|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Improves fine and coarse wrinkles by restoring dermal collagen and stimulating glycosaminoglycan synthesis.
Diminishes skin roughness, presumably via a combination of an increase in epidermal thickness, compaction of the stratum corneum and deposition of GAGs.
Tightens loose and sagging skin, possibly by stimulating the secretion of a basic fibroblast growth factor.
Reduces comedones, papules and pustules, and is often prescribed for mild to moderate cases of acne vulgaris.
Decreases the darkness of brown spots and lentigines by reducing epidermal pigmentation. Also pinkens sallow skin.
Makes the stratum corneum more compact and thickens the epidermal layer.
0.1% tretinoin cream led to fewer actinic keratoses in a double-blind, placebo-controlled trial.
Depigments skin by dispersing keratinocyte pigment granules and interfering with pigment transfer and production.
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Table of contents:
- 1. Sources
- 2. Bioavailability
- 3. Effects on the skin
- 4. Side Effects
Tretinoin, also known as all-trans retinoic acid, is a metabolite of Vitamin A (retinol). It is produced in the body from other retinoids that are ingested, such as retinol, retinyl esters and carotenoids. It is also the main bioactive component of rosehip seed oil, in which its concentration has been found to be at least 0.357 ml/L.
Tretinoin penetrates poorly into the skin. When topically applied, approximately 80% of tretinoin remains on the skin surface, and its penetration through the stratum corneum is vehicle-dependent.
While gel-based formulations of tretinoin tend to trap the molecule, keeping it on the surface of the skin, cream formulations increase penetration to a small extent (less than 5% of the applied amount within 30 minutes). The initial diffusion into the stratum corneum takes place relatively rapidly within a few minutes, but further diffusion into the epidermis and dermis proceeds more slowly.
Nano-lipoidal carriers such as solid lipid nanoparticles and nanostructured lipidic carriers have been shown to enhance the photostability and skin delivery of tretinoin.
3. Effects on the skin
3.1 Anti-wrinkle effect
Tretinoin is the benchmark prescription topical treatment for improving fine facial wrinkles.
In 2 randomized, double-blind, vehicle-controlled clinical trials, a total of 360 subjects with photodamage were treated with once-nightly applications of 0.02% tretinoin cream or a placebo. The results indicated that 0.02% tretinoin cream led to statistically significant improvements in fine wrinkles and coarse wrinkles by the end of 24 weeks. The findings are supported by a separate 24-week study in which wrinkle appearance was significantly improved based on both expert grading and digital image analysis, after application of Renova, a 0.02% tretinoin in an emollient base every evening, along with Neutrogena Healthy Defense Daily Moisturiser, an SPF 30 moisturizing sunscreen. Other studies comparing tretinoin with different wrinkle treatments have also reported that tretinoin complexed with cyclodextrin led to improvements in wrinkle score assessments, wrinkle area measurements and skin elasticity.
There is evidence that collagen synthesis is affected in photodamaged skin, and that topical tretinoin use partially restores this reduction of dermal collagen. As treatment is continued beyond 24 months, collagen organization continues to improve. Retinoic acid therapy also increases the capacity of the epidermis to hold water by stimulating the production of hyaluronic acid in the epidermis, though in the dermis it may have the opposite effect. In addition, tretinoin also inhibits some metalloproteinases responsible for dermal collagen degradation. Specifically, tretinoin has been found to inhibit UVA-induced matrix metalloproteinase-1 (MM1), the only enzyme active at neutral pH that can degrade interstitial collagen, in human skin fibroblasts. These may be the pathways by which tretinoin results in wrinkle effacement at the clinical level.
3.2 Lightening effect
Solar lentigines are benign, hyperpigmented lesions that present in many middle-aged and elderly patients with chronic accumulated sun exposure. Early studies demonstrated that 0.1% tretinoin cream reduced the coloration of brown spots and lentigines in patients, and decreased the number of discrete lentigines. When applied to the face and upper extremities, lesions that disappeared during 10 months of therapy did not return for at least 6 months after therapy is discontinued. 0.05% tretinoin cream (Retin-A) has also been assessed to be effective in improving lentigines in Australian skin.
