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Biomedical subjects

Bernd Jilma

Publications and source records attributed to Bernd Jilma.

At least 19 recordsLinked to original sources
PubMed2003

Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin.

Whereas bleeding is the most frequent adverse event encountered in patients receiving glycoprotein (GP) IIb/IIIa inhibitors, there are currently no recommendations for how to treat such patients. The present study tested the hypothesis that infusion of desmopressin (DDAVP) reverses the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors (+l-aspirin). Study group 1 (10 healthy volunteers) received a DDAVP infusion to establish dose-response curves for the in vitro inhibition of platelet function by eptifibatide, abciximab, and tirofiban together with l-aspirin before and after DDAVP. In a randomized, double-blind, placebo-controlled, crossover study (group 2) volunteers received l-aspirin and a standard eptifibatide infusion. Thereafter, DDAVP or a physiologic saline infusion was given over 30 minutes. In group 1, all GPIIb/IIIa inhibitors prolonged collagen-epinephrine (CEPI) and collagen-adenosine diphosphate (CADP) closure times (CTs), measured with the platelet function analyzer 100 (PFA-100). DDAVP caused a shift in the concentration response curves to the right of all 3 GPIIb/IIIa inhibitors. In group 2, DDAVP accelerated the normalization of CADP-CT and CEPI-CT after the stop of eptifibatide infusion with a maximum effect at 1.5 hours to 2 hours. In contrast, CEPI-CT remained above normal in the placebo group for more than 4 hours. In conclusion, DDAVP accelerates normalization of the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors (+l-aspirin).

Abciximab↗
PubMed2003

Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia.

Inflammatory and procoagulant host responses are closely related in sepsis. The protein C pathway serves as a regulatory pathway with anti-inflammatory and anticoagulant properties. Recently, recombinant human activated protein C (rhAPC) was shown to reduce mortality in severe sepsis. Nevertheless, the effects of rhAPC in humans are still ill defined. The infusion of low endotoxin doses into humans provides a standardized model to study inflammatory and hemostatic mechanisms. Thus, we investigated whether rhAPC acts as an anticoagulant or anti-inflammatory drug in human endotoxemia. There were 24 volunteers randomized to receive either 24 microg/kg per hour rhAPC or placebo intravenously for 8 hours. Lipopolysaccharide (LPS, 2 ng/kg) was administered 2 hours after starting the infusions. rhAPC decreased basal tissue factor (TF)-mRNA expression, and thrombin formation and action. In contrast, rhAPC did not significantly blunt LPS-induced thrombin generation. Consistently, rhAPC did not reduce LPS-induced levels of TF-mRNA or D-dimer and had no effect on fibrinolytic activity or inflammation. Finally, endogenous APC formation was enhanced during endotoxemia and appeared to be associated with inflammation rather than thrombin formation. In conclusion, even low-grade endotoxemia induces significant protein C activation. Infusion of rhAPC decreases "spontaneous" activation of coagulation but does not blunt LPS-induced, TF-mediated coagulation in healthy volunteers, which is in contrast to a number of anticoagulants.

Acute Disease↗
PubMed2003

Influence of tiapride on platelet counts in healthy volunteers and patients with movement disorders.

