Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone) is a naturally occurring, hydrophilic fungal product derived from certain species of Acetobacter, Aspergillus, and Penicillium. It acts by inhibiting the production of free tyrosinase; it is also a potent antioxidant. It is generally univalent to other therapies but may be more irritating. Kojic (KA) acid is used at concentrations ranging from 1 to 4%. In one double-blind study, KA 2% combined with HQ 2% was shown to be superior to glycolic acid (GA) 10% and HQ 2%. Another double-blind study compared GA 5% with either HQ 4% or KA 4% for three months. Both combinations proved equally effective with a reduction of pigmentation in 52% of the patients. KA may be effective if a patient has difficulty tolerating other first-line therapies. It may cause contact dermatitis and erythema.
Retinoids, such as tretinoin, were first used in combination with HQ as penetration enhancers, but were later recognized to have their own effect on melanogenesis. Retinoids affect multiple steps in the melanization pathway. Tretinoin promotes the rapid loss of pigment through epidermopoiesis and increased epidermal turnover decreases the contact time between keratinocytes and melanocytes. Retinoic acid (RA) suppresses UVB-induced pigmentation by reducing tyrosinase activity. The acid acts at a posttranscriptional level on tyrosinase and tyrosinase-related protein. Compared with phenolic compounds like HQ, RA takes a much longer time to act; clinically significant lightening becomes.evident after 24 weeks.
Tretinoin monotherapy has produced a good therapeutic response in clinical trials but better results are obtained in combination with other agents like HQ and corticosteroids. The most common side effects include erythema, burning, stinging, dryness, and scaling. The inflammation may cause hyperpigmentation, particularly in people with dark skin. Patients must be advised to use sunscreens during treatment with retinoic acid. Adapalene, a naphthoic acid derivative with retinoid activity, was found to be equally efficacious in a randomized trial in Indian patients but with significantly less untoward effects than tretinoin.
Glycolic acid is an alpha-hydroxy acid that is usually combined with other agents at a concentration of 5-10% for its skin-lightening property. The mechanism of its effect might be due to epidermal remodeling and accelerated desquamation, which would result in quick pigment dispersion on pigmentary lesions. It also directly reduces melanin formation in melanocytes by tyrosinase inhibition.
A randomized controlled trial has demonstrated that a formulation containing 10% glycolic acid and 4% HQ had good clinical efficacy in treating melasma in a group of Hispanic patients. Irritation was a common side effect which resolved with the temporary cessation of application and application of moisturizers.
Arbutin, the beta-D-glucopyranoside derivative of hydroquinone, is a naturally occurring plant product which has been used successfully in the treatment of hyperpigmentary disorders. The glycosidic bond is hydrolyzed in vivo leading to the controlled release of hydroquinone. Arbutin acts by the inhibition of tyrosinase, thereby decreasing melanin formation. The normal skin microflora may also hydrolyze arbutin; the hydrolyzed hydroquinone shows more potent free-radical scavenging activity and tyrosinase inhibition than arbutin.
The action of arbutin is dose-dependent and less toxic than hydroquinone. Deoxyarbutin is a recently developed derivative of arbutin that has been produced by removing the hydroxyl groups from the molecule. This produces reversible skin-lightening by direct inhibition of tyrosinase. Although good controlled clinical trials are lacking, initial in vitro and in vivo experimental studies have demonstrated that it could be a safe and effective treatment for hypermelanotic disorders.