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Biomedical subjects

H Darius

Publications and source records attributed to H Darius.

At least 73 records · Page 4Linked to original sources
PubMed1995

Platelet receptor desensitization induced by elevated prostacyclin levels causes platelet-endothelial cell adhesion.

OBJECTIVES: The purpose of this study was to investigate the role of platelet prostacyclin receptor desensitization in platelet-endothelial cell adhesion. BACKGROUND: Platelet-endothelial cell adhesion is regulated by endothelial cell-derived mediators, such as prostacyclin and endothelium-derived relaxing factor. Prostacyclin activates platelet adenylate cyclase and augments cyclic adenosine monophosphate formation by way of specific membrane receptors. Platelet exposure to prostacyclin or chemically stable analogs results in a time- and dose-dependent prostacyclin receptor desensitization as it occurs during infusion therapy with prostacyclin analogs or in pathophysiologic situations such as acute myocardial infarction. METHODS: Adhesion of washed and radiolabeled human platelets stimulated with thrombin to cultured umbilical vein endothelial cells was measured under control conditions and under conditions of platelet prostacyclin receptor desensitization induced by incubation with the prostacyclin analog iloprost (10 to 100 nmol/liter) for 3 h. RESULTS: Thrombin (0.08 to 0.2 U/ml) increased platelet adhesion in a dose-dependent manner from 2.7 +/- 0.3% to 6.4 +/- 0.6% (mean value +/- SEM). Preincubation of platelets resulted in a dose-dependent down-regulation of 3H-iloprost binding up to 58.8 +/- 6.7% of control platelets with 100 nmol/liter of iloprost. Co-incubation of prostacyclin receptor-desensitized platelets with endothelial cells resulted in a marked augmentation of thrombin-induced adhesion up to 28.6 +/- 4.5%. Approximately the same increase in platelet adhesion was seen after complete abrogation of endothelial cell prostacyclin synthesis by pretreatment with aspirin. Comparison of iloprost-induced receptor desensitization and increased platelet-endothelial cell adhesion indicated a positive correlation. CONCLUSIONS: Platelet prostacyclin receptor desensitization was observed in humans in vivo during acute myocardial infarction or during therapeutic administration of prostacyclin analogs. In vitro platelet prostacyclin receptor desensitization caused a marked augmentation of platelet-endothelial cell adhesion. This increase in adhesion might result in an enhanced tendency toward thrombus formation in humans.

Blood Platelets↗
PubMed1995

Genetic differentiation of Aedes aegypti, the vector of dengue virus in French Polynesia.

In recent years the incidence of dengue fever epidemics has increased and transmission has tended to be established over a geographically expanding area, including French Polynesia. An increase in air transportation contributes to the diffusion of the dengue virus from Southeast Asia, a region considered to be a hyperendemic dengue zone, to the Pacific region. Presently, little is known about the role of the vector (Aedes aegypti) in the diffusion of the dengue fever virus. A study on the genetic structure of vector populations was conducted using allozyme polymorphism. This study showed a low level of genetic exchange between mosquito populations on different islands. It is concluded that the occurrence of dengue hemorrhagic fever in French Polynesia during the last few years was likely due to the dispersal of the dengue virus via viremic people rather than via infected vectors.

Aedes↗
PubMed1994

Inhibition of human platelets and polymorphonuclear neutrophils by the potent and metabolically stable prostaglandin D2 analog ZK 118.182.