Combination topical therapy using 2% mequinol and 0.01% tretinoin has been shown to markedly reduce the darkness of solar lentigines lesions on the face and forearm, in a randomized, double-blind study of 216 subjects. In 2 other randomized, controlled, double-blind trials, this combination was also found to be more efficacious than each of its active components and the vehicle in the treatment of solar lentigines, except versus tretinoin on the face. The lightening effect appears to be relatively long-lasting when the solution is applied to the back of the hands, for it is maintained for at least 2 months after stopping treatment. This combination therapy has also been establised as effective and safe in Asian, Latin/Hispanic and African American ethnic groups, and in those with dark skin types.
It has been suggested that 2% mequinol and 0.01% tretinoin therapy can also be considered as maintenance therapy following another treatment, such as ablative therapy with cryotherapy, as the primary therapy.
Histologic analysis has evidenced that tretinoin reduces epidermal pigmentation, which is significantly correlated with the degree of clinical lightening of the lesions.
3.3 Smoothing effect
Computerized image analysis of silicone replicas has been used to show that tretinoin emollient cream improves skin topography and smooths skin surface in subjects treated for 24 weeks. 0.05% tretinoin emollient cream has been found to diminish tactile roughness in 16 weeks, and to further improve roughness features after 44 weeks. Areas where improvements have been noted after 0.05% tretinoin cream application include the face, neck, forearms and hands.
Lower concentrations also appear to be effective. 0.02% tretinoin cream alone, applied daily for 52 weeks, also achieved improvements in tactile roughness of the face at 3, 6, 9 and 12 months. When 0.025% tretinoin cream was applied once daily to the neck and chest along with twice daily application of a proprietary copper zinc malonate lotion and 4% hydroquinone cream (Obagi ELASTIderm Décolletage System), significant improvements in tactile roughness were found from the second week onward. Even at 0.01% concentration, tretinoin emollient cream also reduced roughness when applied to the forearms after 24 and 48 weeks. 0.001% concentration however showed little difference from vehicle.
It has been hypothesized that the effect of tretinoin in skin smoothening results from a combination of epidermal changes including an increase in epidermal thickness, compaction of the stratum corneum and deposition of glycosaminoglycans.
3.4 Tightening effect
Tretinoin is frequently prescribed for its dermal tightening effects. 0.05% tretinoin cream has been shown to ameliorate skin looseness after 6 months of treatment. Another randomized, double-blind, vehicle-controlled study supported this finding, showing that significant reductions in skin laxity were observed after 0.05% tretinoin therapy. Efficacy was also shown in photodamaged Australian skin, with significant improvements in laxity noted in a separate multicentre clinical trial. This effect appears to occur soon after starting treatment, with one study noting that patients may observe a tightening of the skin as early as the first month of treatment, and that after 6 months or longer, sagging skin, especially in the area around the eyes, may begin to tighten. A smaller study has also demonstrated that 0.1% tretinoin cream appears to decrease the length, width and severity of stretch marks, as evaluated by physical examinations and analyses of biopsies, when applied daily for 6 months to the affected areas.
In a study on dermal fibroblasts, tretinoin seemed to stimulate the secretion of basic fibroblast growth factor, and this has been postulated as a partial explanation of tretinoin's clinically observed tightening effects.
3.5 Improvement of sallow skin
Skin sallowness (yellowing) is a characteristic of photoaging. Topical tretinoin has been demonstrated to induce the pinkening of sallow skin in patients. 0.1% tretinoin microsphere gel and 0.05% tretinoin emollient cream have both been shown to improve skin yellowing to a statistically significant extent. 2 randomized, double-blind clinical studies have also indicated that 0.02% tretinoin cream led to statistically significant reductions in skin yellowing at the end of 24 weeks, showing that lower concentrations of tretinoin are also effective.
3.6 Other age-related improvements
One of the first studies on the use of topical tretinoin to reverse photodamage noted changes in the histologic structure and function of the skin, including an increase in epidermal thickness and a decrease in the atypia of the keratinocytes. This was confirmed in a subsequent double-blind, placebo-controlled trial of 0.1% tretinoin cream, which also found that it reduced the number of actinic keratoses, among other improvements.
3.7 Epidermal melasma treatment
Melasma is a common disorder of hyperpigmentation that generally involves areas of the face and neck. It is characterized by patches of light brown or gray-brown patches on sun-exposed skin. Tretinoin monotherapy has produced a good therapeutic response in clinical trials but better results are obtained in combination with other agents.
