Simvastatin in Chronic Obstructive Pulmonary Disease (COPD)

• The difference in serum high sensitivity C-reactive protein (HsCRP) between simvastatin and placebo [ Time Frame: 4 checks over a four month period at 2 weeks, 10 weeks, 14 weeks and 22 weeks. ] [ Designated as safety issue: No ]
  

• The difference between treatment with simvastatin and placebo for Clinical COPD Questionnaire [ Time Frame: 4 months ] [ Designated as safety issue: No ]
  
• The difference between treatment with simvastatin and placebo for Spirometry - FEV1, FVC, FEV1/FVC ratio [ Time Frame: 4 months ] [ Designated as safety issue: No ]
  
• The difference between treatment with simvastatin and placebo for Induced sputum differential cell count [ Time Frame: 4 months ] [ Designated as safety issue: No ]
  
• The difference between treatment with simvastatin and placebo for Induced sputum mRNA for MMP and TIMPs [ Time Frame: 4 months ] [ Designated as safety issue: No ]
  
• The difference between treatment with simvastatin and placebo for Exhaled breath condensate 8-isoprostane concentration [ Time Frame: 4 Months ] [ Designated as safety issue: No ]
  
• The difference between treatment with simvastatin and placebo for Serum TNFa [ Time Frame: 4 months ] [ Designated as safety issue: No ]
  
• The difference between treatment with simvastatin and placebo for Cholesterol [ Time Frame: 4 Months ] [ Designated as safety issue: No ]
  

Statins (HMG-Coenzyme A reductase inhibitors) are widely used clinically as lipid lowering drugs; however they have also been shown to exhibit anti-inflammatory and anti-oxidant properties(1). Recently published large retrospective cohort studies, in patients with chronic obstructive pulmonary disease (COPD), suggest that statins reduce mortality and COPD related admissions(2). Possible mechanisms of action include effects on cell adhesion molecules, changes in inflammatory mediator release, antioxidant effect and increased clearance of apoptoic cells. Simvastatin has been shown to reduce the development of smoking induced emphysema in rats with reductions in MMP-9 activity and simvastatin withdrawal leads to increased MMP levels in hypercholesterolaemic patients. Serum concentrations of TNFa and high sensitive C Reactive protein(3) (hs-CRP) are reduced with simvastatin therapy in patients with hypercholesterolaemia and risk of cardiovascular disease respectively. No clinical trial has directly evaluated the clinical effects of statins in patients with COPD in terms of induced sputum MMP profile, alveolar nitric oxide or pulmonary physiology.

We have modified our published method of RNA purification, developed to purify RNA from cartilage, tendon or synovium(4), to yield good quality RNA from sputum with relative simplicity and low cost. We have identified MMP-2, -9 and -14 in the sputum of healthy volunteers (unpublished pilot data) and will utilise this technique in the current study. Exhaled breath condensate (EBC) is completely non-invasive, requires no co-operation from individuals and provides information about a number of inflammatory and oxidation pathways. Markers of oxidative stress (8-isoprostane and hydrogen peroxide) and nitric oxide products can be measured in exhale breath condensate(5) and are related to disease activity in patients with COPD. Markers of oxidative stress increase in concentration in EBC during exacerbations of COPD are reduced after treatment with the antioxidant N-acetyl cysteine(6). Hydrogen peroxide is not stable and therefore 8-isoprostane is a preferable marker of oxidative stress unless the sample is measured on line.