PubMed Health⌕ Search

Biomedical subjects

J Kienast

Publications and source records attributed to J Kienast.

At least 73 records · Page 4Linked to original sources
PubMed1993

Relation of fibrinogen to presence and severity of coronary artery disease is independent of other coexisting heart disease. The ECAT Angina Pectoris Study Group.

Six hundred fifty seven patients with angina pectoris underwent coronary angiography after measurement of plasma fibrinogen levels. Coronary artery disease (CAD) was angiographically confirmed in 75% of the patients. Other cardiac disease, either alone or in combination with CAD, was diagnosed in 8% and 11% of cases, respectively; 17% of the patients had no evidence of overt heart disease. Fibrinogen concentrations showed a graded increase according to the severity of coronary stenosis (p = 0.02) but were not significantly associated with any other cardiac heart disease. However, patients with valvular heart diseases had on average a 5.9% elevation of fibrinogen levels as compared to patients without proven cardiac disease (p = 0.08), similar to the observed 6.9% increase for CAD (p = 0.005). On average, patients with cardiomyopathies or pulmonary hypertension had only a 1.6% or 1.2% increase, respectively. The increase in fibrinogen levels associated with CAD was similar in patients with and without coexisting heart diseases. The results demonstrate a significant positive relation of fibrinogen to the presence and severity of CAD irrespective of a possible confounding influence from other cardiac diseases. The results therefore lend support to the hypothesis of a pathogenetic role for fibrinogen as a cardiovascular risk factor.

Coronary Angiography↗
PubMed1993

Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. European Hirudin in Thrombosis Group.

OBJECTIVES: The purpose of this study was to investigate the biologic efficacy and pharmacokinetics of different doses of recombinant hirudin administered in single or repeated subcutaneous injections in healthy volunteers. BACKGROUND: Hirudin is a highly specific inhibitor of thrombin, the pivotal enzyme in thrombosis. Differences between hirudin and heparin in experimental animals indicate that hirudin may be a superior antithrombotic drug in humans. METHODS: The biologic effect of recombinant desulfato-hirudin (CGP 39393) administered as single or repeated (every 8 h for 3 days or every 12 h for 6 days) subcutaneous injections was studied in 231 healthy human volunteers. RESULTS: Single subcutaneous doses of 0.1, 0.2, 0.3, 0.4, 0.5 and 0.75 mg/kg body weight in 195, 8, 12, 8, 4 and 4 volunteers, respectively, prolonged the activated partial thromboplastin time in a dose-proportional fashion within the 1st 30 min, with a near-maximal effect for 3 to 4 h after the dose. The mean activated partial thromboplastin time increased to 1.48 and 1.93 times baseline values 30 min after single subcutaneous injections of 0.2 and 0.4 mg/kg of CGP 39393, respectively. There was a linear relation over a wide range between the activated partial thromboplastin time prolongation and plasma concentrations of CGP 39393. Plasma clearance was between 1.5 and 1.7 ml/min per kg. The subcutaneous administration of 0.3 and 0.5 mg recombinant hirudin three times a day for 3 days or two times a day for 6 days prolonged the activated partial thromboplastin time by 1.71 to 1.69 and 1.78 to 1.92 times baseline levels, respectively, with the preinjection values maintained in the hypocoagulable range. No prolongation of bleeding time was measured at peak plasma hirudin levels. Because thrombin and prothrombin times are not able to reflect high or low CGP 39393 concentrations, respectively, neither test is suitable for monitoring administration of this drug. CONCLUSIONS: CGP 39393 appears to be well tolerated in volunteers, even after repeated doses. The activated partial thromboplastin time test seems to be well suited to monitor the anticoagulant effect of recombinant hirudin because the dose effect is linear up to 0.5 mg/kg of subcutaneous CGP 39393. The prolongation of activated partial thromboplastin time after subcutaneous injection of CGP 39393 shows a plateau lasting for 3 h. Further studies are now required to determine the dose that will provide the best antithrombotic effect and the lowest bleeding tendency in arterial or venous thrombosis indications.

