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Biomedical subjects

B Jilma

Publications and source records attributed to B Jilma.

At least 55 records · Page 3Linked to original sources
PubMed2000

Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100.

BACKGROUND: Anti-platelet drug therapy is currently performed without monitoring, because the established method of platelet aggregometry is cumbersome. The recently developed platelet function analyzer PFA-100 measures shear stress dependent, collagen epinephrine (CEPI) and collagen adenosine diphosphate (CADP) induced platelet plug formation. As the PFA-100 provides a valuable tool to detect patients with platelet dysfunction more efficiently and cost-effectively than aggregometry, we investigated its potential to monitor the efficacy of aspirin treatment. METHODS: All healthy volunteers (n = 10) received a fractionated infusion of L-aspirin to establish individual dose-response curves. Further, in a randomized, double-blind, placebo controlled two-way cross over study the same volunteers received either 50 or 100 mg aspirin/day p.o. for a period of 11 days to determine the day-to-day variability CEPI induced closure time (CT) under constant intake of low dose aspirin, and to compare the efficacy of those two doses. RESULTS: Intra- and intersubject variability of CEPI-CT averaged 9% and 22%, respectively. Seven volunteers exceeded the maximum of CEPI-CT (>300 s) already after infusion of 100 mg L-aspirin. Intake of 100 mg of aspirin elicited a more rapid onset of effect than 50 mg, which was only significant on days 3 and 4 of aspirin intake. The aspirin induced CEPI-CT prolongation correlated positively with basal CEPI-CT values (r = 0.86; p = 0.001) and were strongly dependent on von Willebrand Factor levels (r = -0.9; p = 0.001). CONCLUSION: Thus, the PFA-100 system appears suitable to demonstrate an aspirin-induced platelet effect in a longitudinal study, and may be adequate to monitor a patient's compliance. However, prospective trials have to be conducted to demonstrate whether the EPI-CT achieved under ASA-intake has predictive value for cardiovascular outcome.

Adenosine Diphosphate↗
PubMed1999

Beneficial effects of protease inhibitors on body composition and energy expenditure: a comparison between HIV-infected and AIDS patients.

OBJECTIVES: (i) To investigate whether protease inhibitor (PI) (nelfinavir)-containing highly active antiretroviral therapy (HAART) affects body composition differently in HIV-infected and AIDS patients without wasting syndrome. (ii) To delineate the changes in resting energy expenditure (REE) under PI therapy, and to determine whether sustained reductions in HIV RNA would decrease REE. DESIGN: Prospective longitudinal cohort study with individually matched healthy controls. SETTING: Tertiary care centre at a University Hospital. METHODS: HIV-seropositive (n = 20) and AIDS patients (n = 17) with a plasma viral load of at least 10000 copies/ml and 37 healthy volunteers were enrolled. All participants were weight stable, free of acute opportunistic infections, and naive to PI therapy. Patients underwent testing of bioelectrical impedance analysis (BIA), indirect calorimetry and food intake, shortly before the initiation of HAART and 24 weeks thereafter. RESULTS: Both patient groups gained weight, body mass index (BMI), and fat-free mass (FFM) (P < 0.05 versus baseline), whereas only AIDS patients gained fat mass. Increases were more pronounced in the AIDS group. REE was elevated compared with corresponding controls at baseline, and decreased similarly in HIV and in AIDS patients during PI therapy (P < 0.05). The reduction in the viral burden preceded the decrease in REE by several weeks. CONCLUSION: Body composition and metabolic parameters improved during PI therapy in HIV-infected and AIDS patients without wasting. Although an early reduction in viral load as a result of HAART does not seem to influence REE directly, sustained viral load suppression may promote a decrease in energy expenditure.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Acetaminophen has greater antipyretic efficacy than aspirin in endotoxemia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in parallel groups. Subjects received an intravenous endotoxin bolus of 4 ng/kg after premedication with either placebo, 1000 mg aspirin, or 1000 mg acetaminophen by mouth. RESULTS: Peak body temperatures were 38.5 degrees C +/- 0.2 degrees C in the placebo group, 37.6 degrees C +/- 0.2 degrees C in the acetaminophen group (P = .001 versus placebo), and 38.6 degrees C +/- 0.2 degrees C in the subjects treated with aspirin (P = .001 versus acetaminophen; P = .570 versus placebo) at 4 hours after lipopolysaccharide infusion. Subjective symptom scores for chills and perception of fever were higher in the placebo group than in the acetaminophen group (chills, 2.5 +/- 0.3 versus 1.0 +/- 0.2, P = .009 and fever, 2.5 +/- 0.2 versus 2.0 +/- 0.2, P = .021). Tumor necrosis factor-alpha, interleukin-6, and interleukin-8 levels rose by several orders of magnitude (P < .001 versus baseline in all groups), without significant intergroup differences. CONCLUSIONS: Acetaminophen was the superior antipyretic drug in endotoxemia compared with aspirin. Treatment with acetaminophen ameliorates subjective symptoms induced by endotoxemia without compromising the humoral response of a subject to endotoxin. This observation has clinical interest and may also help to improve the lipopolysaccharide model, which can be used to test anti-inflammatory and anticoagulatory drugs.

