ABSTRACT
Thalassemia and sickle cell disease (SCD) are among the most common inherited diseases worldwide. Red blood cell transfusion is a cornerstone of their treatment, but its indications have significantly changed over the past years. New therapies are emerging in both syndromes: among them, hematopoietic stem cell transplantation is now routinely proposed, and gene therapy has shown promising preliminary results.
Subject(s)
Erythrocyte Transfusion , Hemoglobinopathies/therapy , Allografts , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/therapy , Child , Emergencies , Exchange Transfusion, Whole Blood , Genetic Therapy , Hematopoietic Stem Cell Transplantation , Humans , Hydroxyurea/therapeutic use , Multiple Organ Failure/therapy , Thalassemia/therapyABSTRACT
OBJECTIVE: On the basis of previous animal studies, we hypothesized that dexamethasone may reduce the expression of L-selectin on neutrophils and lymphocytes in healthy men. METHODS: A double-blind, randomized, placebo-controlled, and three-way crossover trial was conducted in nine healthy men. Every subject received four identical infusions of saline solution, 0.04 mg/kg dexamethasone, or 1.0 mg/kg dexamethasone during three observation periods of 48 hours each. RESULTS: Dexamethasone time and dose dependently decreased the L-selectin expression on neutrophils and lymphocytes as measured by flowcytometry. This effect occurred with a time lag of 8 hours after start of treatment: the L-selectin binding index of neutrophils decreased by a maximum of -50% (confidence interval [CI], -37% to -63%) and that of lymphocytes by -26% (CI, -8% to -45%) at 32 hours after the start of treatment with high-dose dexamethasone (p < 0.016). Low-dose dexamethasone had only a transient effect on L-selectin expression of lymphocytes and a less pronounced effect on L-selectin expression of neutrophils. CONCLUSION: Dexamethasone time and dose dependently decreases L-selectin expression on neutrophils and lymphocytes in health men, an effect that is less pronounced than that previously reported for animals.
Subject(s)
Dexamethasone/pharmacology , Glucocorticoids/pharmacology , L-Selectin/drug effects , Lymphocytes/drug effects , Neutrophils/drug effects , Adult , Analysis of Variance , Cross-Over Studies , Double-Blind Method , Down-Regulation/drug effects , Humans , L-Selectin/blood , Lymphocytes/immunology , Male , Neutrophils/immunology , Reference ValuesABSTRACT
Based on an in vitro study and an uncontrolled in vivo trial we examined the effects of indomethacin on the expression of L-selectin by leukocytes in healthy volunteers. Eight subjects received infusions of 0.7 mg/kg indomethacin and placebo t.i.d. (three times daily) in a randomized, controlled trial. Indomethacin decreased the mean fluorescence intensity of the L-selectin expression on isolated neutrophils incubated with toxic indomethacin concentrations. However, indomethacin did not lower the L-selectin expression in whole blood or in-vivo. Thus, therapeutic doses of the cyclo-oxygenase inhibitor indomethacin do not lower the L-selectin expression on leukocytes. Hence, the inhibition of cyclo-oxygenase cannot explain the previously observed dexamethasone-induced decrease in L-selectin.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Indomethacin/pharmacology , L-Selectin/blood , Adult , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Cross-Over Studies , Cyclooxygenase Inhibitors/pharmacology , Cyclooxygenase Inhibitors/toxicity , Double-Blind Method , Down-Regulation/drug effects , Humans , In Vitro Techniques , Indomethacin/toxicity , Leukocytes/drug effects , Leukocytes/immunology , Neutrophils/drug effects , Neutrophils/immunologyABSTRACT
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.