Tretinoin is an endogenous retinoid metabolite of Vitamin A that binds to intracellular receptors in the cytosol and nucleus, but cutaneous levels of tretinoin in excess of physiologic concentrations occur following application of a tretinoin containing topical drug product. Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms such as irritation, or both.
The effect of tretinoin on skin with chronic photodamage has not been evaluated in animal studies. When hairless albino mice were treated topically with tretinoin shortly after a period of UVB irradiation, new collagen formation was demonstrated only in photodamaged skin. However, in human skin treated topically, adequate data have not been provided to demonstrate any increase in desmosine, hydroxyproline, or elastin mRNA. Application of 0.1% tretinoin cream to photodamaged human forearm skin was associated with an increase in antibody-staining for procollagen I propeptide. No correlation was made between procollagen I propeptide staining with collagen I levels or with observed clinical effects. Thus, the relationships between the increased collagen in rodents, increased procollagen I propeptide in humans, and the clinical effects of tretinoin have not yet been clearly defined.
Tretinoin was shown to enhance UV stimulated melanogenesis in pigmented mice. Generalized amyloid deposition in the basal layer of tretinoin treated skin was noted in a two year mouse study. In a different study, hyalinization at tretinoin treated skin sites was noted at doses beginning at 0.25 mg/kg in CD-1 mice.
The transdermal absorption of tretinoin from various topical formulations ranged from 1% to 31% of applied dose, depending on whether it was applied to healthy skin or dermatitic skin. When percutaneous absorption of RENOVA (tretinoin emollient cream 0.05%) 0.05% was assessed in healthy male subjects (n=14) after a single application, as well as after repeated daily applications for 28 days, the absorption of tretinoin was less than 2% and endogenous concentrations of tretinoin and its major metabolites were unaltered.
Two adequate and well-controlled trials were conducted involving a total of 161 evaluable patients (under 50 years of age) treated with RENOVA (tretinoin emollient cream 0.05%) 0.05% and 154 evaluable patients treated with the vehicle cream on the face for 24 weeks as an adjunct to a comprehensive skin care and sun avoidance program, to assess the effects on fine wrinkling, mottled hyperpigmentation, and tactile skin roughness. Patients were evaluated at baseline on a 10 point scale and changes from that baseline rating were categorized as follows:
No Improvement: No change or an increase of 1 unit or more.
Minimal Improvement: Reduction of 1 unit.
Moderate Improvement: Reduction of 2 units or more.
In these trials, the fine wrinkles, mottled hyperpigmentation, and tactile roughness of the facial skin were thought to be caused by multiple factors which included intrinsic aging or environmental factors, such as chronic sunlight exposure.
The results of these assessments are as follows:
|NO IMPROVEMENT||MINIMAL IMPROVEMENT||MODERATE IMPROVEMENT|
|RENOVA 0.05% + CSP*||36%||40%||24%|
|Vehicle + CSP||62%||30%||8%|
|RENOVA 0.05% + CSP||35%||27%||38%|
|Vehicle + CSP||53%||21%||27%|
|TACTILE SKIN ROUGHNESS|
|RENOVA 0.05% + CSP||49%||35%||16%|
|Vehicle + CSP||67%||23%||10%|
|*CSP = Comprehensive skin protection and sun avoidance programs included use of sunscreens, protective clothing, and non-prescription emollient creams.|
Most of the improvement in these signs was noted during the first 24 weeks of therapy. Thereafter, therapy primarily maintained the improvement realized during the first 24 weeks.
A majority of patients will lose most mitigating effects of RENOVA (tretinoin emollient cream 0.05%) 0.05% on fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin with discontinuation of a comprehensive skin care and sun avoidance program including RENOVA (tretinoin emollient cream 0.05%) 0.05%; however, the safety and effectiveness of using RENOVA (tretinoin emollient cream 0.05%) 0.05% daily for greater than 48 weeks have not been established.
Last reviewed on RxList: 12/10/2008
This monograph has been modified to include the generic and brand name in many instances.
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