Acetaminophen↗
PubMed1999

Fosinopril decreases levels of soluble vascular cell adhesion molecule-1 in borderline hypertensive type II diabetic patients with microalbuminuria.

Angiotensin converting enzyme inhibitors (ACE-I) are a mainstay for the treatment of heart failure, and of diabetic microalbuminuria. Recently ACE-I have been found to decrease plasma levels of circulating vascular cell adhesion molecule-1 (cVCAM-1) in patients with congestive heart failure. As increased cVCAM-1 levels are pathognomonic for diabetics with microangiopathy, we investigated the effects of ACE-I on plasma levels of cVCAM-1, intercellular adhesion molecule (cICAM-1), and cE-selectin in microalbuminuric diabetics. In addition, the effects of ACE-I on plasma levels of plasminogen activator inhibitor (PAI-1) and of tissue plasminogen activator (TPA) were studied. Fosinopril (10 mg/day) was administered over 12 weeks to 11 microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM). As expected, baseline plasma concentrations of cE-selectin, cICAM-1, and cVCAM-1 were markedly higher in patients than in healthy control subjects (n = 82; P < .001). PAI-1 levels in NIDDM were similar to those in control subjects, whereas TPA levels were about 25% lower in patients than in control subjects (P = .013). Serum levels of cVCAM-1 decreased by -19% (CI: -25% to -13%) after treatment with fosinopril (P = .003) and were no longer different from those of the control group. In contrast, plasma levels of cE-selectin, cICAM-1, PAI-1, and TPA were unaffected. As expected microalbuminuria decreased by -44% (CI: -65 to -22; P = .004). In conclusion, fosinopril lowered cVCAM-1 levels along with microalbuminuria in NIDDM. This may represent a novel mechanism of action of ACE-I in diabetes-associated endothelial dysfunction. Whether decreased VCAM-1 expression is responsible for the observed reduction in microalbuminuria, deserves further investigation.

Adult↗
PubMed1999

Heparin lowers plasma levels of activated factor VII.

Based on heparin's antithrombin and anti-FXa activity and its in vitro inhibition of activated factor VII (FVIIa) activity, we hypothesized that unfractionated heparin (UFH) may decrease plasma levels of FVIIa in humans. Therefore, 10 healthy young male volunteers received an intravenous UFH infusion over 24 h. Heparin decreased FVIIa levels by 30% (95% CI 14-47%) at 12 h, which was sustained until 24 h. In contrast, neither the substrate pool (i.e. total factor VII) as measured by FVII antigen nor FVII activity were affected by UFH. These results may improve our understanding of the regulation of FVIIa levels and heparin's mode of action.

Adult↗
PubMed1999

Circadian variation of granulocyte colony stimulating factor levels in man.

Glucocorticoids dose-dependently increase plasma levels of granulocyte colony stimulating factor (G-CSF). Based on the marked circadian rhythm of cortisol levels, we hypothesized that plasma levels of G-CSF may also show a diurnal rhythm. A prospective study was conducted in 12 healthy young volunteers. Blood samples were obtained every 2 h over 24 h. G-CSF levels averaged 18.0 ng/l (CI 13. 1-22.9) at 8.00 am, increased continuously and reached peak values at 10.00 p.m. Individual harmonic regression analysis showed a clear circadian rhythm. The individual differences between nadir and peak levels averaged 54% (CI 43-65%). This pronounced diurnal rhythm of G-CSF levels may help understand the circadian changes in circulating stem cells, bone marrow DNA synthesis, or bone marrow toxicity induced by some chemotherapeutic agents.

Adult↗
PubMed1999

Effects of sodium nitroprusside on hemodialysis-induced platelet activation.