Multiple studies have investigated the efficacy and tolerability of treating melasma using tretinoin together with other compounds. Triple combination (TC) cream consisting of 0.01% fluocinolone acetonide, 4% hydroquinone and 0.05% tretinoin has been tested extensively in both short and long-term trials for the treatment of melasma. In one 12-month long study, 585 patients were instructed to apply TC cream on a daily basis. 327 patients completed 12 months of treatment, and clinically significant improvements in melasma were reported -- by month 12, 80% of patients had lesions completely or nearly cleared. TC cream has also been demonstrated to be more effective than 4% hydroquinone cream in the treatment of moderate to severe facial melasma, with its superior efficacy confirmed in a separate experiment on Asian patients. Another study combined intense pulsed light (IPL) sessions with TC cream treatment and concluded that the combination led to significant improvements in the reduction of melasma area and severity versus treatment with TC cream alone.
To reduce the side effects of treatment with tretinoin and hydroquinone, one split-face study utilized silicone sheets containing both actives on 24 women and compared the results and tolerability to conventional treatment with tretinoin and hydroquinone. The silicone sheets were found to improve epidermal melanosis to the same extent as conventional treatment, but with fewer occurrences of skin irritation. The tolerability of 0.05% topical tretinoin has also been shown to be improved by the use of a SPF 30 facial moisturizer, specifically Cetaphil Dermacontrol Moisturizer.
Tretinoin's depigmentation ability is due to its ability to disperse keratinocyte pigment granules, interfere with pigment transfer, and accelerate epidermal turnover and therefore, pigment loss. There is also evidence that it inhibits the induction of tyrosinase, the rate-limiting enzyme controlling melanin production.
3.8 Acne vulgaris treatment
Topical tretinoin is a well-established treatment for acne vulgaris. A 2013 study of treatment of preadolescent acne in the United States found topical tretinoin to be a leading medication, prescribed in 12.5% of cases.
Historically, tretinoin has been used as a comedolytic agent to treat mild to moderate cases of acne vulgaris. Micronized 0.05% tretinoin gel and 0.1% tretinoin gel microsphere have both been shown to successfully reduce both inflammatory and non-inflammatory lesions.
Tretinoin has also been combined with antibacterials to form topical combination treatments for acne. An alcoholic erythromycin/tretinoin solution has been found to effectively reduce comedones, papules and pustules in a multicenter data investigation of 6,500 patients. 1.2% clindamycin phosphate together with 0.025% tretinoin as a gel (CTG) also reduces comedogenesis, inflammation, and aids the healing of acne lesions. This combination therapy appears to be more efficacious than tretinoin monotherapy or clindamycin monotherapy, and is similarly safe and tolerable. Other combination therapies include 0.05% tretinoin + 50% aloe vera topical gel, which was found to be superior to tretinoin alone in the treatment of mild-to-moderate acne, and a triple combination therapy with oral minocyline HCl, 1.2% clindamycine phosphate/0.025% tretinoin gel and 6% benzoyl peroxide foaming cloths for the treatment of moderate to severe acne. It should be noted however, that the prolonged use of antibiotics such as clindamycin and erythromycin will promote the development of resistance, unlike a non-antibiotic antibacterial agent such as benzoyl peroxide.
For patients of color, a trial comparing treatment with 1% clindamycin + 5% benzoyl peroxide topical gel in combination with 0.04% tretinoin topical gel, 0.01% tretinoin topical gel, or 0.1% adapalene topical gel, found a trend towards better resolution of hyperpigmentation among subjects receiving the clindamycin + benzoyl peroxide gel together with 0.04% tretinoin microsphere gel. 1.2% clindamycin and 0.025% tretinoin gel has also been assessed to be an effective option for treating mild-to-moderate acne in patients with skin of color. For Mexican patients, 0.05% tretinoin and 0.3% adapalene (separately) were found to be more effective than 0.1% adapalene, but 0.1% adapalene offers a better safety profile.
Tretinoin's comedolytic-related activity has been known for many years. It normalizes the exfoliation of the follicular epithelium within the pilosebaceous unit, inhibits transglutaminase activity that results in cellular adhesion, prevents follicular plugging, leads to drainage and expulsion of excess sebum, and helps create a more aerobic environment that is less conducive to P. acnes. Tretinoin also appears to plays a role in phagocytosis by modulating macrophage function, inhibiting proteolytic enzyme release, suppressing respiratory burst and degranulation and dampening the activity of nitric acid synthase, all of which may contribute to its anti-acne activity.
