Healthy Volunteers, Sepsis
Conditions
Keywords
human endotoxemia, tissue factor induced coagulation, platelet activation, thienopyridines
Brief summary
Severe sepsis still carries a high mortality rate despite advantages in intensive care medicine and antimicrobial therapy. The inflammatory and procoagulant host response to infection are intricately linked and interactions between platelets, leukocytes and the endothelium play a central role in the pathogenesis of septic shock and disseminated intravascular coagulation (DIC). Interestingly, one key player cell in coagulation, i.e. the platelet, has been somewhat neglected as to its position in the pathogenesis of coagulation abnormalities in sepsis. However, thienopyridines, irreversible platelet P2Y12 ADP-receptor antagonists, e.g. prasugrel, could potentially provide beneficial anticoagulatory and antiinflammatory effects: P2Y12 ADP-receptor antagonists reduce TF-induced coagulation activation in various ex vivo and in vitro models. Moreover, various lines of evidence indicate that thienopyridines may block platelet leukocyte interactions and thereby reduce the propagation of the coagulation and inflammation process. LPS-infusion in healthy volunteers provides a standardized model to safely study non overt DIC and to document possible effects of therapeutic and prophylactic interventions. The investigators hypothesize that thienopyridines, irreversible platelet P2Y12 ADP-receptor antagonists, may blunt TF-triggered coagulation activation in humans, which will be studied in a TF-dependent coagulation model in humans.
Interventions
DRUGPrasugrel
Prasugrel will be given as loading dose (60mg) on the first trial day two hours prior to endotoxin infusion. Prasugrel is an orally administered prodrug that is converted in the liver by CYP to its active metabolite.
DRUGPlacebo
A pharmacist not otherwise involved in the trial will encapsulate pills consisting of lactose-starch. Six pills will be administered as placebo 2 hours before LPS administration on trial day 1.
Sponsors
Medical University of Vienna
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
19 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Signed informed consent obtained before any trial-related activities. * Men aged \>18 and \<41 years * Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant * Normal laboratory values unless the investigator considers an abnormality to be clinically irrelevant
Exclusion criteria
* Known or suspected allergy to trial product or related products (Prasugrel, Clopidogrel, Ticlopidine) * Known or suspected hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption * Treatment with an investigational drug within three weeks prior to this trial * Treatment with a drug (e.g. ketoconazole, omeprazole) that interferes with cytochrome P450, the enzyme responsible for the conversion of prasugrel to its active form, three weeks prior to this trial * Participation in an LPS trial within the last 6 weeks * Smoking of more than 5 cigarettes per day * Hereditary deficiency of protein C or S, or a mutation of FV (Leiden), or any other known abnormality affecting coagulation, fibrinolysis or platelet function * History of gastro-duodenal ulcera, cardiovascular disease, vasculitis, diabetes mellitus, or hypertension * History of brain tumor or history of neurosurgery * Hemorrhagic diathesis, trauma or surgery within last 3 months * History of hemorrhagic retinopathy * Hematuria or detection of occult blood in stool sample * Liver or kidney dysfunction * Regular use of medication or abuse of alcohol * Use of any medication within one week prior to the first trial day * Symptoms of a clinically relevant illness in the 3 weeks before the first trial day * Excessive sporting activities * Weight \>95kg and \<60kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| prothrombin fragments (F1+2) | -2 to 24 hours after LPS infusion | To explore whether P2Y12 ADP-receptor antagonism can block activation of the coagulation cascade induced by endotoxemia, in particular decrease LPS mediated thrombin formation as measured by prothrombin fragment (F1+2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| platelet-leukocyte co-aggregation | -2 to 24 hours after LPS infusion | to explore whether P2Y12 ADP-receptor antagonism decreases platelet -leukocyte co-aggregation |
| tissue factor expression | -2 to 24 hours after LPS infusion | to investigate the influence of P2Y12 ADP-receptor antagonism on tissue factor expression |
| anti-platelet effects of prasugrel | -2 to 24 hours after LPS infusion | to explore if low dose endotoxemia interferes with the anti-platelet effects of prasugrel |
Countries
Austria
Outcome results
None listed