BACKGROUND: Hemodialysis (HD) is associated with increased platelet activation as reflected by enhanced P-selectin expression on platelets and by increased formation of heterotypic platelet-leukocyte aggregates. Both may play a pathophysiologic role in HD-associated platelet dysfunction or the propagation of atherosclerosis. As nitric oxide (NO) is a potent inhibitor of platelet activation, we were interested in whether HD-induced platelet activation could be blunted by a NO donor. METHODS: After a pilot study in 12 patients to gain an estimate for the sample size, the main trial was conducted as a randomized, double-blind, placebo-controlled, two-way, cross-over study. Twelve patients received an infusion of sodium nitroprusside (1 microgram/kg/min for over 15 min) or placebo into the inlet port of the HD device. RESULTS: Platelet activation increased within five minutes after start of HD (P < 0.05). Infusion of sodium nitroprusside neither decreased platelet activation (P-selectin + platelets) nor affected the number of platelet-leukocyte aggregates (CD41+ neutrophils) as measured by flow cytometry. CONCLUSION: Although NO may have inhibitory effects on platelet activation in vivo, our results confirm recent findings showing that NO donors were ineffective in preventing platelet activation by extracorporeal circulation during cardiopulmonary bypass or plateletpheresis. Thus, NO donors do not appear to be ideal candidate drugs to inhibit HD-associated platelet activation.

Adult↗
PubMed1999

Effects of nitric oxide on platelet activation during plateletpheresis and in vivo tracking of biotinylated platelets in humans.

BACKGROUND: The use of platelet transfusions has risen considerably over the last few years, which leads to the collection and transfusion of a greater number of donor plateletpheresis units. Plateletpheresis activates platelets in platelet concentrates, which determines the degree of the storage lesion subsequently observed. STUDY DESIGN AND METHODS: As nitric oxide (NO) is a potent inhibitor of platelet aggregation and activation, a placebo-controlled crossover trial was performed in healthy young male volunteers to determine whether the NO-donating compound, sodium nitroprusside (SNP), decreases platelet activation during apheresis and whether activated (p-selectin+) platelets circulate in vivo after transfusion. The study also investigated whether nonradioactive biotin labeling of apheresis platelets is feasible for the study of platelet recovery after transfusion in humans. RESULTS: Platelet activation increased after plateletpheresis in the platelet components, but SNP did not inhibit platelet activation during apheresis, as measured by the percentage of p-selectin expression and the secretion of soluble p-selectin and RANTES. Only a minor increase in p-selectin+ platelets was seen in peripheral blood at 60 minutes after transfusion of the platelets, a rise that was considerably less than that calculated in p-selectin+ platelets if they all were recovered as activated platelets after transfusion. Biotin-labeled platelets averaged 1.5 percent at 10 minutes after transfusion and increased slowly to 2.6 and 3.4 percent after 60 minutes and 24 hours, respectively (p<0.05). CONCLUSION: SNP does not decrease platelet activation during apheresis and subsequent storage, and only a minor proportion of activated (p-selectin+) platelets circulate after transfusion in men. Moreover, biotin labeling of PCs can safely be used in humans for the study of platelet recovery after transfusion, and measuring recovery at 1 hour may lead to an underestimation of the true recovery when activated platelets are transfused.

Biotinylation↗
PubMed1999

Safety issues of plateletpheresis: comparison of the effects of two cell separators on the activation of coagulation, fibrinolysis, and neutrophils and on the formation of neutrophil-platelet aggregates.

BACKGROUND: Although many donors undergo repeated plateletpheresis, data on the consequences of plateletpheresis for the donor's health remain scarce. Thus, the effect of plateletpheresis on the activation of coagulation, fibrinolysis, and neutrophils was investigated. STUDY DESIGN AND METHODS: Part 1: Sixteen healthy men were randomly assigned to undergo plateletpheresis on a cell separator (AMICUS, Fenwal Baxter; or MCS 3p, Haemonetics). The effects of plateletpheresis on plasma levels of prothrombin fragment (F(1+2)), D-dimer, plasmin-plasmin inhibitor (PPI) complexes, and plasminogen activator inhibitor (PAI-1); on the activation of neutrophils (% L-selectin+); and on the frequency of platelet-neutrophil aggregates (% CD41+ neutrophils) were compared. Part 2: Ten healthy men received infusions of ACD-A and placebo without apheresis in a randomized, double-blind crossover study to control for the pharmacologic effects of citrate. RESULTS: Part 1: No change in F(1+2) occurred (p>0.05), which indicated that plateletpheresis did not enhance coagulation. Levels of D-dimer, PPI, and PAI-1 decreased over time on the AMICUS (p<0.001). Plateletpheresis did not activate neutrophils (p>0.05), but it decreased the percentage of CD41+ neutrophils (p<0.003). An approximately 80-percent drop in mononuclear cells was observed in the extracorporeal circulation of the AMICUS (p<0.001 vs. baseline and p = 0.005 vs. MCS 3p), and circulating lymphocyte and monocyte counts decreased concomitantly. Part 2: Infusion of ACD-A slightly decreased D-dimer levels (p<0.05), and both infusions decreased the circulating lymphocyte counts. CONCLUSION: Plateletpheresis can be regarded as safe with respect to the activation of coagulation or neutrophils. The consequences for the donor's health of the decrease in D-dimer, PPI, and PAI-1 may deserve further investigation.