3.9 Vitiligo treatment
Vitiligo is an autoimmune disorder characterized by the appearance of lighter patches of skin due to the loss of melanocytes. While repigmentation through approaches such as phototherapy may be feasible in mild cases, if vitiligo involves most of the body, it may be easier to depigment the remaining normal skin. Monobenzone is the most widely used depigmenting agent for this purpose, but a considerable number of vitiligo patients appear to be resistant against the depigmenting effect of monobenzone. It has been found, however, that tretinoin is able to enhance the melanocytotoxic and depigmenting effects of monobenzone.
Interestingly, a separate placebo-controlled, paired comparison, left-right study has also indicated that topical tretinoin + a combination of corticosteroids, may be a possible option for repigmentation in patients with vitiligo.
4. Side Effects
Dermatitis, characterized by dry skin, peeling, irritation and erythema, is a common side effect of tretinoin therapy. When the concentration of tretinoin is low, such adverse reactions tend to be of mild severity. Given that tretinoin can be irritating, the dose must be adjusted to prevent inflammation, which may cause hyperpigmentation. Reducing the concentration of tretinoin used in treatment also lowers the degree of irritation. Further, the development of a tretinoin cyclodextrin complex in which tretinoin is encapsulated by cyclodextrin, has been shown to moderate irritant reactions compared to tretinoin alone, while possessing equal antiwrinkle effects. The combined use of tretinoin and myristyl nicotinate, a lipid derivative of niacin also seems to improve tolerability by mitigating skin barrier impairment and protecting against transepidermal water loss associated with tretinoin therapy.
4.2 Negligible risk of fetal anomalies
Tretinoin has been thoroughly evaluated for its potential as an human developmental toxicant. Unlike isotretinoin, which is known to be teratogenic, studies suggest that the risk of malformations in human fetuses after topical application of tretinoin is negligible. This is due to the poor absorption of tretinoin from the skin, which yields maternal plasma concentrations below the developmentally toxic threshold. One study which followed 106 pregnant women with first-trimester exposure to topical tretinoin found no significant differences in the birth outcomes of these women compared to 389 women with no topical tretinoin exposure, further confirming these results.
- Roos TC, et. al. Retinoid metabolism in the skin. Pharmacol Rev. (1998)
- Concha J, et. al. Effect of Rosehip Extraction Process on Oil and Defatted Meal Physicochemical Properties. JAOCS (2006)
- Lehmann PA, Slattery JT, Franz TJ Percutaneous absorption of retinoids: Influence of vehicle, light exposure, and dose. J Invest Dermatol. (1988)
- Schaefer H Penetration and percutaneous absorption of topical retinoids. A review. Skin Pharmacol. (1993)
- Raza K, et. al. Nano-lipoidal carriers of tretinoin with enhanced percutaneous absorption, photostability, biocompatibility and anti-psoriatic activity. Int J Pharm. (2013)
- Fu JJ, et. al. A randomized, controlled comparative study of the wrinkle reduction benefits of a cosmetic niacinamide/peptide/retinyl propionate product regimen vs. a prescription 0.02% tretinoin product regimen. Br J Dermatol. (2010)
- Nyirady J, et. al. Tretinoin cream 0.02% for the treatment of photodamaged facial skin: a review of 2 double-blind clinical studies. Cutis. (2001)
- Miura T, Takada A, Ooe M. Tretinoin cyclodextrin complex (RA/CyD) causes less irritation with an equal antiwrinkle effect compared with conventional tretinoin: clinical and histologic studies of photoaged skin. Aesthetic Plast Surg. (2012)
- Ooe M, et. al. Comparative evaluation of wrinkle treatments. Aesthetic Plast Surg. (2013)
- Griffiths CE, et. al. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid) N Engl J Med. (1993)
- Bhawan J. Short- and long-term histologic effects of topical tretinoin on photodamaged skin. Int J Dermatol. (1998)