BACKGROUND: The selective D2 antagonist tiapride is administered in various movement disorders. Furthermore, there are indications that tiapride increases platelet counts. AIM: To characterize tiapride's potential to increase platelet counts in healthy subjects and patients with movement disorders. METHODS: In Part A, 10 healthy volunteers received tiapride (300 mg/day) for 21 days in a longitudinal, prospective, open trial. One hundred healthy subjects served as controls. Part B was a retrospective analysis of 15 patients with movement disorders on tiapride [Huntington's disease (n=6), Morbus Little (n=3), hyperkinetic syndromes of undetermined etiology (n=3), blepharospasm (n=1), cervical dystonia (n=1), perioral dyskinesia (n=1)] and 15 age- and sex-matched controls. RESULTS: Part A: Although serum prolactin levels increased by 526+/-14%, confirming good drug compliance, tiapride elicited only minor changes in platelet counts. Part B: Platelet counts correlated positively with the dose of tiapride (100-800 mg/day; r=.67; P=.007). Platelet counts were significantly higher in patients on tiapride compared to healthy age-matched controls (P<.001). Four patients responded to an increase in the tiapride dosage with an increase in platelet count by 97-173 cells/nl. CONCLUSION: Three weeks of treatment with tiapride (300 mg/day) is insufficient to elevate platelet counts to a clinically relevant extent in young healthy volunteers. However, in elderly patients with movement disorders tiapride treatment is associated with markedly increased platelet counts.

Administration, Oral↗
PubMed2003

Levels of adhesion molecules do not decrease after 3 months of statin therapy in moderate hypercholesterolaemia.

Studies in animals and humans indicate a pivotal role for adhesion molecules (AMs) in the pathogenesis of atherosclerosis. Whereas an association between hypercholesterolaemia and AM expression has been suggested, it is unclear whether lowering cholesterol decreases AM expression and release. We compared the effects of a 3-month treatment with standard doses of three different statins (atorvastatin, simvastatin and pravastatin) on plasma levels of circulating AM (cAM) in 75 hypercholesterolaemic patients in a randomized clinical trial. Plasma levels of circulating (c)E-selectin, circulating intercellular adhesion molecule-1 (cICAM-1) and circulating vascular cell adhesion molecule-1 (cVCAM-1) were measured before and after 3 months of therapy. None of the statins lowered plasma cAM levels and pooled analyses of all patients showed a 1.7% [95% confidence interval (CI), -1.4-4.9%] increase in cE-selectin, a 2.1% (95% CI, -0.2-4.4%) increase in cICAM-1, and a 2.7% (95% CI, -0.6-6.1%) increase in cVCAM-1 levels. cAM levels did not decrease, even in patients with a >50% decrease ( n =19) in low-density lipoprotein cholesterol levels. This study provides strong evidence that 3 months of therapy with three different statins does not decrease cAM levels, despite normalization of cholesterol levels, and a minor decrease in C-reactive protein levels in patients with moderate hypercholesterolaemia.

Adult↗
PubMed2003

Glycoprotein Ib polymorphisms influence platelet plug formation under high shear rates.

Platelet polymorphisms (Kozak, VNTR and HPA-2) within glycoprotein (GP)Ib alpha may be associated with an increased risk of arterial thrombosis. However, the functional role of these polymorphisms has not been clarified. Their influence on platelet plug formation under high shear rates was, therefore, examined in 233 healthy individuals. Collagen-adrenaline-induced closure time was shorter in carriers of the C/D versus C/C VNTR allele and in homozygotes with the (-5)T/T versus (-5)C/T Kozak genotype as determined by novel polymerase chain reaction methods. The HPA-2 genotype had no effects, and the density of GPIb alpha molecules was not influenced by GPIb alpha genotypes.

Adult↗
PubMed2003

Endotoxaemia modulates Toll-like receptors on leucocytes in humans.

The modulation of Toll-like receptors (TLR) 1, 2 and 4 was studied during experimental human endotoxaemia. Healthy volunteers received 2 ng/kg of lipopolysaccharide (LPS) endotoxin (n = 10). TLR1, 2 and 4 expression occurred on monocytes and neutrophils, with monocytes expressing higher baseline levels of TLR2. LPS infusion downmodulated TLR4 expression on neutrophils, with maximal downregulation occurring at 24 h (-62% from baseline; P < 0.03 versus baseline). Monocyte TLRs were upregulated in vivo (TLR1 and 2), and in vitro (TLR1, 2 and 4) 8 h after LPS bolus (P < 0.05 versus baseline). Therefore, neutrophils and monocytes differentially express surface TLRs, and endotoxaemia differentially regulates TLR expression.