The actions of the novel metabolically stable and selective prostaglandin D2 receptor agonist ZK 118.182 ((5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-15- hydroxy-16,17,18,19,20-pentanor-3-oxa-5,13-prostadienoic acid) were studied in human platelets and polymorphonuclear neutrophils in vitro and compared to the naturally occurring agonist prostaglandin D2. ZK 118.182 inhibited collagen and ADP induced platelet aggregation more potently than prostaglandin D2 (IC50: 15 nM versus 60 nM) but was less effective than the stable prostacyclin mimetic iloprost (IC50: 3 nM). The same rank order of potencies was observed for the inhibition of collagen-induced platelet ATP secretion. A dose-dependent activation of adenylate cyclase could be demonstrated by ZK 118.182 which was comparable to that of prostaglandin D2 with respect to the concentration needed for half maximal stimulation (ED50) maximal cAMP level achievable. ZK 118.182 also dose dependently reduced the formyl-methionyl-leucyl-phenylalanine (FMLP) or platelet-activating factor (PAF) induced activation of polymorphonuclear neutrophils. Both, the oxygen burst resulting in the generation of superoxide anions and the degranulation of polymorphonuclear neutrophils accompanied by release of the lysosomal enzyme beta-glucuronidase, were significantly and dose dependently inhibited. ZK 118.182 was more potent than prostaglandin D2 in inhibiting polymorphonuclear neutrophil activation in all tests performed. In summary, ZK 118.182 is a prostaglandin D2 mimetic exerting potent inhibitory effects on human platelets and polymorphonuclear neutrophils.

Adenosine Triphosphate↗
PubMed1993

Synergistic platelet antiaggregatory effects of the adenylate cyclase activator iloprost and the guanylate cyclase activating agent SIN-1 in vivo.

The aim of our study was to evaluate the platelet antiaggregatory and hemodynamic effects of the stable prostacyclin analog iloprost and the NO-donor SIN-1, an active metabolite of molsidomine. The number of circulating platelets was determined in anesthetized male Wistar rats as a measure of in vivo platelet aggregation. Platelet count decreased from 648 +/- 25 to 476 +/- 15 x 10(3) platelets/microliter and from 578 +/- 36 to 411 +/- 40 (mean +/- SEM) in response to two repetitive injections of collagen (70 micrograms/kg body weight). Treatment with SIN-1 bolus injections (0.3 or 1 mg/kg bw) and/or continuous i.v. infusion of iloprost (0.2 or 0.4 micrograms/kg bw/min) was initiated 15 min before the second collagen bolus. As a single agent, SIN-1 did not influence platelet count. Iloprost at 0.2 micrograms/kg/min reduced platelet aggregation (PA) by 15.5%, and at 0.4 micrograms/kg/min by 27.1% (p = n.s.). When iloprost (0.2 micrograms/kg) and SIN-1 (0.3 mg/kg) were administered simultaneously, PA was suppressed by 56.2%, iloprost at 0.4 micrograms/kg/min and SIN-1 at 0.3 mg/kg were even more effective and inhibited PA synergistically by 64.9% (p < 0.05). A statistically significant decrease in mean arterial blood pressure (MABP) was seen in response to all SIN-1 and iloprost groups. However, the vasorelaxant effect of both agents given simultaneously was not synergistic but less than additive. In conclusion, iloprost and SIN 1 exert synergistic platelet inhibitory effects in vivo. In contrast, the decrease in MABP is less then additive. These results are of major interest for the therapeutic regimen with NO-donors (nitrovasodilators).

Adenylyl Cyclase Inhibitors↗
PubMed1993

[Revascularization measures after acute myocardial infarct].

Thrombolytic therapy in acute myocardial infarction reduces mortality significantly. This acute effect seems to be counterbalanced by the increased mortality during follow-up whether or not the patient has been treated with thrombolytic therapy. Thrombolysis seems to be a first step in the treatment of acute myocardial infarction. Revascularization procedures are able to improve patient prognosis. Long-term follow-up demonstrated this fact whether or not PTCA was performed in the acute setting or on an elective basis. The 6-year survival was 80%. This survival rate was higher for patients who underwent PTCA than for those who were not undergoing PTCA and those who had no reperfusion of the coronary artery. The best prognosis was found for patients with coronary bypass surgery, indicating that revascularization should be the aim of treatment. The 6-year survival rate was found to be 92% and is thus in the range of patients with coronary artery disease. Acute infarct PTCA is limited to patients with cardiogenic shock and is particularly useful for patients with occlusion of the main stem of the left coronary artery. Acute infarct PTCA is also recommended in patients with contraindications for thrombolytic therapy, when interventions can be performed rapidly, when a large infarct size is present and infarct time is less than 4 hours. Whether or not RESCUE-PTCA should be recommended is under investigation. Patients with an open coronary artery have a better prognosis than patients with occluded coronary arteries, but during the acute stage, spontaneous recanalization is present in many patients. The RESCUE study will address this question. Elective PTCA is recommended as well as coronary bypass surgery, when successful reperfusion is achieved and one-or two-vessel disease is present or there is a two- or three-vessel disease or main stem involvement, respectively. In patients with coronary lesions less than 70% conservative treatment is useful. The guidelines of the American College of Cardiology and the American Heart Association are strongly recommended.