Biological Availability↗
PubMed1993

Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers.

Clinical pharmacology of the intravenously administered recombinant desulfatohirudin CGP 39393 was investigated in 47 healthy volunteers in a multicenter study. Mean peak concentrations after bolus injections of 0.1, 0.3, 0.5, and 1.0 mg/kg were 154, 443, 764, and 1,691 nmol/L, respectively. Intravenous infusions of 0.1 mg/kg/h for 6 h and of 0.2 and 0.3 mg/kg/h for 6 h and 72 h resulted in mean steady-state levels of 78, 227, and 312 nmol/L. Elimination was multiexponential and dose independent. Concordant pharmacokinetic parameters were obtained from both i.v. bolus and infusion experiments (overall average total plasma clearance, 2.20 ml/min/kg; mean residence time, 2.12 h; volume at steady state, 0.27 L/kg). Thrombin inhibition by CGP 39393 was demonstrated ex vivo by the thrombin chromogenic assay (TCA), by activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT). Following a parabolic function APTT doubled and quadrupled at CGP 39393 concentrations of 100 and 1,000 nmol/L, respectively. Whereas TTs (bovine thrombin 3 or 6 IU/ml) were very sensitive to low CGP 39393 levels with unmeasurable clotting times at CGP 39393 concentrations greater than 30 and 60 nmol/L, PT was prolonged by a factor of only 1.3 above baseline at 300 nmol/L. APTT appears to be most suitable for monitoring the anticoagulant effect of CGP 39393 over a broad concentration range. The drug was well tolerated without clinically relevant bleeding episodes or other adverse events.

Adult↗
PubMed1993

[Blood coagulation and fibrinolysis].

A detailed understanding of the hemostatic process and the pathogenesis of thrombosis provides the basis for the development of more selective and potentially more efficient antithrombotic agents. These may allow to tailor antithrombotic treatment strategies for specific disease entities according to relative risk and prevailing pathogenetic mechanisms. Conversely, the use of selective pharmacological inhibitors has become an indispensable tool in experimental hemostasis and thrombosis research. Recent advances in the field have prompted profound reappraisal of concepts and hypotheses related to blood coagulation, thrombogenesis and the biologic role of the plasminogen activator-plasmin system. The present article will focus on the various mediator functions of thrombin, on the key role of tissue factor in the initiation of blood coagulation, and on the potential relevance of the tissue factor pathway inhibitor (TFPI).

Blood Coagulation↗
PubMed1992

[Platelet inhibitors or anticoagulants in prevention after myocardial infarct? The 1991 state of the art].

Recent clinical studies and an indication according to the severity degree provide new insight into the antithrombotic prevention with antiplatelet substances or oral anticoagulants in patients after myocardial infarction. After uncomplicated infarction 0.3-0.5 g acetylsalicylic acid are able to reduce both the reinfarction rate and mortality. Cardiogenic emboli in patients with nonrheumatic atrial fibrillation may be prevented by oral anticoagulants even in reduced dosage (INR 1.5-2.5). Oral anticoagulants in usual dosage may be applied in patients with a complicated course after infarction, i.e. with established intracardial thrombi, with aneurysm or myocardial akinesia, with dilated, large left ventricle or with atrial fibrillation. So far, controlled clinical studies comparing reduced oral anticoagulation and antiplatelet drugs to reduce the reinfarction rate and mortality do not exist. Meanwhile, new anticoagulant drugs, such as hirudins or synthetic thrombin inhibitors are under clinical investigation.

Administration, Oral↗
PubMed1990

Guanine nucleotide-dependent inhibition of phospholipase C in human endothelial cells.