Adult↗
PubMed2003

Activation of calcium-dependent calmodulin by calcium(II)3(3,5-diisopropylsalicylate)6(H2O)6 decreases thrombin receptor activating peptide-induced P-selectin expression.

We examined the influence of 3,5-diisopropylsalicylic acid (3,5-DIPS) and calcium(II)3 (3,5-diisopropylsalicylate)6 (H2 O)6 [Ca(II)3 (3,5-DIPS)6 ], a new activator of calcium-dependent calmodulin-triggered nitric oxide synthase, on thrombin-induced platelet P-selectin expression. Citrated whole blood samples were incubated with either ethanol vehicle, 3,5-DIPS, or Ca(II)3 (3,5-DIPS)6. These whole blood samples were also co-incubated with thrombin receptor activating peptide (TRAP) or adenosine diphosphate (ADP), to up-regulate P-selectin (CD62P) on platelets. Both TRAP and ADP up-regulated P-selectin on platelets compared with platelets in whole blood samples that were not incubated with either platelet activator. Co-incubation of whole blood samples with TRAP, ADP together with 3,5-DIPS, or Ca(II)3 (3,5-DIPS)6 revealed that Ca(II)3 (3,5-DIPS)6 caused a decrease in platelet P-selectin expression for TRAP, ADP, and no-activator co-incubated samples of whole blood. Incubation of platelets with 3,5-DIPS also caused a decrease in ADP-induced up-regulation of P-selectin but failed to affect TRAP or no-activator-treated platelets. Incubation of whole blood with Ca(II)3 (3,5-DIPS)6 induced some hemolysis. We found that hemolysis increases basal P-selectin expression on platelets. We therefore conclude that Ca(II)3 (3,5-DIPS)6 decreased not only basal, but also hemolysis-induced P-selectin expression on platelets. In contrast, incubation of haemolysed whole blood with SIN-1 (standard nitric oxide-releasing drug) had no effect on P-selectin expression. In summary, Ca(II)3 (3,5-DIPS)6, a new calmodulin-dependent nitric oxide synthase activator, decreases P-selectin expression of human platelets in response to thrombin receptor activation. Improved calcium-dependent calmodulin activators may become useful drugs for the treatment of disorders associated with platelet activation, and P-selectin may decrease expression due to hemolysis.

Adenosine Diphosphate↗
PubMed2003

Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia.

OBJECTIVE: Cytokines and adhesion molecules have a decisive role in the development of early inflammatory response as well as the late sequelae of sepsis. Because L-selectin-deficient mice are protected from lethal endotoxemia, blockade of L-selectin may provide a useful therapeutic option in human sepsis. Heparin has immunomodulatory properties and effectively inhibits L- and P-selectin binding in vitro. We therefore investigated whether clinically applied doses of unfractionated or low-molecular-weight heparin affect early inflammatory response in human endotoxemia. DESIGN: The study was randomized, double-blinded, placebo-controlled, in three parallel groups consisting of 30 healthy male volunteers. SETTING: University medical center. INTERVENTIONS: All subjects received a 2-ng/kg intravenous bolus of lipopolysaccharide and 10 mins later unfractionated heparin, low-molecular-weight heparin, or placebo as bolus primed continuous infusion for 6 hrs. MEASUREMENTS AND MAIN RESULTS: Lipopolysaccharide infusion induced similar increases of tumor necrosis factor-alpha, interleukin-6, interleukin-8, C-reactive protein, and soluble E-selectin levels in all treatment groups. CD11b expression increased by approximately 400%, but L-selectin decreased by 41% in the placebo arm 6 hrs after lipopolysaccharide infusion. Interestingly, both heparins (in particular unfractionated heparin) decreased L-selectin down-regulation as compared with placebo. Similarly, the decrease in lymphocyte counts was significantly less in the unfractionated heparin group during the first 24 hrs (p <.05 vs. placebo) CONCLUSIONS: Heparins displayed little effects on cytokine production and endothelial cell activation in endotoxemia. Of note, however, unfractionated heparin reduced L-selectin down-regulation and lymphocytopenia. These could present novel mechanisms of action of unfractionated heparin.

