Mequinol and tretinoin

Uses

Mequinol is a topical agent used in combination with tretinoin to treat solar lentigines.

Mequinol is currently primarily available only as an active ingredient in combination products combined with tretinoin that are indicated for the treatment of solar lentigines and related hyperpigmented lesions resulting from chronic sun exposure .

• For the treatment of acne vulgaris in which comedones, papules and pustules predominate.
• For the treatment of hyperpigmentation, roughness and fine wrinkling of photodamaged skin due to chronic sun exposure.
• For the treatment of Acute promyelocytic leukaemia

Mequinol and tretinoin is also used to associated treatment for these conditions: Acne Vulgaris, Alopecia, Cornification and dystrophic skin disorders, FAB classification M3 Acute promyelocytic leukemia, Skin hyperpigmentation, Solar Lentigines, Facial fine wrinkling, Keratinization disorders of the feet, Keratinization disorders of the hand, Moderate Melasma, Mottled hyperpigmentation, Severe Melasma, Severe, recalcitrant Cystic acne, Tactile roughness of facial skin

How Mequinol and tretinoin works

Solar lentigines and related hyperpigmented lesions are localized, pigmented, macular lesions of the skin, usually on the areas of the body which have been chronically exposed to sunlight . These lesions are characterized by increased numbers of active melanocytes and increased melanin production .

Although the mechanism of action of mequinol is not fully elucidated , when employed as an active ingredient in combination with other agents like tretinoin in skin depigmentation products, a synergy between a number of potential mechanisms is proposed.

Firstly, mequinol is in fact considered a melanocytotoxic chemical which when oxidized in melanocytes results in the formation of toxic compounds like quinones . Such cytotoxic agents are subsequently capable of damaging and destroying pigment cells, which results in skin depigmentation of solar lentigines or other related hyperpigmented lesions. Nevertheless, skin cells are naturally capable of protecting themselves against such cytotoxic entities by endogenous intracellular glutathione (GSH) . This protection is elicited through the enzymatic action of glutathione S-transferase (GST), which is responsible for the conjugation of agents toxic to glutathione . Conversely, tretinoin has been observed to serve as a potent inhibitor of mammalian GSTs and to be capable of reducing the level of intracellular GSH in various cells . As a result, the combination of mequinol with tretinoin seemingly allows for a synergistic enhancement of a melanocytotoxic effect that involves the inhibition and impairment of GSH and GST cytoprotection .

Secondly, even though mequinol is a substrate for the enzyme tyrosinase and therefore acts as a competitive inhibitor of the formation of melanin precursors by way of tyrosinase facilitated reactions, the clinical significance of this action is unknown .

Tretinoin binds to alpha, beta, and gamma retinoic acid receptors (RARs). RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone. Although the exact mechanism of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced. Tretinoin is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. When Tretinoin is given systemically to APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

Dosage

Mequinol and tretinoin dosage

Tretinoin cream: Tretinoin cream should be applied sparingly to the whole affected area once or twice daily. The skin should be thoroughly cleaned and dried before application. Patient should be advised that 6 to 8 weeks of treatment may be required before a therapeutic effect is observed. Moisturisers and cosmetics may be used during treatment with Cosmotrin cream but should not be applied to the skin at the same time. Astringent toiletries should be avoided.

Tretinoin gel: Tretinoin gel should be applied once or twice a day, before retiring, to the skin where lesions appear, using enough to cover the entire affected area lightly. The frequency of application can be adjusted to obtain maximum clinical efficacy with minimal erythema and scaling.

If Tretinoin gel is applied excessively, no more rapid or better results will be obtained and marked redness, peeling or discomfort may occur. Should this occur accidentally or through over-enthusiastic use, application should be discontinued for few days.

Patience is needed in this treatment, since the therapeutic effects will not usually be observed until after 6-8 weeks of treatment. During the early weeks of treatment, an apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication on deep, previously unseen comedones and papules. Once the acne lesions have responded satisfactorily, it should be possible to maintain the improvement with less frequent applications.