Adult↗
PubMed1999

The proportion of reticulated platelets is higher in bone marrow than in peripheral blood in haematological patients.

Since the detection that platelets originate from megakaryocytes (MK), the site of megakaryocyte fragmentation has been disputed. Some authors have even postulated that platelets are solely produced in the lungs. Thus, we have directly measured platelet generation in the bone marrow (BM) by comparing the relative number of young RNA-containing, so-called reticulated platelets (%RP) in the BM and in the peripheral blood (PB). Two separate prospective, cross sectional trials have been conducted in patients routinely undergoing BM biopsies for diagnostic purposes. In the first part of the study 30 patients with stem cell or bone marrow transplantation were examined. The second part of the study was performed in 62 haematological patients visiting the outpatient's clinic. Median %RP were higher in BM than in PB (p <0.001). In the second part of the study the difference averaged 133% (interquartile range: 30-383%). There was a moderate correlation between %RP in BM and in PB (r = 0.67; p <0.001). The absolute number of RP in PB correlated weakly with the number of megakaryocytes (0.42; p = 0.001), which was due to a correlation between the platelet counts and the megakaryocyte counts (r = 0.55; p <0.001 in biopsies). Two patients with autoimmune antibodies against GPIIb/IIIa exhibited 10% and 16% RP in PB, and had 29% and 59% RP in BM, respectively. It is concluded that the relative number of RP is significantly higher in BM than in blood. This supports the notion that platelets are at least in part released from MK in the bone marrow, particularly in patients suffering from immune thrombocytopenia.

Antigens, Surface↗
PubMed1999

Endotoxin-induced activation of the coagulation cascade in humans: effect of acetylsalicylic acid and acetaminophen.

During Gram-negative septic shock, lipopolysaccharide (LPS, endotoxin) induces tissue factor (TF) expression. TF expression is mediated by nuclear factor kappaB and amplified by activated platelets. TF forms a highly procoagulant complex with activated coagulation factor VII (FVIIa). Hence, we hypothesized that aspirin, which inhibits LPS-induced, nuclear factor kappaB-dependent TF expression in vitro and platelet activation in vivo, may suppress LPS-induced coagulation in humans. Therefore, we studied the effects of aspirin on systemic coagulation activation in the established and controlled setting of the human LPS model. Thirty healthy volunteers were challenged with LPS (4 ng/kg IV) after intake of either placebo or aspirin (1000 mg). Acetaminophen (1000 mg) was given to a third group to control for potential effects of antipyresis. Neither aspirin nor acetaminophen inhibited LPS-induced coagulation. However, LPS increased the percentage of circulating TF(+) monocytes by 2-fold. This increase was associated with a decrease in FVIIa levels, which reached a minimum of 50% 24 hours after LPS infusion. Furthermore, LPS-induced thrombin generation increased plasma levels of circulating polymerized, but not cross-linked, fibrin (ie, thrombus precursor protein), whereas levels of soluble fibrin were unaffected. In summary, a single 1000-mg dose of aspirin did not decrease LPS-induced coagulation. However, our study showed, for the first time, that LPS increases TF(+) monocytes, substantially decreases FVIIa levels, and enhances plasma levels of thrombus precursor protein, which may be a useful marker of fibrin formation in humans.

Acetaminophen↗
PubMed1999

Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin.

Gram-negative septic shock is mediated in part by endotoxin (lipopolysaccharide; LPS), and animal models have shown that blockade of even single adhesion molecules considerably improves survival. Thus interference with the adhesion cascade may provide a useful therapeutic approach in human sepsis. Young healthy men (n = 30) each received a bolus of 4 ng/kg LPS intravenously to study the effects of endotoxemia on adhesion processes in humans and to identify potential targets for pharmacologic intervention. One third of subjects received pretreatment with 1,000 mg aspirin and 1,000 mg paracetamol to study potential antiinflammatory effects of aspirin or effects of antipyresis. Circulating neutrophils dropped by -80% at 67 min after LPS, monocytes by -96% at 90 min, and lymphocytes by -85% at 240 min. L-selectin expression decreased, particularly on monocytes. Circulating (c)E-selectin levels increased by 820%, von Willebrand factor-Ag (vWF), soluble thrombomodulin, circulating (c)P-selectin, circulating intercellular adhesion molecule-1 (cICAM-1), and circulating vascular cell adhesion molecule-1 (cVCAM-1) by a mean of 65 to 98% (p < 0.001 for all), but cL-selectin by only 15%. Urinary excretion of soluble adhesion molecules was negligible. Aspirin had no influence on the LPS-induced changes of adhesion parameters, but paracetamol blunted the relative increase in vWF while having no effects on the other parameters measured. The consistent, profound, and early upregulation of cE-selectin during endotoxemia indicates that cE-selectin may be a better surrogate marker to monitor the activation status of endothelial cells in systemic inflammation than the other markers measured. Although aspirin did not have any antiinflammatory effects in this model, paracetamol lowered the relative increase in vWF.