Treatment of intact human umbilical vein endothelial cells with NaF results in a dose-dependent biphasic response in both prostacyclin and inositol phosphate production: the stimulation observed with 10-20 mM NaF decreases with higher concentrations. High concentrations of NaF furthermore reduce thrombin- or A23187-stimulated prostacyclin production. Direct assay of phospholipase C activity in cell homogenates shows a similar biphasic response to NaF, also after chelation of Ca2+; addition of AlCl3 shifts the inhibition toward lower NaF concentrations. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) also causes a dose-dependent biphasic response in inositol phosphate formation in permeabilized cells and homogenates; a higher inhibitory concentration of GTP gamma S abolishes the stimulation of inositol phosphate production by low NaF concentrations. A high concentration of NaF furthermore inhibits the non-G-protein-dependent activation of phospholipase C by deoxycholate. NaF also induces a dose-dependent biphasic response in cyclic AMP formation in intact cells, indicating that the inhibition of phospholipase C at higher NaF concentrations does not result from a rise in cyclic AMP. The data are compatible with the existence of a guanine nucleotide-dependent, cyclic AMP-independent, phospholipase C-inhibitory pathway in endothelial cells.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Flow cytometric analysis of thiazole orange uptake by platelets: a diagnostic aid in the evaluation of thrombocytopenic disorders.

Thiazole orange (TO), a fluorescent dye originally synthesized for reticulocyte analysis, is characterized by a large fluorescence enhancement and high quantum yield on binding to nucleic acids, particularly RNA. In addition, the dye readily permeates live cell membranes. We applied TO staining, followed by fluorescence-activated flow cytometric analysis, to platelets in whole blood samples from hematologically normal subjects and patients with various quantitative platelet disorders. The percentage of TO-positive platelets in 50 control subjects was 8.6 +/- 2.8% (mean +/- SD) ranging from 2.8% to 15.8%. In 21 thrombocytopenic patients whose bone marrow contained normal to increased numbers of megakaryocytes, the percentage of fluorescently labeled platelets was significantly elevated (P less than .0001) to 26.9 +/- 10.9% (range, 13.3% to 57.1%). In contrast, the proportion of positively stained platelets in 23 patients with thrombocytopenia due to impaired platelet production (various conditions with reduced marrow megakaryocytes) did not significantly differ from the controls, whereas the absolute counts of TO-positive platelets were significantly lowered (P less than .0001). Differences in the distributions of the percentage values as well as of the absolute counts for TO-positive platelets between the two patient groups were again highly significant (P less than .0001). Both the sensitivity and the specificity of this method in distinguishing between these categories of thrombocytopenia were greater than or equal to 95%. We conclude that flow cytometric analysis of platelets after staining with TO is a sensitive and specific test that rapidly provides information on the thrombopoietic activity in thrombocytopenic disorders. Our data further suggest that increased amounts of residual RNA characterize platelets released under conditions of "stress thrombopoiesis."

Benzothiazoles↗
PubMed1990

Non-receptor-mediated refractoriness in prostacyclin production by human endothelial cells in a continuous flow system is delayed by a low-molecular-weight plasma fraction devoid of reducing cofactors for peroxidase-catalysed reactions.

Using a microcarrier perfusion model, we have investigated the effects of a low-molecular-weight plasma fraction (mol. wt. less than 10,000) on the capacity of human umbilical vein endothelial cells (HUVECs) to synthesize and release prostacyclin (PGI2) during repeated stimulation with either calcium ionophore A23187 or arachidonic acid (AA). This plasma fraction (filtrate 10,000), which has recently been shown to contain most of the activity previously referred to as 'prostacyclin regulating plasma factor', delayed the exhaustion of the PGI2 generating capacity of the HUVECs during repeated stimulation with either inducer. No such effect was seen with whole plasma. The PGI2 regulatory activity of the filtrate was not significantly affected by removal of reducing cofactors for peroxidase-catalysed reduction of hydroperoxides, accumulation of which inhibits cyclooxygenase. In contrast, albumin added to the filtrate abolished its protective effect on endothelial PGI2 synthesis. We conclude that low-molecular-weight plasma constituents partially preserve the PGI2-generating capacity of human vascular endothelium during repeated stimulation. Under continuous flow conditions, as applied in our study, this effect appears not to be related to reducing cofactor activity for peroxidase-catalysed reactions. In whole plasma, this PGI2 regulatory activity may be partially masked by the presence of plasma proteins.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

