A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome

Exclusion Criteria

• •Patients who have had stem-cell transplantation.
• •Current use of metformin or other anti-diabetic agents, or hypersensitivity or allergy to metformin.
• •Patients who are receiving any other investigational agents.
• •Patients with history of chronic alcohol use
• •History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or other agents used in study.
• •Patients with congestive heart failure requiring pharmacological management.
• •Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• •Gastric paresis
• •Short gut syndrome
• •Inflammatory bowel disease\*
• •Celiac sprue
• •Pancreatic insufficiency or disease
• •Any malabsorption disease/syndrome
• •Chronic PPI use or H2 blocker use that cannot be temporarily discontinued (at least 48 hours)
• •Any acetaminophen, aspirin, NSAID, or statin use within 2 days of testing (known to affect mitochondrial function)
• •Drugs that interfere with mitochondrial function if they are unable to be discontinued 48 hours prior to (13)MBT testing will be excluded for this test only but eligible for the rest of the protocol.
• •Any oral steroid use within 2 weeks of testing
• •Chronic alcohol use\*\* defined as \> 2 standard drinks per day (more than 2 beers, 2 glasses of wine, or 2 shots of liquor per day)
• •* Inflammatory bowel disease will be exclusion for the (13)C-MBT only, because even if well controlled we do not know the effect chronic inflammation in the bowel and steroid use may have on the test. The test analyzes exhaled CO2 in the breath and this can be affected by diet (carbohydrate heavy), exercise, and certain pathologies like liver disease. Also pro-inflammatory mediators have been shown to cause hepatocellular injury that may also interfere with results of the test.
• •* The test is currently being studied as an early detection, non-invasive method for liver cirrhosis. Therefore, patients who have had chronic alcohol use consistent with a regular pattern of alcohol consumption may have underlying liver disease that may affect the CO2 measurement. Further, alcohol changes the NADH/NAD ratio intracellularly and studies have shown that alcohol can inhibit methionine oxidation. Previous protocols utilizing the (13)C-MBT have excluded patients who consume greater than 20 g/day of alcohol. A standard drink is equivalent to approximately 14 g/day of alcohol (one 12 oz beer, one 5 oz glass of wine, or one shot of liquor). This information was obtained from the National Institute of Health/National Institute of Alcohol Abuse and Alcoholism (NIAAA):
• •http://pubs.niaaa.nih.gov/publications/Practitioner/pocketguide/pocket\_guide2.htm). We will also evaluate LFTs and should clinical concern arise, check PT/PTT and albumin. Patients with normal liver function and no substantial history of alcohol abuse will be eligible.
• •Inability to perform exercise with dominant leg
• •Claustrophobia and/or inability to lie flat in MRI machine
• •Metal medical implantable device or other MRI incompatible materials
• •Body mass index under 19 or over 45
• •Prior stem cell transplantation