Angioplasty, Balloon, Coronary↗
PubMed1992

Synergistic platelet inhibitory effect of the phosphodiesterase inhibitor piroximone and iloprost.

Platelet activity is regulated through synthesis and degradation of the intracellular second messengers cAMP or cGMP. The antiplatelet effect of the phosphodiesterase (PDE) III inhibitor Piroximone (PIR) was studied in vitro in platelet rich plasma. ADP induced aggregation was inhibited by PIR with an IC50 of 67 +/- 43 microM. The inhibitory effect was time and dose dependent. The antiaggregatory effects in vivo were studied in anaesthetised rats. Reduction of platelet count following injection of 100 micrograms/kg bw collagen was measured after bolus injection of PIR and vehicle. Piroximone bolus 2 mg/kg bw resulted in a 50% inhibition of platelet aggregation in rats. Cyclic AMP levels in washed platelets rose time and dose dependently after PIR. Coincubation of PDE III inhibitor PIR and adenylate cyclase activator Iloprost (ILO) resulted in a significant synergistic enhancement of the antiaggregatory effect. The PDE III inhibitor PIR exerted an effective inhibition of platelet aggregation in vivo and in vitro. The inhibitory effects in vitro were synergistically augmented by the prostacyclin analog Iloprost. These platelet inhibitory effects might be of clinical importance.

Adenosine Diphosphate↗
PubMed1992

Receptor binding properties of the new and specific thromboxane receptor antagonist Bay U 3405.

Human platelet membranes were used to characterize the receptor binding properties of the specific thromboxane receptor antagonist 3H-SQ 29548 and the displacement of 3H-SQ 29548 from its binding site by the new thromboxane receptor antagonist Bay u 3405. The specific binding of 3H-SQ 29548 was saturable with an association rate constant of 1 x 10(-11) mol-1 min-1 and a dissociation rate constant of 0.032 min-1. Nonspecific binding of 3H-SQ 29548 was below 10%. When Scatchard plot analysis was performed on equilibrium saturation binding the kD was 69 nmol/l and the Bmax was calculated as 3.9 pmol/mg membrane protein. 3H-SQ 29548 was dose dependently displaced from its binding site by addition of increasing concentrations of Bay u 3405 yielding an IC50 value of 68 +/- 12 nmol/l, being not significantly different from the IC50 of nonlabelled SQ 29548 (38 +/- 13 nmol/l). The results show that Bay u 3405 is a potent and specific thromboxane receptor antagonist, displacing 3H-SQ 29548 from its binding site on human platelet membranes with IC50 values being not significantly different. These receptor binding properties and the long biological half life reported in vivo make Bay u 3405 a promissing compound for the treatment of human cardiovascular diseases.

Binding, Competitive↗
PubMed1992

Increase in endogenous fibrinolysis and platelet activity during exercise in young volunteers.

