Effect of Modulating the nNOS System on Cardiac, Muscular and Cognitive Function in Becker Muscular Dystrophy Patients

• Status: Completed
• Trial end date: 2013-04-01
• Target enrollment: 0
• Participant gender: Male

Summary

This study is done to evaluate whether treatment with the drug sildenafil (Revatio®) can improve muscular, cardiac, cerebrovascular or cognitive function in patients with Beckers muscular dystrophy when compared to placebo (inactive medication). The study is based on the recent findings of an improved cardiac function in a mouse model of muscular dystrophy (Adamo et al 2010) and the previous findings of changed cognitive function in people with Becker dystrophy.

In muscular dystrophy, the cellular protein, dystrophin is affected. During normal conditions, the enzyme neuronal nitric oxide synthase (nNOS), which produce nitric oxide (NO), is attached to dystrophin. NO is important in normal vascular function in each of muscle, heart and brain by stimulating production of cyclic GMP. However, in muscular dystrophy with dystrophin deficiency, nNOS do not have the normal cellular anchor, resulting in decreased NO levels and subsequent reduced cyclic GMP production. Sildenafil inhibits degradation of cGMP thus prolonging and increasing a cGMP response. Such effects are the basis for use of sildenafil in pulmonary hypertension and erectile dysfunction. Current hypothesis: Sildenafil restores the cyclic GMP function affected in muscular dystrophy wit nNOS deficiency resulting in improved muscle, cardiac, cerebrovascular and cognitive function.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Rigshospitalet, Denmark
• Collaborator: Glostrup University Hospital, Copenhagen
• Treatments: Sildenafil Citrate

Criteria

Inclusion Criteria:

• Muscular dystrophy with known deficiency in nNOS

• Reduced cardiac function (<50%) and/or reduced muscular function (MRC<4+)

• Stable dosing (> 3 month)of cardiovascular medication

• Signed informed consent

Exclusion Criteria:

• Recent (< 6 month) cerebral or cardiac stroke

• Use of nitrate containing compounds, alpha receptor blocking agents or potent CUP3A4 inhibitors.

• Intolerance or allergy to sildenafil, or intake of drugs not compatible with sildenafil intake

• Overuse of drugs or alcohol

• inclusion in other trials of experimental medication within last 30 days

• known epilepsy

• reduced liver function (ASAT >500U/l in 2 repeated measurements when corrected for increase in creatinkinase levels.

• non-arteriitis anterior ischemic optic neuropathy (NAION) with reduced vision

• contraindications for MRI scan (metal implants, claustrophobia)

• hypotension (<90 mmHg systolic at baseline)

• conditions, medical or psychosocial which makes the subject inclusion inadvisable