tretinoin and mequinol

Melasma is a common hyperpigmentation disorder that typically affects women, though up to 10% of white individuals seeking treatment for melasma are men. Melasma can be a source of embarrassment for men because of its association with women and pregnancy. We performed a case series assessing the use of mequinol 2%/ tretinoin 0.01% topical solution in 5 men with melasma. Four of 5 patients achieved complete clearance of melasma at 12 weeks, and 1 patient showed moderate improvement. Side effects were minimal and consisted of stinging in one patient. All patients maintained results at the 16-week follow-up visit. Mequinol 2%/tretinoin 0.01% topical solution was an effective and well-tolerated treatment of melasma in men. The vehicle resulted in good compliance and minimal adverse effects in patients. This is the first report describing the use of mequinol 2%/tretinoin 0.01% topical solution for the treatment of melasma in men; there are no reports in women.

Topics: Administration, Topical; Adult; Anisoles; Antioxidants; Facial Dermatoses; Humans; Keratolytic Agents; Male; Melanosis; Middle Aged; Solutions; Treatment Outcome; Tretinoin

Solar lentigines represent a common feature of photoaging, particularly on the back of the hands. Bleaching agents are usually proposed to lighten the shade of the lesions.. The study was randomized and designed to assess the effect of a bleaching solution containing 2% mequinol (4-hydroxyanisole, 4HA) and 0.01% tretinoin (Solagé). The formulation was applied twice daily for 3 months on solar lentigines present on the back of one hand. The lesions on the other hand were treated with the ethyl alcohol vehicle which served as a control. Clinical diagnosis was confirmed using dermoscopy. In addition, objective measurements of the hypermelanosis were performed at 1-month intervals during and after treatment. Clinical assessments were used as well as narrow-band reflectance spectrophotometry, image analysis of video-recorded ultraviolet light-enhanced visualization (ULEV method) and photodensitometry of the corneomelametry test.. The multipronged assessment of the lesional color demonstrated a significant lightening effect of the 4HA/tretinoin solution. This was demonstrated after 2 months of treatment and was maintained at least 2 months after stopping treatment.. Both the visual ratings and the objective bioinstrumental methods indicate the rapid lightening effect of the 4HA/tretinoin formulation. After stopping treatment, the rate of repigmentation appeared to have slowed compared to the depigmentation phase.

Topics: Absorptiometry, Photon; Administration, Cutaneous; Aged; Anisoles; Antioxidants; Dermoscopy; Drug Therapy, Combination; Female; Follow-Up Studies; Hand Dermatoses; Humans; Keratolytic Agents; Lentigo; Middle Aged; Skin Aging; Spectrophotometry; Sunlight; Tretinoin; Ultraviolet Rays; Video Recording

While the efficacy and safety of topical 4-hydroxyanisole (mequinol) 2%/tretinoin 0.01% therapy has been established in Caucasian populations, those with skin types I-II, little research has focused on individuals with darker skin types. The purpose of this open-label study was to evaluate the efficacy and safety of mequinol 2%/tretinoin 0.01% solution in the treatment of solar lentigines in Asian, Latin/Hispanic, and African American ethnic groups with skin types II-V. Subjects were required to have >or= 10 solar lentigines on the dorsal forearms/hands and >or= 3 on the face. One lesion was designated the target lesion, however, all lesions were treated. Patients were treated with topical mequinol 2%/tretinoin 0.01% and clinically evaluated at 4, 8, 12, 16, 20, and 24 weeks as well as 4 weeks following treatment cessation. At each visit, lesions were evaluated using Target and Overall Lesion Pigmentation Index scores ranging from 0 (lightest) to 8 (darkest), where 4 indicated equal pigment with surrounding skin. Efficacy was determined based on pigmentation index scores, and safety was assessed using laboratory monitoring and adverse event (AE) reporting. Over 80% of the 259 subjects completing this study responded to mequinol 2%/tretinoin 0.01% therapy, with a majority of subjects maintaining clinical benefit at 4 weeks post-treatment. Most AEs reported were tolerable and overall mequinol 2%/tretinoin 0.01% therapy had a favorable benefit-to-risk ratio. This study therefore supports the theory that topical mequinol 2%/tretinoin 0.01% is an effective and safe treatment of solar lentigines in ethnic populations, and in those with dark skin types.