- Tammi R, Tammi M. Influence of retinoic acid on the ultrastructure and hyaluronic acid synthesis of adult human epidermis in whole skin organ culture. J Cell Physiol. (1986)
- Lundin A, Berne B, Michaëlsson G. Topical retinoic acid treatment of photoaged skin: its effects on hyaluronan distribution in epidermis and on hyaluronan and retinoic acid in suction blister fluid. Acta Derm Venereol. (1992)
- Tammi R, et. al. Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture. J Invest Dermatol. (1989)
- Deshpande M, et. al. All-trans retinoic acid is an effective inhibitor of hyaluronate synthesis in a human dermal equivalent. Arch Dermatol Res. (2014)
- Fisher GJ, et. al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med. (1997)
- Pan L, Eckhoff C, Brinckerhoff CE. Suppression of collagenase gene expression by all-trans and 9-cis retinoic acid is ligand dependent and requires both RARs and RXRs. J Cell Biochem. (1995)
- Kim BH. Safety Evaluation and Anti-wrinkle Effects of Retinoids on Skin. Toxicol Res. (2010)
- Farris PK. Combination therapy for solar lentigines. J Drugs Dermatol. (2004)
- Goldfarb MT, Ellis CN, Voorhees JJ. Topical tretinoin: its use in daily practice to reverse photoageing. Br J Dermatol. (1990)
- Ellis CN, et. al. Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin. J Am Acad Dermatol. (1990)
- Rafal ES, et. al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med. (1992)
- Lowe PM, et. al. Topical tretinoin improves the appearance of photo damaged skin. Australas J Dermatol. (1994)
- Jarratt M. Mequinol 2%/tretinoin 0.01% solution: an effective and safe alternative to hydroquinone 3% in the treatment of solar lentigines. Cutis. (2004)
- Fleischer AB Jr, et. al. The combination of 2% 4-hydroxyanisole (Mequinol) and 0.01% tretinoin is effective in improving the appearance of solar lentigines and related hyperpigmented lesions in two double-blind multicenter clinical studies. J Am Acad Dermatol. (2000)
- Piérard-Franchimont C, et. al. Analytic quantification of the bleaching effect of a 4-hydroxyanisole-tretinoin combination on actinic lentigines. J Drugs Dermatol. (2008)
- Draelos ZD. The combination of 2% 4-hydroxyanisole (mequinol) and 0.01% tretinoin effectively improves the appearance of solar lentigines in ethnic groups. J Cosmet Dermatol. (2006)
- Ortonne JP, et. al. Treatment of solar lentigines. J Am Acad Dermatol. (2006)
- Grove GL, et. al. Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream. J Am Acad Dermatol. (1991)
- Draelos ZD. Novel approach to the treatment of hyperpigmented photodamaged skin: 4% hydroquinone/0.3% retinol versus tretinoin 0.05% emollient cream. Dermatol Surg. (2005)
- Creidi P Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol. (1998)
- Kircik LH. Safety and efficacy evaluation of tretinoin cream 0.02% for the reduction of photodamage: a pilot study. J Drugs Dermatol. (2012)
- Leyden JJ, Parr L. Treating photodamage of the décolletage area with a novel copper zinc malonate complex plus hydroquinone and tretinoin. J Drugs Dermatol. (2010)
- Andreano JM, Bergfeld WF, Medendorp SV. Tretinoin emollient cream 0.01% for the treatment of photoaged skin. Cleve Clin J Med. (1993)
- Griffiths CE, Voorhees JJ. Topical retinoic acid for photoaging: clinical response and underlying mechanisms. Skin Pharmacol. (1993)
- McCormack MC, Nowak KC, Koch RJ. The effect of copper tripeptide and tretinoin on growth factor production in a serum-free fibroblast model. Arch Facial Plast Surg. (2001)
- Leyden JJ, et. al. Treatment of photodamaged facial skin with topical tretinoin. J Am Acad Dermatol. (1989)
- Monti M, Caputo R. Clinical efficacy and patient tolerance of topical tretinoin therapy in photo-ageing. J Int Med Res. (1990)
- Weinstein GD, et. al. Topical tretinoin for treatment of photodamaged skin. A multicenter study. Arch Dermatol. (1991)
- Kang S, et. al. Topical tretinoin (retinoic acid) improves early stretch marks. Arch Dermatol. (1996)
- Hashizume H. Skin aging and dry skin. J Dermatol. (2004)
