Effect of Propranolol as Antiadhesive Therapy in Sickle Cell Disease

Abstract

Sickle red blood cells (SSRBCs) adhere to both endothelial cells (ECs) and the extracellular matrix. Epinephrine elevates cAMP in SSRBCs and increases adhesion of SSRBCs to ECs in a β adrenergic receptor and protein kinase A-dependent manner. Studies in vitro as well as in vivo have suggested that adrenergic stimuli like epinephrine may contribute to vaso-occlusion associated with physiologic stress. We conducted both animal studies and a Phase I dose-escalation study in sickle cell disease (SCD) patients to investigate whether systemically administered propranolol inhibits SSRBC adhesion and to document the safety of propranolol in SCD. Systemically administered propranolol prevented SSRBC adhesion and associated vaso-occlusion in a mouse model. In patients receiving a single oral dose of 10, 20 or 40 mg propranolol, SSRBC adhesion to ECs was studied before and after propranolol, with and without stimulation with epinephrine. Propranolol administration significantly reduced epinephrine-stimulated SSRBC adhesion in a dose dependent manner (p=0.03), with maximum inhibition achieved at 40 mg. Adverse events were not severe, did not show dose dependence, and were likely unrelated to drug. No significant heart rate changes occurred. These results imply that β blockers may have a role as anti-adhesive therapy for SCD.

Sickle cell disease biochip: a functional red blood cell adhesion assay for monitoring sickle cell disease

“…148 Beta-adrenergic receptor blockade, which targets epinephrine-mediated red cell adhesion, 95,149-152 has been used in patients, using an U.S. Food and Drug Administration (FDA) approved medication (propranolol). 153 Red cell adhesion to an activated endothelium has specifically been targeted with small molecules ( α V β 3 ), 154 low-molecular-weight heparin (P-Selectin), 155,156 and an oral agent in phase I/II studies in humans (P-selectin). 125,157,158 Abnormal interactions between leukocytes and activated endothelium and endothelial selectins have been targeted in vitro and in vivo with antibodies and small molecules 159-162 and are now the focus of phase II and III clinical studies in SCD.…”

Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies

“…Propranolol was administered to SCD patients in a phase 1 dose escalation study and significantly reduced epinephrinestimulated SS-RBC adhesion in a dose-dependent manner. 38 Adverse events were not severe, did not show dose dependence, and were likely unrelated to drug. These results imply that b-blockers have a potential role as antiadhesive therapy via inhibition of cAMP-mediated inhibition of SS-RBC adhesion, which did not always correlate with areas of leukocyte adhesion.…”

Emerging drugs for sickle cell anemia

“…Adverse events were not severe, did not vary with the dose administered and no elevation in heart rate was noted. These results imply that β-blockers have a potential role in inhibiting RBC adhesion [61]. A phase 2 study of propranolol in SCD has been completed and no data has been reported at the time that this manuscript was written (NCT 01077921).…”