Moisturizers and cosmetics may be used during treatment with Tretinoin gel but should not be applied to the skin at the same time. The skin should be thoroughly washed before application of Tretinoin gel. Astringent toiletries should be avoided.

Capsule: The recommended dose is 45 mg/m2/day administered as two evenly divided doses until complete remission is documented. Therapy should be discontinued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.

If after initiation of treatment of Tretinoin the presence of the translocation is not confirmed by cytogenetics and/or by polymerase chain reaction studies and the patient has not responded to Tretinoin, alternative therapy appropriate for acute myelogenous leukemia should be considered.

Side Effects

True allergic contact dermatitis is rare but a primary irritant dermatitis, manifesting itself as irritation, erythema, peeling and sensation of warmth, is common. Slight stinging is common as a mild reaction in many people but usually settles with continuous use and/or reduction in the frequency of application of the drug.

Toxicity

If a mequinol and tretinoin combination topical product is applied excessively, some potential adverse effects like marked redness, peeling of skin, discomfort, discoloration, or hypopigmentation may occur . Such products are not indicated for oral ingestion .

MSDS data reports that chronic exposure to a dose of 25 UMOL/L in humans can result in mutagenic effects like DNA inhibition in lymphocytes .

Interaction

Particular caution should be exercised in using preparations containing peeling agents (i.e. sulfur, resorcinol, benzoyl peroxide or salicylic acid). Use of topical preparations with high concentrations of alcohol, menthol, spices or lime- such as shaving lotions, astringents and perfume- should be avoided, especially during initial therapy.

Volume of Distribution

The volume of distribution is one that suggests mequinol is distributed throughout the total body water, and intracellular concentrations are not expected to vary greatly from gross measurements .

Elimination Route

The systemic exposure to mequinol was assessed in eight healthy subjects following two weeks of twice-daily topical treatment of a tretinoin and mequinol combination product . About dose of the product corresponding to about 37.3 ug/cm^2 of mequinol was applied to the subjects' backs . The mean Cmax for mequinol was 9.92 ng/mL (range between 4.22 and 23.62 ng/mL) and the Tmax was 2 hours (range between 1 to 2 hours) . The safety of mequinol in this combination formulation is supported by the low systemic exposures of the agent in the subjects .

1-31% (topical)

Half Life

Mequinol demonstrated an elimination half-life of 30 to 90 minutes following intravenous infusion of 5 or 10 grams/m^2 over 3 to 5 hours in melanoma patients; similar values were reported after intra-arterial infusion .

0.5-2 hours

Clearance

Readily accessible data regarding the clearance of mequinol is not available. The use of mequinol containing products is typically indicated for topical use.

Elimination Route

Mequinol is predominantly renally eliminated as its metabolites .

Pregnancy & Breastfeeding use

Tretinoin is contraindicated in pregnancy or suspected pregnancy. The drug should be avoided by breast feeding mothers.

Contraindication

Tretinoin is contraindicated in patients who are allergic to this drug. It is contraindicated in pregnancy or suspected pregnancy. It is also contraindicated in personal or familial history of cutaneous epithelioma.

Local irritation: The presence of cutaneous irritative signs (e.g. erythema, peeling, pruritus, sunburn, etc.) should prohibit initiation or recommencement of treatment with Tretinoin until the symptoms resolve. Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with caution in patients with this condition.

Exposure to sunlight: Exposure to sunlight, including ultraviolet sun-lamps, should be avoided or minimised during the use of Tretinoin.

General precaution: Before application of Tretinoin, areas to be treated should be cleansed thoroughly. Abstain from washing the treated area frequently; twice daily is sufficient. Use of mild soap is recommended. Dry the skin without rubbing.

Avoid contact with eyes, eyelids, nostrils, mouth and mucous membranes. If contact in these areas occurs, careful washing with water is recommended.

Storage Condition

Store in a cool and dry place, away from light. Keep out of reach of children.

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