Topics: Adult; Aged; Aged, 80 and over; Anisoles; Antioxidants; Drug Combinations; Ethnicity; Face; Female; Humans; Keratolytic Agents; Lentigo; Male; Middle Aged; Tretinoin

The objective of this open-label, noncontrolled study was to evaluate the safety of a combination solution containing 4-hydroxyanisole (mequinol) 2%/tretinoin 0.01% (Solagé) with a sunscreen in the treatment of solar lentigines. The study included a total of 406 subjects for a treatment period up to 24 weeks. Efficacy was evaluated clinically by grading the pigmentation level of the treated areas on the face and forearms. A total of 378 subjects were included in the safety population. Of the 173 subjects with skin-related and treatment-related adverse events, severity was reported as mild in 79 subjects, moderate in 71, and severe in 23. Hypopigmentation was observed in 4 subjects and had definitively resolved in 3 of these subjects at the end of the study or after treatment had been discontinued. Halo hypopigmentation was reported in 16 subjects. No allergic reactions were observed. Efficacy evaluation was based on data for 370 subjects. A total of 325 (88%) subjects had facial target lesions almost clear to clear, and a total of 298 (81%) subjects had forearm target lesions almost clear to clear. Our study shows that the mequinol 2%/tretinoin 0.01% solution is effective, convenient, and safe in the treatment of solar lentigines.

Topics: Administration, Cutaneous; Adult; Anisoles; Dermatologic Agents; Female; Humans; Hypopigmentation; Keratolytic Agents; Lentigo; Male; Severity of Illness Index; Sunscreening Agents; Time Factors; Treatment Outcome; Tretinoin

A new topical solution containing 4-hydroxyanisole (mequinol) 2%/tretinoin 0.01% (Solagé) was compared with its active components, its vehicle, and hydroquinone (HQ) 3% in the treatment of solar lentigines. In a randomized, parallel-group, double-masked study, 216 subjects applied the treatments twice daily for 16 weeks and were followed up for a further 24 weeks. A significantly higher proportion (P < or = .05) of subjects achieved clinical success with mequinol 2%/tretinoin 0.01% compared with HQ 3% as measured by both the lesional pigmentation on the forearm and the physician global assessment at the end of treatment. The proportion of subjects achieving clinical success on the face in the mequinol 2%/tretinoin 0.01% group was consistently higher than that in the HQ 3% group. Some treatment effects remained at the end of the treatment-free follow-up, with trends apparent on the face in favor of mequinol 2%/tretinoin 0.01% over HQ 3%. In all treatment groups, skin-related adverse events were mild or moderate and transient. In conclusion, the mequinol 2%/tretinoin 0.01% solution is a highly effective and well-tolerated treatment for solar lentigines and related hyperpigmented lesions, being superior to HQ 3% for lesions on the forearm and of similar efficacy for lesions on the face.

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Anisoles; Double-Blind Method; Drug Therapy, Combination; Face; Female; Forearm; Humans; Hydroquinones; Keratolytic Agents; Lentigo; Male; Middle Aged; Treatment Outcome; Tretinoin