The influence of physical exercise and intake of oral contraceptives on endogenous fibrinolytic activity and platelet aggregation behaviour was studied in young healthy women and compared to an age matched group of male volunteers. Physical exercise beyond the anaerobic threshold significantly increased the activity of tissue-plasminogen activator (t-PA) in male and female volunteers from initial values of 1.6 +/- 0.1 and 1.8 +/- 0.2 IU/ml to 5.5 +/- 1.0 and 5.3 +/- 0.9 IU/ml (P less than 0.01), respectively. In women taking low-dose estrogen oral contraceptives t-PA increased from 1.5 +/- 0.2 to 3.8 +/- 0.5 (P less than 0.01). There were no major alterations in plasminogen activator inhibitor - I (PAI-I) plasma activities. Platelet activity during exercise was significantly enhanced in male test persons indicated by a significant decrease in the ED50 values for ADP. In contrast, in women ED50 values were basically unaltered, irrespective of the intake of oral contraceptives.

Adolescent↗
PubMed1992

Effects of ciprostene on restenosis rate during therapeutic transluminal coronary angioplasty.

Ciprostene, a chemically stable prostacyclin analog was studied for its effects on restenosis in patients with coronary artery disease undergoing therapeutic percutaneous transluminal coronary angioplasty (PTCA). In a double-blind, randomized trial 32 patients were randomized to receive either ciprostene or the respective placebo. The infusion started intracoronarily at a rate of 40 ng/kg/min 20 min before introduction of the balloon catheter into the coronary artery. Thereafter infusion was continued intravenously for 36 hours at a rate of 120 ng/kg/min and a tapering off period until 48 hours. The quantitative analyses of the degree of coronary artery stenoses on the angiographic films before PTCA, after PTCA and after 6 month of follow-up was performed in 24 patients available. In patients receiving placebo (n = 12) coronary artery stenoses was 81 +/- 3% before PTCA and was reduced to 34 +/- 3% by angioplasty. At the 6 month follow up angiography stenoses diameter was measured as 63 +/- 8%, being not significantly different from the % stenoses before PTCA. In contrast, coronary artery stenoses in patients receiving ciprostene (n = 12) measured 83 +/- 3% before PTCA, 31 +/- 4% after PTCA and 55 +/- 9% at 6 month, being still significantly different from pre-PTCA value (P less than 0.05). When patients were characterized according to their clinical status, these differences were accounted for by patients with unstable angina receiving ciprostene. Ciprostene seems to reduce restenosis 6 month after coronary angioplasty in patients with unstable angina. The infusion rate of 40 ng/kg/min i.c. followed by 120 ng/kg/min i.v. was tolerated well, although the incidence of catheter associated bleeding was increased.

Adult↗
PubMed1992

Spontaneous echo contrast imaging in infective endocarditis: a predictor of complications?

Infective endocarditis is associated with significant morbidity and mortality. Valvular destruction and congestive heart failure are more common in patients with echocardiographically detectable vegetations. In addition, spontaneous platelet aggregation is increased when vegetations are present on cardiac valves. The aim of the study was to assess the prognostic value of spontaneous echo contrast (SEC) imaging, as SEC is supposed to reflect red blood cell aggregates stimulated by platelet activity. We studied 293 patients with clinical signs of infective endocarditis. Vegetations, attached to the aortic or mitral valve, were found in 130 patients (44.4%) who were followed for a mean period of 12 months. In 34 of these 130 patients (26.2%) SEC was imaged during the initial transesophageal echocardiographic examination. In these patients SEC indicated a prolonged healing of infective endocarditis with a specificity of 91.2%, a sensitivity of 77.3%, a positive accuracy of 77.3%, a negative accuracy of 74.3%. Multivariate analysis revealed that SEC is a risk factor for valve replacement (p less than 0.001) and for embolic events (p less than 0.001), less for mortality (p less than 0.01), and lowest for abscess formation (p less than 0.05). The dose of ADP to induce half-maximal platelet aggregation was significantly lower in patients with SEC (0.71 +/- 0.15 microliters) than without SEC (1.05 +/- 0.12 microliters; p less than 0.05), implying an increased spontaneous platelet aggregation in the presence of SEC. Our data provide evidence that systemically activated coagulation plays an important role in infective endocarditis. SEC, the echocardiographic implication of an increased platelet aggregation, predicts complications such as thromboembolic events and the need for surgery and is closely related to the prolonged healing period of infective endocarditis. In addition to demonstrating vegetations, transesophageal echocardiography provides information helpful in assigning patients to a high-risk subgroup. Transesophageal echocardiography may play an important role in assessing the clinical outcome of these patients.

