The Effects of ATLAS Therapy on Nitric Oxide Bioavailability in Patients With Intermittent Claudication

The primary objective of this study is to show that ATLAS Therapy, (L-Arginine; Tetrahydrobiopterin; L-Ascorbate) is bioavailable in humans and exerts a measurable effect on its in vivo biological signature, Flow Mediated Vasodilation (FMD) in people with intermittent claudication caused by peripheral arterial disease. This will be a Phase I / dose finding study. All subjects will receive 2 different drug doses of the Kuvan the first 45 days they will receive 10 mg/kg/day. The second 45 days they will receive 20/mg/kg/day.

Inclusion criteria

• PAD as demonstrated by an ABI <0 .9 in one leg or TBI less than <0.7 in patients with an ABI >1.3 (non compressible vessels)
• Rutherford Classification II, III
• Age >18 years old
• Willingness to discontinue phosphodiesterase (PDE) 5 inhibitors such as Viagra, Cialis, Levitra, Revatio
• Willingness to discontinue phosphodiesterase (PDE) 3inhibitors cilostazol, milrinone or Vesnarinone
• Willing and able to comply with all study procedures
• Willing and able to provide informed consent
• Sexually active subjects willing to use an acceptable method of contraception while participating in the study

Exclusion criteria

• Hypotension defined as a systolic blood pressure less than 100mmhg systolic at screening or baseline visit
• Critical Leg Ischemia (Rutherford Classification IV, V, VI)
• Surgical intervention to alleviate symptoms of claudication in the study leg within the past 6 months or any endovascular interventions within 3 months or who is scheduled to undergo surgical revascularization in the next 6 month
• Walking limited by reasons other than claudication (e.g. arthritis, lung disease, severe neuropathy, lower extremity amputation except single digits)
• Serum creatinine >1.5mg/dl or Hepatic enzymes >2X the upper limit of normal
• Serum potassium greater than 5.0 or use of a potassium sparing diuretic at screening
• Pregnant, breast feeding or planning to become pregnant (subject or partner) at any time during the study.
• Myocardial Infarction, Cerebrovascular Accident or deep vein thrombosis within 12 months of screening
• Known history of nephrolithiasis
• History of ever having a seizure
• Concurrent disease or condition that would interfere with study participation or safety such as bleeding disorders, organ transplant, long term immunosuppression (excluding inhaled steroids), current neoplasm or severe gastroesophageal reflux
• History of vertigo or syncope within the past 10 years
• Enrollment in another drug or device study within 30 days of screening
• Required treatment with a drug known to inhibit folate metabolism (e.g. Methotrexate)
• Taking any of the following medications; PDE3 Inhibitors, PDE5 inhibitors, trental, nitrates, ginkgo biloba, levodopa, warfarin,
• Axillary lymph node dissection
• Presence of an amputation except single digits in either leg
• Preexisting illness that limits ambulation such as severe COPD, class III-IV heart failure, severe arthritis or back pain
• Glucose-6-dehydrogenase deficiency