changes of lipoproteins and PAF-degrading capacity described previously in serum from atherosclerotic patients and extend it to patients suffering from diabetes mellitus.

Adult↗
PubMed1989

Apolipoproteins as risk indicators of ischemic heart disease.

About 50% of the individuals with a coronary risk show lipid levels within the normal range. Therefore, apolipoprotein profiles could be better risk indicators than TC or TG. Apolipoproteins generally discussed in this context are apo A1, apo B, and apo E. Their diagnostic validity, however, is ambigously evaluated. The individual iso-protein pattern of apo E is important for the differential diagnosis of the type III hyperlipidemia with its strong predisposition for premature atherosclerosis. Moreover, the extent of the apo E sialylation seems to be important because the modification of apo E by sialic acid alters its metabolism. Our date provide evidence that in IDDM and NIDDM the degree of apo E sialylation is increased. Concerning apo A1 and B we tried to find out parameters suitable for the prediction of the coronary risk both in the hyperlipidemic and the normolipidemic state. 64 male survivors of a myocardial infarc"ion and 60 matched controls were included in the study (group I). From group I a supopulation showing non-pathological values for TC and TG was selected (group II with 31 survivors and 44 controls). The diagnostic validity of the parameters apo A1, apo B, TC, HDL-C, apo A1/apo B, TC/apo B, HDL-C/apo B, TG, TG/apo A1, TG/HDL-C, TC-HDL-C/apo B determined by calculation of their sensitivities, specificities, efficiencies, and predictive values. Only the parameters TC/apo B, HDL-C/apo B, and apo B were suitable in the order given for detection of the coronary risk. Using the TC/apo B ratio 71-76% of the controls and 79% of the survivors could be exactly reclassified independent of the group they belonged to.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins↗
PubMed1989

[Assay of fructosamine. Value and limits in diabetology].

Fructosamine test using a Nitroblue Tetrazolium (NBT) method offers many advantages: quickness, reproducibility, easy automation and unexpansiveness, but a standardization of the different methods is needed. The results can be expressed in absolute value of equivalent DMF per liter, except in pregnancy where mumol per g of protein is used. The interpretation of the results can be difficult in case of quantitative and/or qualitative proteins abnormalities: icterus and severe chronic renal insufficiency. Fructosamine is significantly higher in diabetic patients. It gives a good correlation with glycated haemoglobin but the provided information is different, concerning a shorter period of 2 to 3 weeks and perhaps more sensitive to recent glycaemic variations. Fructosamine test does not seem to be a good screening test for diabetes and impaired glucose tolerance. The test indications of the assay could be: situations where the dosage of glycated haemoglobin is not interpretable, diabetic pregnancy follow-up and short term evaluation of a therapeutic change on glycaemic control. However, the individual significance of fructosamine concentration remains to be assessed and seems to be less accurate than glycated albumin.

Biological Assay↗