Adult↗
PubMed1992

The effects of the nitric oxide donors molsidomine and SIN-I on human polymorphonuclear leucocyte function in vitro and ex vivo.

The nitrovasodilator and nitric oxide donor molsidomine and its metabolite SIN-I dilate vascular smooth muscle and inhibit platelet activation by increasing intracellular concentrations of cyclic GMP. We have therefore studied the effects of molsidomine and SIN-I on isolated human polymorphonuclear leucocytes (PMN) in vitro and ex vivo. In vitro molsidomine dose-dependently reduced beta-glucuronidase release and the generation of superoxide anions from non-activated and from FMLP- or PAF-stimulated human PMNs. SIN-I was equally effective in reducing beta-glucuronidase release and totally inhibited oxygen radical generation at a concentration of 580 mumol.l-1. In a double-blind, placebo-controlled, randomized trial we also studied beta-glucuronidase release and the generation of superoxide anions from isolated PMNs. Blood was drawn from 12 healthy volunteers before and 3 h after oral molsidomine (16 mg) or placebo. There was no statistically significant difference in beta-glucuronidase release and superoxide anion formation when the PMNs were isolated before or after molsidomine or placebo. This was the case for non-activated, as well as FMLP- or PAF-stimulated PMNs. Thus, the nitric oxide donors molsidomine and its metabolite SIN-I caused a dose-dependent inhibition of PMN functions in vitro, but no significant inhibition when the PMNs were isolated after oral molsidomine.

Adult↗
PubMed1992

[Acetylsalicylic acid in unstable angina, after coronary revascularization and in prevention of cardiac thromboembolism].

Acetylsalicylic acid (ASA) inhibits platelet function via cyclooxygenase inhibition. The selective inhibition of platelet cyclooxygenase is possible with the use of low doses of ASA due to presystemic acetylation of the platelet enzyme in the portal circulation. The clinical efficacy of ASA has been demonstrated for a number of indications. ASA reduces the rate of myocardial infarctions and cardiovascular deaths in patients with unstable angina. Simultaneous intravenous infusion of heparin has an additional positive effect. The prevention of acute coronary thromboses during PTCA and of early bypass graft occlusion has been convincingly demonstrated, if therapy is initiated immediately after surgery. Neither ASA nor any other drug has been effective in the prevention of late restenosis following PTCA and of late bypass graft occlusions. Thromboembolic complication after implantation of biological valve prostheses is significantly reduced by ASA, if no rheumatic valve disease is present. The rate of peripheral or cerebral thromboembolic events is markedly increased in patients with lone atrial fibrillation. In contrast to the very positive results obtained for anticoagulants, the reports with ASA were contradictory. ASA may be effective in preventing thromboembolic complications in younger patients with a lower risk or in elderly patients with contraindications for anticoagulation. For most clinical indications the efficacy of ASA has been demonstrated for doses of 75-324 mg/d. Following a loading dose of 300 mg on the first day, continuation of therapy with 100 mg/d should combine maximal therapeutic efficacy with a low rate of unwanted drug effects.

Angina, Unstable↗
PubMed1991

Nonradical oxidants of the phagocyte type induce the activation of plasmatic single chain- urokinase.

