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Download Tadalafil (Cialis) or Sildenafil (Viagra) to Protect Muscles in DMD?
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Tadalafil (Cialis) or Sildenafil (Viagra) to Protect Muscles in DMD? Ron Victor, M.D. Burns & Allen Chair Associate Director, Cedars-Sinai Heart Institute Professor of Medicine, UCLA (Center for DMD) Outline • Premise -why Cialis or Viagra for DMD? • Promise -benefits in children with pulmonary HTN -benefits in mdx mice and zebrafish model of DMD • Preview -our PPMD study in boys with DMD Premise Neuronal nitric oxide synthase (nNOS) is a dystrophinassociated protein in skeletal muscle. Muscle cell Lai, Thomas et al., JCI 2009; commentary by Heydermann & McNally Healthy muscles make nitric oxide working muscle Nitric Oxide nNOS blood vessels enlarge oxygen delivery Dystrophin-deficient muscles make only tiny amounts of nitric oxide nNOS Nitric Oxide DMD muscle oxygen deficit blood vessels clamp down Victor, Thomas et al. mdx mouse nNOS knock out mouse boys with DMD Cialis and Viagra boost cGMP … in blood vessels that feed muscles DMD muscle Nitric Oxide nNOS Less hurt? cGMP oxygen restored? blood vessels enlarge? Promise Cialis and Viagra prevent postexercise fatigue in mdx mice mdx mice untreated “fatigue” Kobayashi et al., Nature 2008 Blood vessels clamped down Cialis Blood vessels enlarged The clinical translation gap # research papers per year 60 50 mdx mice 40 30 20 10 dystrophin gene discovered DMD BMD 0 1980 1985 1990 1995 2000 2005 2010 Acute Cialis for BMD? Cialis or Viagra for DMD? Preview (study starts next week)…. Objec&ves To plan for a multicenter clinical outcomes trial, we first designed a dose-finding study comparing open-label Cialis and Viagra on: Muscle oxygen delivery Safety and tolerability Clinically meaningful outcomes Cialis or Viagra? Cialis • Long acting (1 /day) • Less costly • Well absorbed • No drop in BP • Specific cGMP Viagra • Short acting (4 /day) • More costly • Less well absorbed • Small drops in BP • “Off target” cAMP Enrollment Target enrollment 30 patients Inclusion criteria -Proven DMD -Ages 7-15 -Ambulatory (6 MWT) -Normal echocardiogram (standard measures) Exclusion criteria -Heart failure -Very high blood pressure -Irregular heart rhythm -Other risk factors -Severe attention deficit Participation Duration of participation 6 research clinic visits in 8 weeks Study protocol -Baseline visits- weeks 1 and 2 -Randomize patients to Cialis or Viagra target week enrollment 30 dose-week boys -First drug: low dose3, high 4 -Washout- weeks 5 and 6 -Second drug: low dose- week 7, high dose week 8 Research Clinic Tests Muscle Six oxygen and blood flow—handgrip test target enrollment 30 boys minute walk test (2 in a row: fatigability?) Special Echocardiogram (early abnormalities) Other Measures Home -Accelerometer -Holter monitor Patient reported outcomes -Quality of life target enrollment 30 boys -Perceived effort and perceived hurt (6MWT) Safety Monitoring How -Questionnaires -Nurse phone calls -Holter monitoring -Blood pressure checks Side-effects -Indigestion -Headaches -Dizziness Adverse events -Prolonged erection -Loss of vision -Loss of hearing -Irregular heart rhythm -Low blood pressure Closing comments Cialis and Viagra • will not cure DMD • may permit more exercise with less muscle injury (skeletal & heart muscle) • may slow disease progression • no new drug development is needed • adjunct to gene therapy for DMD Hypertension & Vascular Biology Clinical Research Center Many thanks! Gail Thomas UPenn-CHOP Lee Sweeney Rick Finkel U of Florida Barry Byrne Krista Vandendborne Glenn Walter Melissa Spencer, R. Elashoff, Stan Nelson, Carrie Miceli Parent Advisors Stan Nelson and Carrie Miceli Mindy Cameron Ariane Salvatori Amy Martin Cathy and Scott Jones Debra Miller Pat Furlong Sharon Hesterlee