- Weiss JS, et. al. Tretinoin treatment of photodamaged skin. Cosmesis through medical therapy. Dermatol Clin. (1991)
- Weiss JS, et. al. Tretinoin microsphere gel 0.1% for photodamaged facial skin: a placebo-controlled trial. Cutis. (2006)
- Kang S, et. al. Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial. Am J Clin Dermatol. (2005)
- Millikan LE. The rationale for using a topical retinoid for inflammatory acne. Am J Clin Dermatol. (2003)
- Weiss JS, et. al. Topical tretinoin improves photoaged skin. A double-blind vehicle-controlled study. JAMA. (1988)
- Grimes P, Watson J. Treating epidermal melasma with a 4% hydroquinone skin care system plus tretinoin cream 0.025%. Cutis. (2013)
- Griffiths CE, et. al. Topical tretinoin (retinoid acid) improves melasma: A vehicle-controlled, clinical trial. Br J Dermatol. (1993)
- Kimbrough-Green CK, et. al. Topical retinoid acid (tretinoin) for melasma in black patients: A vehicle-controlled clinical trial. Arch Dermatol. (1994)
- Bandyopadhyay D. Topical treatment of melasma. Indian J Dermatol. (2009)
- Torok H, et. al. A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads. J Drugs Dermatol. (2005)
- Ferreira Cestari T, et. al. A comparison of triple combination cream and hydroquinone 4% cream for the treatment of moderate to severe facial melasma. J Cosmet Dermatol. (2007)
- Chan R, et. al. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol. (2008)
- Figueiredo Souza L, Trancoso Souza S. Single-session intense pulsed light combined with stable fixed-dose triple combination topical therapy for the treatment of refractory melasma. Dermatol Ther. (2012)
- Iida S, et. al. Silicone sheet containing all-trans retinoic acid and hydroquinone for the treatment of epidermal melanosis. Dermatol Surg. (2013)
- Schorr ES, Sidou F, Kerrouche N. Adjunctive use of a facial moisturizer SPF 30 containing ceramide precursor improves tolerability of topical tretinoin 0.05%: a randomized, investigator-blinded, split-face study. J Drugs Dermatol. (2012)
- Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. (1975)
- Gupta AK, et. al. The treatment of melasma: a review of clinical trials. J Am Acad Dermatol. (2006)
- Thorne EG. Long-term clinical experience with a topical retinoid. Br J Dermatol. (1992)
- Davis SA, et. al. Treatment of preadolescent acne in the United States: an analysis of nationally representative data. Pediatr Dermatol. (2013)
- Schmidt N, Gans EH. Tretinoin: A Review of Its Anti-inflammatory Properties in the Treatment of Acne. J Clin Aesthet Dermatol. (2011)
- Lucky AW, Sugarman J. Comparison of micronized tretinoin gel 0.05% and tretinoin gel microsphere 0.1% in young adolescents with acne: a post hoc analysis of efficacy and tolerability data. Cutis. (2011)
- Torok HM, Pillai R. Safety and efficacy of micronized tretinoin gel (0.05%) in treating adolescent acne. J Drugs Dermatol. (2011)
- Nighland M, Grossman R. Tretinoin microsphere gel in facial acne vulgaris: a meta-analysis. J Drugs Dermatol. (2008)
- Eichenfield LF, et. al. Tretinoin microsphere gel 0.04% pump for treating acne vulgaris in preadolescents: a randomized, controlled study. Pediatr Dermatol. (2012)
- Berger R, et. al. A double-blinded, randomized, vehicle-controlled, multicenter, parallel-group study to assess the safety and efficacy of tretinoin gel microsphere 0.04% in the treatment of acne vulgaris in adults. Cutis. (2007)
- Kreusch J, Bextermöller R. Efficacy and tolerability of a topical erythromycin/tretinoin combination preparation in acne treatment: post-marketing surveillance study involving over 6500 patients. Curr Med Res Opin. (2000)
- Abdel-Naser MB, Zouboulis CC. Clindamycin phosphate/tretinoin gel formulation in the treatment of acne vulgaris. Expert Opin Pharmacother. (2008)
- Feneran AN, et. al. Retinoid plus antimicrobial combination treatments for acne. Clin Cosmet Investig Dermatol. (2011)
- Schmidt N, Gans EH. Clindamycin 1.2% Tretinoin 0.025% Gel versus Clindamycin Gel Treatment in Acne Patients: A Focus on Fitzpatrick Skin Types. J Clin Aesthet Dermatol. (2011)
