Phase 1 Study of the Effects of Combining Topical FDA-approved Drugs on Age-related Pathways on the Skin of Healthy Volunteers

The primary endpoint of the study is the profile of differences in transcript levels of age-associated genes such as those in the lamin-A, insulin like growth factor (IGF) and NFKB pathways as well as noncoding RNAs in topical agent-exposed arm skin versus placebo exposed arm skin in healthy volunteers. The secondary endpoints include (1) differences in skin wrinkling using a 4 point Likert scale for wrinkle severity between placebo and topical agent exposed arm skin after 4 weeks of usage; (2) the type and severity of adverse events, both systemic and skin localized after exposure to both topical agent and placebo vehicle cream.

Inclusion criteria

• Age greater than or equal to 55 years
• Female
• All 4 grandparents of European descent
• Fitzpatrick Skin type 1-3 (fair skin type)
• Presence of moderate to severe fine wrinkling on arm skin
• Presence of moderate to severe dyspigmentation on arm skin
• Normal or overweight body mass index

Exclusion criteria

• History of laser treatment or chemical peels to to arm
• History of topical anti-aging products (includes retinol, tretinoin, tazarotene, azelaic acid, hydroquinone) to skin within 6 weeks of starting study
• History of surgical procedures to arm skin area including removal of benign or malignant skin cancers in the area of topical study agent application
• Current skin conditions in the area of arms including seborrheic keratosis, rosacea, eczema that may obscure study assessment
• History of abnormal scarring
• Uncontrolled medical problems including concurrent infection or malignancy at time of enrollment
• Unable to provide and sign written informed consent
• Unable to comply with study-related procedures including keeping study diary, application of topical study agents, avoidance of direct sun exposure >5 minutes per day or ultraviolet tanning bed usage
• Not willing to provide two small skin biopsies at end of study
• Known allergy to sirolimus, diclofenac or metformin.
• Known immunosuppression including organ transplant, HIV, autoimmune disease, and chronic leukemia or lymphoma
• Fasting blood sugar above the upper limit of normal for Stanford laboratory
• Diarrhea
• Use of greater than one alcoholic beverage per day
• Stress such as surgery or trauma within 2 weeks of enrollment
• Liver disease such as hepatitis B or C
• Planning to embark on dieting, caloric restriction or new exercise regimen during the study to lose weight.
• Unable to refrain from using any topical agent on arms besides the study agents provided for duration of study.
• Hematocrit, hemoglobin, platelets, white blood cell count, serum Na, K, Cr, aspartate aminotransferase (AST), alanine aminotransferase (ALT) greater or lesser than 1.5 times limits of normal.
• History of heart failure, coronary artery disease, including angina, coronary artery bypass graft, pacemaker or stent placement
• History of bleeding or ulcers of the gastrointestinal tract
• History of diabetes mellitus
• Current use of blood thinners (includes heparin, warfarin and aspirin)
• Current use of strong cytochrome P 450 (CYP) 3A4 inhibitor and/or P-gp (examples include ketoconazole, voriconazole, itraconazole, erythromycin, clarithromycin) or strong inducers of CYP3A4 and/or P-gp (examples include rifampin or rifabutin)
• Abnormal lipid panel as defined by upper limit of normal at Stanford laboratory