Adult↗
PubMed2003

Enalapril does not alter adhesion molecule levels in human endotoxemia.

The angiotensin-converting enzyme inhibitor (ACE-I) enalapril has been shown to lower elevated levels of circulating adhesion molecules (cAM) in critically ill patients. To delineate the mechanisms of this possibly beneficial effect of enalapril, we studied the acute effects of enalapril in a well-defined model of endotoxin-triggered, cytokine-mediated cAM up-regulation. In a randomized, controlled trial, 30 healthy male volunteers received 2 ng/kg lipopolysaccharide (LPS) after pretreatment with placebo or 20 mg/day enalapril for 5 days or with a single dose of 20 mg of enalapril 2 h before LPS infusion. LPS infusion increased TNF levels 300-fold above normal, circulating (c) E-selectin levels by 425% (CI, 359%-492%), and P-selectin, VCAM-1, ICAM-1, and von Willebrand factor levels by 47%-74%. LPS infusion also enhanced ICAM-1 and CD11b expression 2- to 3-fold on monocytes. However, no differences were seen between treatment groups (P > 0.05), despite 95% inhibition of ACE activity by enalapril. Inhibition of ACE activity by enalapril does not influence plasma indices of endothelial activation after endotoxin infusion in healthy individuals. Our results do not support the concept of a beneficial clinical effect of enalaprilat in septicemia.

Adult↗
PubMed2002

Effect of factor X inhibition on coagulation activation and cytokine induction in human systemic inflammation.

Anticoagulants have gained increasing attention in the treatment of sepsis. This study used danaparoid to investigate the role of factor Xa in endotoxin-induced coagulation and inflammation and its effectiveness when coagulation activation has already occurred. Thirty healthy volunteers were enrolled in the randomized, placebo-controlled trial. Subjects received 2 ng/kg endotoxin and danaparoid 10 min or 3 h thereafter or placebo. Endotoxin increased prothrombin fragment 1+2 (F(1+2)) levels from 0.5 to 7.0 nmol/L at 5 h in the placebo group. Early danaparoid infusion inhibited endotoxin-induced thrombin formation: maximum F(1+2) levels reached only 1.8 nmol/L (P<.01, vs. baseline or placebo). Delayed danaparoid infusion effectively blocked further thrombin formation. However, danaparoid did not alter endotoxin-induced changes in the fibrinolytic system, cytokine levels, activation of leukocytes, or tissue factor expression on monocytes. Danaparoid therefore selectively attenuates endotoxin-induced coagulopathy, even with delayed administration when coagulation activation is well under way.

Adult↗
PubMed2002

Point of care measurement of lepirudin and heparin anticoagulation during systemic inflammation.

BACKGROUND: The number of indications for recombinant human hirudin lepirudin therapy has increased in recent years, and now includes acute coronary syndromes and heparin-induced thrombocytopenia. Hence, point of care monitoring appears desirable for therapy with lepirudin. As CoaguChek Plus (CCP) provides a rapid bedside test to monitor therapy with other anticoagulants, we aimed to determine its suitability for lepirudin therapy. METHODS: Forty-four healthy volunteers received a 2 ng/kg endotoxin infusion (to induce coagulation) together with clinically relevant doses of lepirudin or heparin in a prospective, placebo-controlled, randomised fashion. Measurements of CCP-partial thromboplastin time (aPTT) were compared to laboratory STA-aPTT. RESULTS: As expected, baseline values of CCP-aPTT were shorter than STA-aPTT. Lepirudin increased CCP-aPTT 3-fold, and STA-aPTT 2-fold 1 h after bolus infusion. During lepirudin infusion, the correlation between CCP-aPTT and STA-aPTT was excellent (r=0.86-0.92). Both methods were equally sensitive to over-anticoagulation with heparin. Acute systemic inflammation had little effects on CCP-aPTT. CONCLUSION: CCP-aPTT is suitable for longitudinal point of care monitoring of lepirudin therapy. As baseline values of CCP-aPTT are shorter than STA-aPTT, it is recommended not to indiscriminately change between methods in the follow-up of individual patients.