Acetaminophen↗
PubMed1999

Effects of endotoxemia on thrombopoiesis in men.

BACKGROUND: Febrile conditions are often associated with increased platelet turnover and refractoriness to platelet transfusions, although several pyrogenic cytokines enhance thrombopoiesis. This study aimed to characterize the effects of experimental human endotoxemia on platelet turnover and thrombopoiesis. METHODS: Endotoxin (4 ng/kg) was infused into 30 healthy men to study the regulation of thrombopoiesis in systemic human inflammation. Platelet counts, plasma thrombopoietin (TPO) and glycocalicin levels, and reticulated platelets (RP) were measured to evaluate the effect of acute endotoxemia on thrombopoiesis. Ten subjects received pretreatment with 1000 mg aspirin po. to evaluate possible effects of aspirin on platelet turnover, and ten subjects received paracetamol to control for effects of antipyresis. RESULTS: Platelet counts dropped by about 15% (p <0.001) one hour after LPS infusion, began to recover at 24 h, and exceeded baseline values by 81% (CI: 5-12; p <0.001 ) at 7 days after LPS iv. Reticulated platelet counts increased from 1.62% (CI: 1.24-2.0) to a maximum of 2.39% (CI: 1.81-2.98; p = 0.003) at 6 h. TPO levels increased from baseline values of 10 A.U/ml (CI: 8.8-11.2) to 15.5 A.U/ml (CI: 13.6-17.3) at 24 h (p <0.001), whereas plasma glycocalicin was not changed (p >0.05). The number of circulating platelet-neutrophil aggregates increased more than 100% at 6 h (p <0.001). Neither aspirin nor paracetamol affected changes in any of the parameters measured. CONCLUSION: Low grade endotoxemia induces a rapid fall of platelet counts, which is followed by an early increase in reticulated platelets and TPO levels but not of glycocalicin levels. Finally peripheral platelet counts increase several days after LPS infusion.

Adult↗
PubMed1998

Effects of histamine and nitric oxide synthase inhibition on plasma levels of von Willebrand factor antigen.

Endothelial cells release von Willebrand factor (vWf) either constitutively or by a regulated pathway. Based on various studies in vitro, we hypothesized that the stimulatory action of histamine on vWf release could also be induced in vivo and that it may be inhibited by endogenous production of nitric oxide (NO). Nine healthy subjects received placebo or one of two dosages of a primed constant infusion of the NO-synthase inhibitor N-monomethyl-L-arginine (L-NMMA) in a randomized, double-blind, three-way crossover trial. Histamine was coinfused for 15 minutes at 0.16 microg/kg/min after 30 minutes of pretreatment with either placebo or L-NMMA. Thirty minutes after either the low or the high L-NMMA dose was started, which caused, respectively, a 40% decrease and a 60% decrease in exhaled end expiratory NO level (p = 0.008), there was no increase in von Willebrand factor antigen (vWf-Ag) level (p > 0.05). Histamine caused an 11% (95% confidence interval (CI): 0.4% to 22%; p = 0.011) increase in vWf-Ag level at 125 minutes. After pretreatment with the low and the high L-NMMA doses, vWf-Ag level increased by 18% (Cl: 5% to 31%; p = 0.011) and by 29% (CI: 15% to 42%; p = 0.008), respectively. At 125 minutes, vWf-Ag level was significantly higher after either L-NMMA pretreatment when compared with the results after histamine alone (p < 0.05). In conclusion, the infusion of histamine increased vWf-Ag level, and the inhibition of NO-synthase enhanced this effect, whereas it did not by itself elevate vWf-Ag level. Thus endogenously produced NO may dampen the regulated pathway of vWf secretion; it will be interesting to investigate whether endogenous NO production also inhibits vWf release caused by other stimulators.

Antigens↗