• Evaluate the effect of simvastatin on biomarkers of: 1) vasoreactivity (NO, ET-1), 2) endothelial adhesion (VCAM-1), VEGF), and 3) inflammation (CRP, IL-6, TF) in three escalating dosage (low, moderate, and high) groups. [ Time Frame: 25 days ]
  

• Safety and tolerability of simvastatin in patients with sickle cell disease, as measured by changes in clinical (P.E.; adverse affects) and laboratory (hematologic, renal, hepatic and lipid) profiles. [ Time Frame: 25 days ]
  

Drug: Simvastatin
20 mg PO once daily for 21 days, followed by a 4-day taper. If this dose is safe and tolerable in the first group of 12 subjects, then the dose will be escalated to 40 mg PO once daily for 21 days, followed by a 4-day taper in the second group of 12 subjects. If the drug is safe and tolerable in this group, then the dose will be escalated to 80 mg PO once daily for 21 days, followed by a 4-day taper in the final group of 12 subjects.

Although statins have been used extensively for their cholesterol-lowering effects, recent clinical and experimental data indicate that statins regulate yet other processes, many of which play a major role in sickle cell disease (SCD). Independent of their cholesterol-lowering effects, statins have been shown to prevent damage to blood vessels in several ways, including the upregulation of endothelial nitric oxide (NO). Numerous studies documenting the protective effects of statins, together with data showing the therapeutic role of NO in SCD, provide the basis for investigating the potential clinical benefit of simvastatin in SCD.

Data supporting the safety and tolerability of simvastatin in patients with SCD are now needed. For this phase I/II dose-escalation study of oral simvastatin in SCD, we propose the following specific aims:

1. To determine specific dose-response effects of oral simvastatin on patients with SCD, and
2. To assess the safety and tolerability of oral simvastatin in patients with SCD.