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Anti-Acne.
Pharmacology: Pharmacodynamics: Adapalene: Adapalene is a retinoid-like compound for the treatment of acne vulgaris. It is a naphthoic derivative with a methoxyphenyl adamantyl side chain. Biochemical and pharmacological profile studies have demonstrated that adapalene is a modulator of cellular differentiation, keratinization, and inflammatory processes all of which represent important features in the pathology of acne vulgaris.
Adapalene binds to specific retinoic acid nuclear receptors but does not bind to the cystolic receptor protein. It has been suggested that topical adapalene may normalize the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.
Clindamycin: Clindamycin acts by inhibiting the bacterial protein synthesis by binding to the 50S ribosomal subunit and inhibiting the process of peptide chain initiation. Clindamycin inhibited all tested Propionibacterium acnes cultures at a minimum inhibitory concentration (MIC) of 0.4 μg/mL, in vitro. Cross-resistance between clindamycin and erythromycin has been demonstrated.
Microsphere technology is believed to contribute towards reduced side effects, improved stability, increased elegance, and enhanced formulation flexibility without reducing the efficacy. Microspheres averaging 12 μm in diameter act like microscopic sponges, storing the active drug until its release is triggered by application to the skin surface. Absorption takes place in a time controlled manner that reduced the incidence and severity of skin irritation, it also protects from photo degradation, therefore contributes to the long term stability of active ingredients.
Pharmacokinetics: Adapalene: The pharmacokinetics of topical adapalene has not been extensively studied. Therapeutic effects of the drug usually appear within 8 to 12 weeks of initiation of treatment. The transdermal absorption of adapalene is low. Only trace amounts of the parent substance (<0.25 ng/mL) have been found in the plasma of acne patients following chronic topical application of adapalene gel in controlled clinical trials. Excretion appears to be primarily by the biliary route.
Absorption of Clindamycin when applied topically is 4% to 5%. Less than 0.04% of the total dose was excreted in the urine, following multiple doses of clindamycin.
Toxicology: Carcinogenesis, Mutagenesis and Impairment of Fertility: Carcinogenicity studies with adapalene have been conducted in mice (topical) and in rats (oral doses) at approximately 4 to 75 times the maximum human topical dose. In the oral study, positive linear trends were observed in the incidence of follicular cell adenomas and carcinomas in the thyroid glands of female rats and in the incidence of benign and malignant phaeochromocytomas in the adrenal medullas of male rats.
No photocarcinogenicity studies have been performed with adapalene. Animal studies have shown an increased tumorigenic risk with the use of pharmacologically similar drugs (e.g. retinoids) when exposed to ultraviolet radiation or sunlight. Patients should therefore be advised to avoid or minimize exposure to either sunlight or artificial ultraviolet radiation sources.
In a series of in vitro and in vivo studies, adapalene did not exhibit mutagenic or genotoxic activity.
The carcinogenicity of a 1% clindamycin was evaluated by daily application for two years. The daily doses used in this study were approximately 3 and 15 times higher than the human dose of clindamycin used, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals.
Clindamycin (1%) caused a statistically significant shortening of the median time to tumor onset in a study in hairless mice in which tumors were induced by exposure to simulated sunlight.
Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Reproduction studies in rats using oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride have revealed no evidence of impaired fertility.
