Tretinoin side-effects

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

Tretinoin, also referred to ATRA, which stands for all-trans-retinoic acid, is a retinoic acid that is not cytotoxic but promotes the maturation of early promyelocytic cells and is specific to the t(15 17) cytogenetic marker. The time to peak concentrations is 1 to 2 hours after an oral dose. The elimination half-life is 21 to 51 minutes.32 These maroon-and-gold capsules are dosed at 45 mg/m2 per day divided into two doses. The most significant side effect is the retinoic acid syndrome, which may occur anywhere from the first couple of days of therapy until the end of therapy and consists of symptoms of... 

The past twenty years have witnessed considerable progress in the synthesis and use of other retinoid-like molecules related to vitamin A. The aromatic retinoid etretin (8.54) and its ester etretinate (8.55) had some effectiveness in the treatment of psoriasis, a disorder of skin. 13-cA-Retinoic acid (isotretinoin) produces sebaceous gland atrophy and could prove useful in the treatment of severe acne vulgaris. Although these compounds have toxic side effects and are not in regular use, they have opened up new therapeutic possibilities. Retinoic acid (tretinoin, 8.56) has been employed in the treatment of acne. 

Retinoids, topical as well as systemic, have been tried in EHK but were often found to be irritating. Nonetheless some patients are improved by oral acitretin,39 but the dose must be kept low in order to avoid the epidermolytic side effect of the drug. If correctly used, topical tretinoin and tazarotene may also be effective in some patients with EHK (Figure 8.7). Interestingly, the response to retinoid therapy seems to be partially determined by which keratin gene (Kl, K2e, or K10) is mutated patients with K2e and K10 mutations have the best response probably because they tolerate a retinoid-induced down-regulation of K2e expression better than other patients.40 However the... 

Side effects associated with use of topical tretinoin ointment include transient hyperemia, irritation, or burning. Ocular pharmacokinetic studies in rabbits show low levels of drug in the aqueous humor after topical application of [ H]-tretinoin, with major tissue uptake in the surface epithelium and the iris. Because retinoic acid has poor stability in the presence of light and oxygen and is insoluble in water, its formulations and clinical use are limited. Although it is capable of reversing squamous metaplasia and keratinization, these ocular surface changes are seen only in severe, not mild to moderate, cases of dry eye. 

Widespread use of tretinoin and related naturally occurring retinoids is limited by undesirable side effects, which probably arise from their activation of multiple receptors. Recently, compounds selective for the retinoid X receptors... 

This dermatitis is in fact a positive side-effect when tretinoin is used to prepare for a TCA-SAS peel, at least to... 

Retinoids induce neoangiogenesis, whereas AHAs act on the dermis without necessarily going through a phase of inflammatory reaction. We can therefore assume that their combined effects can produce better results at the same time as reducing the incidence of side-effects thanks to the use of lower doses of each of these two potential irritants. For example, if there is resistance to (daily or twice daily) monotherapy with tretinoiff at 0.1%, applying an 8-10% glycolic acid gel beforehand helps the retinoid to penetrate more efticiently. Tretinoin and AHAs can be applied separately, but they can also be mixed in the same gel. 

Tretinoin became available as a topical treatment for acne in the United States in 1971. Tretinoin is also known by its chemical name, z)X-trans-retinoic acid. It increases the turnover of skin cells at the surface of the hair follicle. This leads to the extrusion of comedones. Side effects include local skin irritation and increased stm sensitivity. Newer preparations of tretinoin, designed to achieve slow absorption of the drug into epithelial cells, cause less skin irritation than forms available initially. Improvement in acne may not be noticeable until two to three weeks after treatment begins. 

It may be used at different concentrations (from 0.01% to 0.05%, although 0.025% is the concentration most frequently used in rosacea). Its efficacy is comparable with oral isotretinoin at a daily dosage of 10 mg [56]. Side effects are much more frequent and severe than all the other topical drugs used in rosacea (burning, xerosis, redness, scaling). Because of these side effects, tretinoin is a second choice in rosacea. 

Tretinoin was compared with glycolic acid in ten Indian women with melasma, an acquired symmetrical hypermelanosis characterized by irregular light to gray-brown macules on sun-exposed skin that is more frequently seen in women and is more prevalent in darker complexioned individuals [308]. In this study, a 1 % tretinoin peel was applied on one side of the face weekly for 12 weeks, and 70 % glycolic add was appUed similarly to the other side. The tretinoin solution contained 1 % tretinoin in a 95 % isopropyl alcohol base and 5 % chloroform with antioxidant butylated hydroxy-toluene. There was a significant decrease in the melasma score from 6 to 12 weeks, with no difference between the tretinoin- and glycolic-acid-treated sides. Side effects were minimal and tretinoin was well tolerated [308]. 