Single chain- urokinase (scu-PA) is the proenzyme of the plasminogen activator urokinase (tcu-PA). In human blood scu-PA is of great stability. Activated phagocytes generate large amounts of single chain- urokinase and of reactive oxidants (chloramines and HOCl). Since these cells participate in physiologic fibrinolysis, we were interested in the interaction between plasmatic scu-PA and chloramines. The oxidants dose dependently induce the activation of plasmatic scu-PA. Optimal activation of scu-PA occurs at about 3-5 mmol/l of chloramine-T. The findings suggest a control mechanism of scu-PA stability/activity by oxidatively modifiable plasma proteins, such as alpha-2-antiplasmin. The oxidation mechanism seems to be mediated by singlet molecular oxygen, an excited oxygen species. Basing on this scu-PA/oxidant synergism a sensitive and fast functional assay of scu-PA in human plasma is presented. Plasmatic inhibitors normally interfering with functional scu-PA measurements are inactivated by addition of chloramine-T, imitating the physiological oxidants generated by activated phagocytes. The scu-PA concentration in plasma of n = 36 healthy individuals has been determined to be 5.8 +/- 1.6 ng/ml. The lower detection limit of plasma scu-PA by the procedure described is about 1.5 ng/ml of plasma. By means of this technique scu-PA concentration during thrombolytic therapy can be measured within minutes in undiluted (direct) plasma samples, allowing adjustments of the scu-PA dosage. The present study gives further credence for a role of singlet molecular oxygen, possibly a new type of locally acting hormones (autacoid), in the regulation of the fibrinolytic pathway.

Adult↗
PubMed1991

Platelet-activating factor type activity in plasma from patients with septicemia and other diseases.

The purpose of the present study was to determine whether increased levels of platelet-activating factor (PAF) type activity can be detected in plasma from patients with septicemia and other diseases. A level of PAF below 0.5 ng/mL of plasma was considered normal. We found that plasma from a patient with adverse anaphylactoidic reaction to intravenous analgetics contained 2.1 ng PAF/mL. In seven patients with septicemia, including urosepsis, endocarditis and peritonitis, and with positive blood culture, increased plasma PAF levels (1-20 ng PAF/mL) were observed. Other patients with clinical indications of septicemia had negative blood cultures and/or increased levels of C-reactive protein (CRP). Yet, in the plasma from these patients, no increased PAF levels were detected under the assay conditions used. Two patients with allergic asthma, requiring treatment with steroids, had no measurable plasma PAF. In the plasma from a patient with idiopathic thrombocytopenic purpura (ITP) only an "endogenous" inhibitor of PAF induced platelet aggregation was initially observed. In spite of this, the patient responded to treatment with the PAF antagonist WEB 2086 with a dramatic increase in platelet count (Lohmann et al., Lancet ii, 1147, 1988). Thereafter, also increased PAF levels (3.3 ng PAF/mL) were detected in plasma, although some "endogenous" inhibitor of PAF was still present. In conclusion, increased PAF levels in plasma from patients support a role of PAF in certain human disease states, such as in anaphylactoid reaction, sepsis and septic shock. The type, relevance and specificity of endogenous inhibitors of PAF deserve further study.

Adult↗
PubMed1991

[Effect of molsidomine on fibrinolytic activity: a double-blind, randomized study].

The influence of molsidomine on endogenous fibrinolytic activity was studied in a double-blind, randomized, placebo-controlled trial involving 12 male healthy volunteers. When measured 3 h after oral intake of molsidomine (16 mg, slow-release formulation) the activity of tissue plasminogen activator (t-PA) in plasma was significantly increased from 1.1 +/- 0.1 to 1.6 +/- 0.1 IU/ml. In contrast, the activity of plasminogen activator inhibitor (PAI-I) decreased from 17 +/- 2 to 12 +/- 1 AU/ml. The ratio of t-PA/PAI-I (x 100), calculated as index for the endogenous fibrinolytic activity increased significantly from 8.1 +/- 1.1 to 14.5 +/- 1.6. The ratio was unaltered after intake of placebo. Additionally, collagen-induced platelet aggregation was significantly inhibited following intake of molsidomine. The results demonstrate a significant increase in endogenous fibrinolytic activity after oral intake of molsidomine. These effects may be of therapeutic value in patients with coronary heart disease and unstable angina.

Administration, Oral↗