Disease relevance of Tazorac

• Preliminary observations on the use of topical tazarotene to treat basal-cell carcinoma [1].
• The ability of tazarotene to inhibit BCC formation in this mouse model provides encouragement for the use of tazarotene in skin cancer chemoprevention trials in humans [2].
• A retinoic acid receptor beta/gamma-selective prodrug (tazarotene) plus a retinoid X receptor ligand induces extracellular signal-regulated kinase activation, retinoblastoma hypophosphorylation, G0 arrest, and cell differentiation [3].
• Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis [4].
• Topical tazarotene 0.1% gel significantly reduced lesion counts in patients with mild to moderate facial acne vulgaris [5].

High impact information on Tazorac

• Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions [6].
• Topical tazarotene chemoprevention reduces Basal cell carcinoma number and size in Ptch1+/- mice exposed to ultraviolet or ionizing radiation [2].
• MRP-8 expression is also down-regulated in vivo in psoriatic lesions after topical application of an anti-psoriatic RARbeta/gamma-selective synthetic retinoid, tazarotene [7].
• However, when used in combination with a retinoid X receptor (RXR)-selective ligand, tazarotene caused ERK activation, RB tumor suppressor protein hypophosphorylation, G0 arrest, and myeloid differentiation [3].
• Tazarotene used with RXR-selective ligand may thus be a useful antineoplastic agent in differentiation induction therapy as exemplified by the prototypical RA treatment of acute promyelocytic leukemia [3].

Chemical compound and disease context of Tazorac

• Oral retinoids can reduce basal cell carcinoma (BCC) incidence in genetically susceptible patients, and one topical retinoid, tazarotene, has been reported to cure some sporadic BCCs [2].
• All other treatment options for psoriasis, such as tazarotene, phototherapy and systemic treatment with methotrexate, acitretin and cyclosporin are often not indicated or not suitable for treatment of the scalp [8].
• Induction of hyperplasia by all-trans retinoic acid and the RAR-specific retinoids TTNPB, tazarotene and AGN 190121 varied over a wide range (ED50 = 0.2-100 nmol/animal in three daily applications) [9].
• The efficacy and tolerability of tazarotene 0.1% gel in the treatment of acne vulgaris have been compared with those of tretinoin 0.025% gel and adapalene 0.1% gel in multicenter, double-blind, randomized, parallel-group trials [10].
• Calcipotriol vs. tazarotene as combination therapy with narrowband ultraviolet B (311 nm): efficacy in patients with severe psoriasis [11].

Biological context of Tazorac

• Dose-response studies showed that diminishing tazarotene progressively diminished both induced cell differentiation and G0 arrest, where the doses for cellular effects were consistent with the transcriptional transactivation data [3].
• CONCLUSIONS: The pharmacokinetics of tazarotene cream 0.1% in patients with acne vulgaris or photodamaged skin are similar [12].
• Evidence of increased apoptosis and reduced proliferation in basal cell carcinomas treated with tazarotene [13].
• The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene [4].
• Taken together, these data suggest that these markers may be down-regulated by tazarotene in psoriasis through direct action on keratinocyte gene expression rather than by an overall tazarotene effect on lesional therapeutic status [14].

Anatomical context of Tazorac

• TIG2 is neither expressed nor induced by tazarotene in primary keratinocyte and fibroblast cultures [15].
• At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis [4].
• Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms [16].
• Metabolic deesterification of tazarotene in human blood and rat and human liver microsomes [17].
• Third, tazarotene and its metabolites are rapidly eliminated from the blood in the urine and feces [18].

Associations of Tazorac with other chemical compounds

• The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin [4].
• However, the mean serum LH concentration on cycle day 2 of the third cycle was lower than that of the second cycle.CONCLUSIONS: Oral tazarotene up to 6 mg once daily does not affect the pharmacokinetics and efficacy of Ortho-Novum 1/35 [19].
• The results from these studies, and a separate split-face tolerability study, suggest that the tolerability of tazarotene gel is clinically comparable to that of tretinoin 0.025% gel, tretinoin 0.1% gel microsphere, and adapalene 0.1% gel [10].
• To establish the relative cost-effectiveness of these drugs (fluocinonide, calcipotriene, and tazarotene), we conducted a pharmacoeconomic study from the perspective of a third-party payer, using a decision-analytic model validated by clinical experts [20].
• The selectivity of tazarotene for the beta and gamma subtypes of retinoic acid receptors suggests a targeted action on psoriatic keratinocytes, which may help to minimize the risk of adverse effects [21].

Gene context of Tazorac

• Finally, we demonstrate that TIG1 is induced by AGN 190168 in psoriatic lesions during the course of clinical treatment of the disease [22].
• Thus, TIG2 is expressed and induced by tazarotene only when keratinocytes and fibroblasts form a tissue-like 3-dimensional structure [15].
• Tazarotene selectively transactivates RAR beta and RAR gamma subtypes and is inactive at retinoid X receptors (RXRs) [23].
• These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors [16].
• By subtraction hybridization, we found that migration inhibitory factor-related protein (MRP-8) and skin-derived anti-leukoproteinase (SKALP) are down-regulated by AGN 190168 [14].

Analytical, diagnostic and therapeutic context of Tazorac

• In the other study, tazarotene cream 0.1% was applied either to the face (six females, two males) or to 15% body surface area (8 females, 8 males) of patients with photodamaged skin [12].
• Topical tazarotene 0.05% or 0.1% gel was effective in the treatment of plaque psoriasis in clinical trials and its therapeutic effect was maintained for at least 12 weeks after treatment discontinuation in some patients [5].
• In addition, two other investigational therapies, oral tazarotene and oral pimecrolimus will be discussed [24].
• Treatment-related systemic adverse effects were not observed in clinical trials involving approximately 2000 patients treated with tazarotene 0.1% or 0.05% gel for periods of up to 1 year [25].
• The disposition and biotransformation of tazarotene were investigated in six healthy male volunteers, following a single oral administration of a 6 mg (100 microCi) dose of [14C]tazarotene, in a gelatin capsule [26].

References