We hypothesize that treatment of sickle cell patients with NAC results in reduced red cell PS exposure, reduced endothelial activation, increased NO availability, reduced coagulation activation and reduced inflammation detectable with specific…
ID
Bron
Verkorte titel
Aandoening
sickle cell disease (anemia), hypoxia-reperfusion injury, endothelial damage, oxidative stress, NO-availability, inflammation, sikkelcelziekte, chronische ontsteking, endotheelschade.
Ondersteuning
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
Primary end-points are the effects of NAC on the laboratory markers (hemoglobin, red blood cell counts, reticulocyte counts, leukocyte counts and differentiation, platelet counts, erythrocyte sedimentation rate, a blood smear will be analyzed microscopically for the number of ISC per field, as well as the number of Heinz bodies, intra-erythrocytic GSH and GSSG levels, NO availability, SRBC phosphatidylserine (PS) exposure, annexin V, creatinine, BUN, electrolytes, transaminase levels, albumin levels, LDH, indirect bilirubin levels, free hemoglobin levels, high sensitive CRP, sVCAM-1, ET-1, IL-8, pro-thrombin fragments (F1.2), D-dimer levels, protein S (free and total) and C activity, vWF-Ag activity).
Achtergrond van het onderzoek
The pathophysiology of sickle cell vasoocclusion is of a complex nature. It is now clear that, next to erythrocyte rigidity, the pathophysiology of sickle cell vasoocclusion involves cytokines, adhesion molecules, thrombus formation, platelet-, leukocyte- and endothelial activation, reactive oxygen species (ROS). Thus, it seems that in vivo, a complex interplay between many biological factors determine the extent to which vasoocclusion occurs in a given patient.
Gluthation (GSH), an amino-thiol (a thiol is a molecule with a SH group) is the most abundant antioxidant in our body and is a crucial defense against free radicals. Our body is equipped with a vast array of antioxidant substances for protection against oxidative stressors in health (varying from sun-light exposure to tobacco smoking) and disease (atherosclerosis, sepsis). NAC is highly permeable to cell membranes and within the cytoplasm it is converted to L-cysteine, which is a precursor to GSH. It is well known as a mucolytic agent and for treatment of acetaminophen induced liver toxicity. NAC has been investigated for treatment of many disease states, such as cardiovascular disease, human immunodeficiency virus infections, sepsis and acute respiratory distress syndrome. NAC is an important antioxidant with pleiotropic effects on inflammation and vasomotor function. Reactive oxygen species (ROS) may play a central role in the pathophysiology of SCD related vascular occlusion and organ damage, and NAC administration to patients with SCD may be of benefit via several mechanisms as detailed below.
Objectives:
To determine whether NAC therapy results in decreased red cell PS exposure, endothelial activation, inflammation, and reduction in clotting activation in the steady state.
Doel van het onderzoek
We hypothesize that treatment of sickle cell patients with NAC results in reduced red cell PS exposure, reduced endothelial activation, increased NO availability, reduced coagulation activation and reduced inflammation detectable with specific laboratory testing, as well as a reduction of ISC's and Heinz Body formation
Onderzoeksproduct en/of interventie
N-acetylcysteine 1200 mg or 2400 mg a day.
Publiek
P.O. Box 22660
B.J. Biemond
Meibergdreef 9
Amsterdam 1100 DD
The Netherlands
+31 (0)20 5667391
b.j.biemond@amc.uva.nl
Wetenschappelijk
P.O. Box 22660
B.J. Biemond
Meibergdreef 9
Amsterdam 1100 DD
The Netherlands
+31 (0)20 5667391
b.j.biemond@amc.uva.nl
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
1. High performance liquid chromatography confirmed diagnosis of HbSS, HbSC or HbSâ genotype .
2. Aged 18-65 years
3. Written informed consent
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
1. Bloodtransfusion in the preceding four months.
2. Pregnancy or the desire to get pregnant in the following 7 months.
3. Concommitant use of hydroxyurea, vitamin K antagonists or other oral anticoagulants, or contraindications for NAC.
4. Impaired renal function of more than 60% (as assessed by the Kockroft-Gauld equation)
5. Known gatsric or duodenal ulcer
6. Concomittant use of anti-hypertensives, sildefanil or nitrates.
Opzet
Deelname
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Andere (mogelijk minder actuele) registraties in dit register
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In overige registers
| Register | ID |
|---|---|
| NTR-new | NL985 |
| NTR-old | NTR1013 |
| Ander register | : |
| ISRCTN | ISRCTN28828586 |
Samenvatting resultaten
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