Adult↗
PubMed2002

Human monocyte stimulation by experimental whole body hyperthermia.

The thermal effect of fever, an evolutionarily conserved acute-phase response, has been associated with better survival and a shorter duration of disease in cases of infection. The molecular consequence of this beneficial fever response is poorly understood. To determine the influence of hyperthermia on human monocytes, which are important for the recognition and elimination of pathogens, twelve healthy volunteers were immersed in a 39.5 degrees C hot water bath to increase their body temperature. The expression of the endotoxin receptor CD14 and the complement receptor CD11b increased after the hot water bath (P < 0.05), whereas the expression of the selectin CD62L, which mediates the initial attachment of leukocytes at the endothelium during inflammation, was downregulated after hyperthermia (P < 0.05). Comparable changes in monocyte receptor expression were observed after in vitro hyperthermia. Furthermore, 3 hours after in vivo hyperthermia, the response of monocytes to endotoxin was enhanced in an ex vivo lipopolysaccharide stimulation assay, as expressed by a greater TNF-alpha release (P < 0.05). We conclude that the thermal effect of fever directly activates monocytes, which increases their ability to respond to bacterial challenge.

Adult↗
PubMed2002

Leukocyte scintigraphy with 99mTc-exametazime-labeled leukocytes is not useful for follow-up of systemic vasculitis.

BACKGROUND: The prognosis of systemic vasculitis, for instance Wegener's granulomatosis (WG), was greatly improved by the introduction of immunosuppressive treatment. However, relapses are frequent and predictors are scarce. 111In-leukocytes have been found to indicate unknown manifestations of WG and to predict later relapse. We prospectively investigated the value of 99mTc-Exametazime (99mTc-HMPAO)-labeled leukocytes with regard to specific patterns and for their usefulness in the follow-up of patients with WG. METHODS: The vasculitis group consisted of 8 patients with WG and 2 with idiopathic necrotizing glomerulonephritis (ING). Seven patients with different inflammatory diseases served as controls. Leukocyte labeling with 99mTc-HMPAO was done using a slightly modified Hammersmith protocol. Cell viability after labeling was verified in vivo by the exclusion of early lung and splenic uptake and in vitro by means of propidium iodide and FACS analysis. Static gamma camera images from the head, chest, abdomen, and pelvis were obtained up to 18 hours after injection of approximately 300 MBq 99mTc-HMPAO-labeled leukocytes. Scintigrams were analyzed visually; for semiquantitative analysis ROIs were drawn over the nasal region, the right lung, kidneys, and liver. RESULTS: Increased nasal leukocyte accumulation was found in 7/8 patients with WG and in 2/2 patients with ING. Of 2 patients who had a relapse 6 months later, one presented with, and one without nasal uptake. The kidney/liver ratio was higher in controls (0.24 +/- 0.07 vs. 0.37 +/- 0.11, p < 0.05). Distinct to moderate lung uptake was observed in 2 patients with WG and in one with ING. No correlation was found between scintigraphic results, medication, ANCA status or cretinine levels. CONCLUSION: Nasal leukocyte accumulation is increased in systemic vasculitis, independent of the immunosuppressive treatment and later clinical course. However, this finding is not specific for vasculitis. 99mTc-HMPAO leukocyte scintigraphy failed to indicate or exclude a later relapse and is therefore not suitable as a diagnostic tool in the management of patients with systemic vasculitis.

Adult↗