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

The current clinical trial including people with Becker's muscular dystrophy and established deficiency in muscular content of nNOS protein consist of three sub-studies focusing on each of muscle function, cardiac function and brain function. In muscular dystrophy the dystrophin cellular complex usually located to muscle cells, is disrupted resulting in a known reduced nNOS activity. The reduced nNOS leads to reduced cyclic GMP production. nNOS and cyclic GMP are involved in the vascular response in striate muscle, cardiac vessels as well as the cerebrovascular response to hypercapnia and regional activation. In muscular dystrophy, the is an affected muscular and cardiac function and in some patients a changed cognitive function in described. Whether such is related to a reduced nNOS function and subsequent cGMP production is not fully understood. Inhibition of cGMP degradation by inhibiting the cGMP degrading enzyme phosphodiesterase 5 (PDE5) using PDE5 inhibitors such as sildenafil may result in restoration of vascular responses.

The study is designed as a double blind, randomised, balanced, placebo-controlled cross-over study performed during a 10 week treatment period. The patients will receive 4 weeks of either sildenafil or placebo with a 2 week washout period in between treatments. The study out-come parameters will be performed on two consecutive days at baseline, 4 weeks and 10 weeks, at two collaborating centers, Rigshospitalet for muscle and cardiac parameters and Glostrup Hospital for cerebrovascular and cognitive parameters.

The primary endpoints relate to each sub-study, assessing and comparing individual changes from baseline and during placebo/sildenafil treatment.

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