TOPICAL VITAMIN D TREATMENT FOR SKIN DISEASE AND AGING

DESCRIPTION: (adapted from applicant's abstract) The objectives of this proposal are two-fold: a) the development of a new topical product for the treatment of acne vulgaris, and b) the development of a new topical product for the treatment of premature aging of the skin caused by inflammation, PMNL activation, and keratinization disorders. The hypothesis is that infection and corresponding PMNL activation increase the level of inflammatory response in skin and induce oxidative bursts in PMNLs. The enhanced oxidative stress results in damage to the skin. The new topical product(s) will contain a fluorinated derivative of Vitamin D3, ST-630 as the active ingredient. This Phase I proposal is hoping to establish that ST-630: a) penetrates into and through human skin in vitro; b) inhibits the generation of reactive oxygen species (ROS) in keratinocytes and neutrophils (hence preventing oxidative stress); c) has antiproliferative and prodifferative activities in keratinocytes; d) inhibits the growth of P. acnes, one of the primary pathogenic factors for acne development; and, ) reduces the oxidative damage and antioxidant depletion in animals after UV irradiation. The formulations proposed are oil-in-water creams which will be designed to minimize the potential for systemic signs of hypercalcemia and the potential for local irritation. Penederm has developed a proprietary excipient, PP2 (polyolprepolymer 2, a liquid polyol, molecular weight 4000 Daltons). This ingredient has been shown to retain ST-630 within the skin and, hence, will hopefully reduce systemic accumulation of the drug. Several Vitamin D derivatives have been reported in the literature including calcitriol and calcipotriene (calcipotriol). These were observed to be effective in the treatment of psoriasis. Recently, Wiseman showed that cholecalciferol and calcitriol inhibit iron-dependent lipid peroxidation in vitro. Vitamin D3 is formed in humans by the action of sunlight on the skin, and thus, its antioxidant action should help protect the cells in which it is formed against the aging and carcinogenic effects of UV light caused in part by peroxidation of cell - CONTINUED ON NEXT PAGE 1QUERY 1536 ID SEARCH 06/01/98 PAGE 14 --PROJECT NUMBER......1 R43 AG13572-01A1 (Continued) membranes. ST-630 is a synthetic analog of calcitriol and was found more potent than the parent compound in several assays: 10-fold in the in vitro suppression of the proliferation of human promyelocytic leukemia cells, 20-50-fold increase in the in vitro differentiation of HL-60 cells, etc. This higher activity may be due to the longer half-life of ST-630 or due to the fact that its major metabolite, ST-232, is both stable and active. $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 15 --PROJECT NUMBER......2 R44 AG13731-02 INVESTIGATOR NAME/ADDRESS FY 97 CUTLER, NEAL E IRG/INTRAMURAL UNIT..ZRG2 NATIONAL COUNCIL ON THE AGING AWARD AMOUNT......... $415,226 409 THIRD STREET WASHINGTON, DC 20024 PERFORMING ORGANIZATION: NATIONAL COUNCIL ON AGING DEVELOP CORP. TITLE DECISION SUPPORT SOFTWARE FOR FINANCING LONG TERM CARE ABSTRACT: This research will produce two consumer-oriented software products to assist middle-aged and older adults to identify personal health and financial risks of needing long-term care, long-term care service and finance options, and alternative strategies for financing needed care. The project will create two information Domains: (1) The Duke University Center for Demographic Studies will use existing health care models and NLTCS longitudinal data to estimate individual-level probabilities of long-term care need; (2) NCOADC will create a comprehensive inventory of LTC service and financing options. Using these Domains, the software will assist the consumer in answering such questions as: -- if you are given estimates of your probable lifetime need for and costs of LTC, what (different) decisions might you make? -- How might information about alternatives to nursing homes influence your financial and health care planning? (1) In partnership with Intuit Corporation, we will develop a long-term care module for Intuit's Quicken Financial Planner, whose primary market is middle-agers doing retirement and financial planning. (2) NCOADC will develop a separate package, Your Long-term Care Counselor Software and Consumer Guide, whose primary market is older people, their families, and professionals involved with more current LTC decisions.