Solar lentigines are a chronic condition of the aging population resulting from years of cumulative sun exposure. A topical treatment that is both safe and effective would be welcome and useful. Combinations of therapeutic agents are often used and allow synergy of mechanisms with tolerability. A tyrosinase inhibitor in use in Europe, 4-hydroxyanisole (Mequinol), and the retinoid tretinoin have been used singly as depigmenting agents.. The efficacy and safety of the combination product of 2% 4-hydroxyanisole (4HA [mequinol]) /0.01% tretinoin solution (tradename Solagé) were evaluated in two phase III, randomized, controlled, double-blind trials.. Subjects were randomized to treatment with 4HA/tretinoin solution, one of the active components (4HA or tretinoin), or vehicle. Subjects applied the test solution with a wand applicator twice daily to all solar lentigines and related hyperpigmented lesions on the face, forearms, and backs of hands for up to 24 weeks. Trial 1 had a 24-week no-treatment regression phase and trial 2 had a 4-week no-treatment regression phase. Information collected included clinical assessments of Target Lesion Pigmentation, Physician's Global Assessment of Improvement/Worsening, an Assessment of Overall Cosmetic Effect, and a Subject's Self-Assessment Questionnaire.. The 4HA/tretinoin combination was clinically superior to each of its active components and to the vehicle in the treatment of solar lentigines. At the end of treatment, in trial 1 and trial 2, 4HA/tretinoin was statistically superior to each of its active components and vehicle on the forearms and face (P

Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Anisoles; Antioxidants; Arm; Double-Blind Method; Drug Therapy, Combination; Facial Dermatoses; Female; Hand Dermatoses; Humans; Hyperpigmentation; Keratolytic Agents; Lentigo; Male; Middle Aged; Severity of Illness Index; Treatment Outcome; Tretinoin

A challenge in anticipating generic entry is elucidating which patents and regulatory protections constrain generic entry.

Topics: Anisoles; Ciprofloxacin; Dexamethasone; Drug Combinations; Drug Industry; Drugs, Generic; Humans; Patents as Topic; Tretinoin; United States

Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are, in fact, melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones. These cytotoxic compounds are responsible for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.

Topics: Animals; Anisoles; Drug Therapy, Combination; Enzyme Inhibitors; Glutathione; Glutathione Transferase; Guinea Pigs; Humans; Hydroquinones; Keratolytic Agents; Melanocytes; Skin Pigmentation; Swine; Tretinoin

The purpose of this open-label study was to determine the adverse event rate of topical 4HA/tretinoin when used twice daily for up to 24 weeks with concomitant sunscreen in the treatment of solar lentigines and related hyperpigmented lesions. There were two treatment areas: bilateral dorsal forearms, including the back of the hands; and the face, including the forehead and cheek areas. Each treatment area had a target lesion at least 5 mm in diameter and was moderately darker than the surrounding skin. A nine-point bipolar scale was used for evaluation of Target Lesion Pigmentation (0 = extremely lighter than pigment of the surrounding skin, 4 = equal with pigment of surrounding skin, 8 = extremely darker than pigment of surrounding skin). The other solar lentigines present in the treatment areas also had to have an overall pigmentation grade of at least Grade 6. Twice daily applications to individual lesions in each treatment area were made for up to 24 weeks followed by a 4-week follow-up phase. Sunscreen applications (sunscreen with sun protection factor (SPF) 25 or greater) were made every morning and reapplied after six hours if additional sun exposure was expected. Clinical evaluations were performed at weeks 0, 4, 8, 16, 24 and 28. The clinical signs of Target Lesion Pigmentation and Overall Lesion Pigmentation were evaluated at each visit. A total of 96 subjects were enrolled at four study centers; 77 (80%) subjects completed the study. Treatment-related adverse events (AEs) for 4HA/tretinoin included erythema, burning/stinging/tingling, desquamation, pruritus, skin irritation, halo hypopigmentation and hypopigmentation. Five (5%) subjects discontinued from the study due to adverse events considered to be related to study medication. When used with sunscreen of SPF 25 or greater, 4HA/tretinoin was safe and well tolerated and did not produce any unexpected or unusual adverse events.

Topics: Adult; Aged; Aged, 80 and over; Anisoles; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperpigmentation; Male; Middle Aged; Sunscreening Agents; Tretinoin

Solagé is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution, which is being studied for its safety and efficacy as a topical treatment for disorders of skin hyperpigmentation. The purpose of this study was to evaluate the extent of percutaneous absorption of [3H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 cm2 area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% [3H]tretinoin solution. After 12 h, the radiolabelled dose was removed and bid treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [3H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 h) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).