[Anti-phospholipid antibody with recurrent venous thromboembolism and severe autoimmune thrombocytopenia].

A 51 year-old man with a history of deep venous thromboses and recurrent pulmonary embolism on long-term anticoagulant treatment was admitted to our department because of insidious onset thrombocytopenia. He had neither a history nor clinical signs of abnormal bleeding. On admission, the platelet count was reduced to 21 x 10(9)/l, platelet associated IgG was increased, and bone marrow specimens showed megakaryocytic hyperplasia. Platelet survival was slightly shortened with enhanced platelet sequestration in a normal size spleen. Laboratory evaluation after discontinuation of anticoagulant treatment revealed persisting prolongation of both the prothrombin time and the activated partial thromboplastin time which could be attributed to the presence of a lupus-type circulating anticoagulant. Further relevant laboratory findings included an elevated titer of IgG anti-cardiolipin antibodies and a reduced euglobulin clot lysis activity after venous occlusion due to increased plasminogen activator inhibitor activity. In recent years, it has become apparent that a striking correlation exists between the presence of antibodies to phospholipids and thromboembolic disease and immune thrombocytopenia respectively. The present case report on the association of these autoantibodies with both, recurrent venous thromboembolism and severe thrombocytopenia, supports the hypothesis that anti-phospholipid antibodies may play a crucial part in the pathogenesis of these clinical conditions. A reduced vascular fibrinolytic capacity may be involved in the thrombophilic state induced by anti-phospholipid antibodies.

Autoantibodies↗
PubMed1987

Sodium fluoride mimics effects of both agonists and antagonists on intact human platelets by simultaneous modulation of phospholipase C and adenylate cyclase activity.

Using intact human platelets, we studied the effect of sodium fluoride (NaF) on platelet aggregation and release reaction and correlated the functional changes to intracellular events specific for either agonist-induced or antagonist-induced platelet responses. At lower concentrations, with a peak activity between 30 and 40 mmol/L, NaF induced aggregation and release of adenosine 5'-triphosphate (ATP) that was associated with increased formation of inositol phosphates, a rise in cytosolic free Ca2+, and phosphorylation of 20-kd and 40-kd proteins. At NaF concentrations greater than 40 mmol/L, aggregation and ATP release decreased dose-dependently in parallel with a decrease in Ca2+ mobilization, whereas neither inositol phosphate formation nor 40-kd protein phosphorylation was reduced. At these concentrations, NaF caused a dose-dependent transient rise in platelet cyclic adenosine 3',5'-monophosphate (cAMP) levels that was sufficient to account for the observed reduction in Ca2+ mobilization, aggregation, and ATP release. Stimulated cAMP levels started declining rapidly within 30 seconds of addition of NaF, however. Similarly, prostacyclin (PGI2)-induced cAMP accumulation was temporarily enhanced but subsequently suppressed by NaF, suggesting either stimulation of a cAMP phosphodiesterase or delayed inhibition of adenylate cyclase. Evidence for the latter was provided by the finding that NaF pretreatment of platelets resulted in partial inhibition of PGI2-stimulated cAMP formation in the presence of the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (MIX). We conclude that NaF exerts a dual (stimulatory and inhibitory) effect on adenylate cyclase in intact platelets that is accompanied by simultaneous activation of a phosphoinositide-specific phospholipase C; in addition, a cAMP phosphodiesterase may be activated.

Adenosine Triphosphate↗