Paroxetine substantially decreases intraplatelet serotonin content and thereby reduces platelet plug formation under shear stress, and responsiveness to thrombin receptor activating peptide-induced platelet activation. Further studies will reveal whether these pharmacodynamic effects can be exploited for treatment of thrombotic artery disease.
Bleeding due to impaired platelet function is a major side effect of the Bruton´s tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 CTC grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs. 28 U; p<0.0001). RIPA was impaired in patients receiving concomitant anti-platelet therapy or anticoagulation (14 U vs. 25 U, p=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values above 36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.
MCP-1 levels are about 30 percent higher in men than in premenopausal women, and MCP-1 levels are also higher in persons with RBCs expressing Fy antigens than in Fy(a-b-) persons. These findings have direct implications for the concept and interpretation of clinical studies measuring MCP-1 levels; the role of the observed differences in MCP-1 levels for the pathogenesis of MCP-1-dependent diseases, such as atherosclerosis, merits further investigation.
The previously described anti-endotoxin effect of colistin has not been investigated in humans yet. We performed a randomized, double-blind, placebo-controlled crossover trial to determine the degree of colistin-driven modulation of inflammatory response in blood of lipopolysaccharide (LPS)-challenged healthy volunteers in a human endotoxemia model. After a single intravenous dose of 2.5 million IU colistin methanesulfonate, interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), and IL-1β concentrations as well as other biomarkers of inflammation such as C-reactive protein, differential leukocyte counts, and body temperature were measured up to 24 h postdose. Colistin significantly decreased the inflammatory cytokine response to LPS in blood of healthy volunteers. This effect was most evident for IL-6, IL-8, and TNF-α. This study is the first to confirm the anti-endotoxin effect of colistin in humans in vivo. Further studies might increase our knowledge on the interaction between colistin and the effectors of the immune system.
A protective role against atherosclerosis can be attributed to angiotensin converting enzyme inhibitors (ACE-I), since they have been shown to reduce mortality in patients at cardiovascular risk. Since plasma levels of adhesion molecules are considered surrogate markers of endothelial cell activation and atherogenesis, we compared the levels of adhesion molecules after treatment with the ACE-I enalapril or the direct angiotensin- receptor antagonist losartan or placebo. In a randomized, controlled trial, 21 hypercholesterolemic volunteers received 50 mg/d losartan or 20 mg/d enalapril or placebo for twelve weeks. Plasma levels of circulating intercellular adhesion molecule-1 (cICAM-1), vascular adhesion molecule-1 (cVCAM-1), and E-selectin (cE-SEL) were measured by ELISA. Surface expression of ICAM-1 on circulating leukocytes was determined by flow cytometry. Enalapril and losartan but not placebo induced a small but stable decrease of cICAM-1 and cVCAM-1, while cE-SEL and leukocyte expression of ICAM-1 remained unchanged. The lowering of plasma adhesion molecules may indicate an antiatherogenic effect of angiotensin II blockade in hypercholesterolemia. While such preventive effect will have to be proven in clinical trials, our results do not support a preference for either enalapril or losartan with regard to their possible vasoprotective role.
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