Topics: Administration, Topical; Adult; Animals; Anisoles; Antineoplastic Agents; Area Under Curve; Drug Combinations; Female; Gas Chromatography-Mass Spectrometry; Half-Life; Humans; Male; Mice; Middle Aged; Rats; Skin Absorption; Tretinoin

A combination of 4-hydroxyanisole (4HA) and all-trans retinoic acid (TRA) was found to synergistically cause moderate to complete depigmentation of Yucatan swine skin. Two hyperpigmentation models were used: Natural dark-skinned swine, a potential model for melasma-like disorders, and ultraviolet light-stimulated hyperpigmentation, a model of solar lentigines. Test materials were applied twice daily, 5 d/week, to dorsal flank skin. Application sites were graded at weekly intervals for skin color using a 0 to 4 grading scale. After 8 weeks of treatment of naturally dark swine skin, a combination of 2% 4HA and 0.01% TRA produced grade 2 hypopigmentation (definite but moderate hypopigmentation). In contrast, 2% 4HA alone or 0.01% TRA alone did not produce significant hypopigmentation. After cessation of treatment, the 4HA/TRA-treated sites reverted to normal color within 7-12 weeks. The 4HA/TRA combination completely reversed the hyperpigmentation induced by ultraviolet light after 8 weeks of treatment. In vitro skin-penetration studies using hairless mouse and human skin show that skin penetration of 4HA was not significantly affected by adding 0.01% TRA. These data suggest that the observed synergy is not due to enhanced bioavailability of 4HA. We have demonstrated that combining low concentrations of 4HA and TRA results in effective skin lightening without causing irreversible depigmentation and with minimal local skin irritation.

Topics: Animals; Anisoles; Drug Synergism; Mice; Mice, Hairless; Skin; Skin Absorption; Skin Pigmentation; Swine; Swine, Miniature; Tretinoin; Ultraviolet Rays

Several reports have demonstrated that exposure to ultraviolet light elicits increased pigmentation in the skin of the Skh:HR2 mouse. We have reexamined this model to assess its potential as a screen for compounds with skin-depigmenting activity. The application of the previously reported ultraviolet light-B (UVB) doses led to marked necrotic damage to the skin which greatly diminished the usefulness of the model for drug testing. We have modified this model by exposing the mice to a progressively increasing dose of UVB that promotes pigmentation with a marked reduction of skin irritation. Furthermore, for compound evaluation, we preselected only those mice which developed signs of increased pigmentation after the first week of UVB exposure. This was critical for any meaningful compound evaluation, since only about 50% of the mice eventually showed signs of increased pigmentation with UVB. Our modifications make it possible to use this model for evaluating new compounds with skin-depigmenting activity. The validity of this method has been examined with a number of compounds including hydroquinone, 4-hydroxyanisole, kojic acid and all-trans retinoic acid, all with known depigmenting activity.

Topics: Animals; Anisoles; Female; Hydroquinones; Mice; Mice, Hairless; Pyrones; Skin; Skin Pigmentation; Tretinoin; Ultraviolet Rays

The melanocytotoxic effects of 4-hydroxyanisole (4-OHA) are thought to depend upon its conversion to toxic oxidation products by the enzyme tyrosinase. In this study, the cytotoxicity of 4-OHA was examined in different B16 melanoma cell lines that show varying levels of tyrosinase and after stimulation by melanocyte-stimulating hormone (MSH) and all-trans-retinoic acid (RA). 4-OHA decreased cell survival of three melanotic and one amelanotic cell line in culture, but the effect was unrelated to their tyrosinase activity or the subcellular localization of the enzyme. Although stimulation of tyrosinase activity with RA enhanced the cytotoxicity of 4-OHA, no similar enhancement occurred with alpha-MSH. It appears that there is no relationship between the cytotoxic effects of 4-OHA and intracellular tyrosinase and the enhancement of its cytotoxicity by RA may well be related to the antiproliferative effects of the retinoid.

Topics: Animals; Anisoles; Catechol Oxidase; Cell Survival; Ditiocarb; Melanocyte-Stimulating Hormones; Melanoma; Mice; Monophenol Monooxygenase; Tretinoin; Tumor Cells, Cultured