Topical tretinoin was a major advance in dermatologic therapeutics, finding application in a wide variety of dermatoses including acne. Skin irritation is the most common and frequently limiting side effect and reversible hypopigmenta-tion may occur as they do with other irritants. Treatment of some diseases may be impeded because of poor penetration through the thickened stratum comeum. 

In a study by Peachy and Conner (1971), 22 patients were treated for acne with topical tretinoin. Almost all patients experienced unacceptable degrees of erythema and peeling. The skin irritation associated with the treatment presented a major barrier to successful treatment. When the side effects were sufficiently diminished by decreasing the intensity of therapy, there was no improvement in the acne. According to Christianson et al. (1974), 80% of patients treated with tretinoin experience side effects of erythema and/or desquamation. Contact dermatitis, severe irritation, and reversible hypopigmentadon were side effects experienced by patients with acne vulgaris (Handajo, 1977). 

Koch (1978) conducted a study comparing various retinoids in the treatment of precancerous oral lesions. Fifty percent of the patients on oral tretinoin exhibited general symptoms of hypervitaminosis A such as dizziness and headache in 11% of the patients, the severity of the side effects necessitated the interruption of therapy. In patients with leukoplakia, Koch and Schettler (1973) found a strikingly larger incidence of side effects, including intolerable headaches, dizziness, and nausea among patients under 50 years of age, particularly when dosage was rapidly increased. 

The usual classification of chemical peels comprises superficial, medium and deep peels. For superficial peels, AHA, Jessner s solution, tretinoin, TCA in concentrations of 10-30% and most recently hpo-hydroxy add are used to induce an exfoliation of the epidermis. Medium-depth agents such as TCA (30-50%) cause an epidermal to papillary dermal peel with subsequent regeneration. Deep peels using TCA (>50%) or phenol-based formulations penetrate the reticular dermis to induce dermal regeneration. The success of peeling in darker skin is crudally dependent on the physician s understanding of the chemical and biological processes, as well as of indications, clinical effectiveness and side effects of the procedure (see Box 9.1). 

Isotretinoin was also found to be highly effective in the clearing of refractory rosacea lesions. The anti-inflammatory action of isotretinoin is considered to be the responsible mechanism for efficacy in rosacea. A daily dose of 0.4 to 1 mg/kg/day for up to six months is beneficial and was reported by many authors [36, 63]. Remissions of up to two years after discontinuation have been documented. Mucocutaneous side-effects were predictable and dose-dependent and systemic side-effects were rarely problematic. A study with 22 patients with severe or recalcitrant rosacea revealed that low-dose oral isotretinoin (10 mg/d), topical applied tretinoin (0.025% cream), and the combined treatment were beneficial in the treatment of severe or recalcitrant rosacea [22]. 

A successful prevention of basal cell carcinomas and squamous cell carcinomas in patients with Xeroderma pigmentosum has been reported for systemic isotretinoin [46] and etretinate therapy [3]. Over a period of two years, isotretinoin was shown to reduce the occurrence of basal cell carcinomas by 80% and of squamous cell carcinomas by 60%. For etretinate, a reduction of 75% was reported with respect to the prevention of squamous cell carcinomas. Both retinoids have also been shown to be effective in preventing basal cell carcinomas in organ transplant recipients [40] and in the basal cell nevus syndrome [28, 34]. Furthermore, a combination of topical tretinoin and low-dose oral etretinate (10 mg/d) has been suggested for chemoprevention with reduced side-effects [69]. 

Retinoids cause a variable amount of irritation, more properly a heightening of cutaneous reactivity termed retinoid dermatitis, early in therapy [39-42,44]. In the first few weeks approximately 80% of patients experience stinging, hyperesthesia or pruritus, fine scaling, dryness and mild erythema (Fig. 7). These effects are dose-dependent and peak within the first month of therapy. Weiss et al. reported 92% incidence with 0.1% tretinoin and Leyden et al. a 70% incidence using 0.05% tretinoin. However, in a double blind, vehicle controlled study of 179 patients, only 4% of patients using Renova discontinued the medication as a result of adverse reactions [57]. Retinoid dermatitis usually improves markedly during the course of treatment but may not completely disappear. Other side effects are rare. 

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