- Jarratt MT, Brundage T. Efficacy and safety of clindamycin-tretinoin gel versus clindamycin or tretinoin alone in acne vulgaris: a randomized, double-blind, vehicle-controlled study. J Drugs Dermatol. (2012)
- Hajheydari Z, et. al. Effect of Aloe vera topical gel combined with tretinoin in treatment of mild and moderate acne vulgaris: a randomized, double-blind, prospective trial. J Dermatolog Treat. (2014)
- Zaenglein AL, et. al. A phase IV, open-label study evaluating the use of triple-combination therapy with minocycline HCl extended-release tablets, a topical antibiotic/retinoid preparation and benzoyl peroxide in patients with moderate to severe acne vulgaris. J Drugs Dermatol. (2013)
- Tan HH. Topical antibacterial treatments for acne vulgaris : comparative review and guide to selection. Am J Clin Dermatol. (2004)
- Taylor SC. Utilizing combination therapy for ethnic skin. Cutis. (2007)
- Callender VD, et. al. Efficacy and Safety of Clindamycin Phosphate 1.2% and Tretinoin 0.025% Gel for the Treatment of Acne and Acne-induced Post-inflammatory Hyperpigmentation in Patients with Skin of Color. J Clin Aesthet Dermatol. (2012)
- Tirado-Sánchez A, et. al. Efficacy and safety of adapalene gel 0.1% and 0.3% and tretinoin gel 0.05% for acne vulgaris: results of a single-center, randomized, double-blinded, placebo-controlled clinical trial on Mexican patients (skin type III-IV). J Cosmet Dermatol. (2013)
- Berson DS, Shalita AR The treatment of acne: the role of combination therapies. J Am Acad Dermatol. (1995)
- Thiellitz A, Abdel-Naser MB, Fluhr JW, et al. Topical retinoids in acne-an evidence-based overview. J Dtsch Dermatol Ges. (2008)
- Wolf JE Jr. Potential anti-inflammatory effects of topical retinoids and retinoid analogues. Adv Ther. (2002)
- Dillehay DL, Walia AS, Lamon EW. Effects of retinoids on macrophage function and IL-1 activity. J Leukoc Biol. (1988)
- Varani J, et. al. Effects of all-trans retinoic acid on neutrophil-mediated endothelial cell injury in vitro and immune complex injury in rats. Am J Pathology. (1991)
- Fumarulo R, et. al. Retinoids inhibit the respiratory burst and degranulation of stimulated human polymorphonuclear leukocytes. Agents Actions. (1991)
- Bécherel PA, et. al. CD23-mediated nitric oxide synthase pathway induction in human keratinocytes is inhibited by retinoic acid derivatives. J Invest Dermatol. (1996)
- Alkhateeb A, et. al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. (2003)
- AlGhamdi KM, Kumar A. Depigmentation therapies for normal skin in vitiligo universalis. J Eur Acad Dermatol Venereol. (2011)
- Kasraee B, et. al. Retinoic acid synergistically enhances the melanocytotoxic and depigmenting effects of monobenzylether of hydroquinone in black guinea pig skin. Exp Dermatol. (2006)
- Kwon HB, et. al. The therapeutic effects of a topical tretinoin and corticosteroid combination for vitiligo: a placebo-controlled, paired-comparison, left-right study. J Drugs Dermatol. (2013)
- Taylor SC, et. al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis. (2003)
- Torok HM. A comprehensive review of the long-term and short-term treatment of melasma with a triple combination cream. Am J Clin Dermatol. (2006)
- Griffiths CE, et. al. Two concentrations of topical tretinoin (retinoic acid) cause similar improvement of photoaging but different degrees of irritation. A double-blind, vehicle-controlled comparison of 0.1% and 0.025% tretinoin creams. Arch Dermatol. (1995)
- Jacobson MK, et. al. Effect of myristyl nicotinate on retinoic acid therapy for facial photodamage. Exp Dermatol. (2007)
- Johnson EM. A risk assessment of topical tretinoin as a potential human developmental toxin based on animal and comparative human data. J Am Acad Dermatol. (1997)
- Kochhar DM, Christian MS. Tretinoin: a review of the nonclinical developmental toxicology experience. J Am Acad Dermatol. (1997)
- Loureiro KD, et. al. Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Am J Med Genet A. (2005)