EFFECT OF EETINOIC ACID IN PSORIASIS

The effect of topical retinoic acid on the clinical and histological features and mitotic counts of lesions in 12 patients with psoriasis have been studied for a 2-week period. Serial biopsies were performed on lesions treated with retinoic acid in all 12 patients; control lesions treated with unmedicated ointment base were similarly biopsied in 7. There was a significant clinical improvement in 11 of the 12 patients treated with retinoic acid, and in all these patients it was greater than that achieved in the control lesions. Reformation of the granular layer, which was previously absent or only partially formed, occurred in 6 of the 12 psoriatic lesions treated with retinoic acid, but in none of the controls. Mitotic counts for the treated group fell after the 2-week period, but not in the controls. Topical retinoic acid would seem to be of therapeutic value in the treatment of psoriasis. The possible mechanisms of action are discussed.     

Treatment of acne vulgaris with the retinoic acid derivative Ro 11-1430. A controlled clinical trial against retinoic acid.

In a double-blind, randomized, group-comparative clinical trial, 31 patients with acne vulgaris received topical treatment for 6-8 weeks with a lotion containing either 0.05% retinoic acid or 0.1% of the retinoic acid derivative Ro 11-1430. The side-effects erythema, desquamation and burning were significantly less frequent with Ro 11-1430 than with retinoic acid. The treatments appeared to be approximately equally effective in reducing the number of acne elements, but due to the limited number of patients studied, the trial was admittedly not sufficient to detect differences with regard to therapeutic efficacy.     

Topical retinoic acid enhances, and a dark tan protects, from subedemal solar-simulated photocarcinogenesis

Studies into the effects of topical retinoic acid on photocarcinogenesis have yielded ambiguous findings. This may be due to different Experimental protocols and ultraviolet spectra. Retinoic acid is commonly used for a range of dermatologic conditions, and therefore it is important to resolve whether it affects skin tumor formation. To address this issue we used a protocol to mimic as closely as possible human use of retinoic acid. Two mouse strains were used: Skh:HR-1 (albino) and Skh:HR-2 (lightly pigmented). The pigmented mice more closely resemble Caucasian skin as they develop a light tan in response to ultraviolet radiation. This tan is greatly augmented by retinoic acid. As these are congenic mice, any differences can be attributed to the development of a tan. Mice were exposed to solar-simulated ultraviolet radiation, followed by treatment with 0.05% retinoic acid. This modeled exposure to sunlight during the day followed by retinoic acid treatment and a night-time period in the absence of sunlight. As it is recommended that ultraviolet exposure is minimized when using topical retinoic acid, the mice were only exposed to one-third of minimal edemal dose of ultraviolet radiation per day. This retinoic acid protocol augmented photocarcinogenesis. Retinoic acid decreased the latency period, reduced the probability that a mouse would survive without a tumor, and increased the number of tumors per mouse. All tumors induced were squamous cell carcinomas, and the skin between the tumors on mice treated with retinoic acid was found to contain carcinoma in situ upon histologic diagnosis. The light tan of the solvent-treated pigmented mice did not provide any protection, whereas the dark tan, which developed in Skh:HR-2 mice in response to retinoic acid, reduced photocarcinogenesis but did not overcome the augmenting effect of retinoic acid. Thus, using this experimental design, topical retinoic acid augmented photocarcinogenesis, and the ability to develop a dark but not light tan provided some, but limited, protection.     

NAEVES COMEDONICUS TREATMENT WITH RETINOIC ACID

Summary.— Two patients are described with naevus comedonicus. Both patients were successfully treated with topical retinoic acid with a minimum of irritation. Continued periodic application of retinoic acid is necessary to prevent reaccumulation of horny material in the involved follicles.     

市售六种维A酸外用制剂对皮肤累积刺激性的评估

目的 评价常用维A酸外用制剂对皮肤的累积刺激作用.方法 采用随机对照、双盲法将试验药与对照药分为7组.对受试者每周每种药品进行4次24h的斑贴试验和1次72h的斑贴试验观察.共进行3周的观察.结果 累积刺激最小的是0.1%阿达帕林凝胶组,累积刺激指数为0.09±0.11,其20d的累积刺激指数为0.09±0.11;累积刺激作用最大的0.1%维A酸霜组为0.59±0.24,2组比较差异有显著性(P<0.001).0.1%阿达帕林凝胶的累积刺激指数还明显小于0.025%维A酸霜组(0.41±0.22)和0.05%维A酸霜组(0.25±0.22).结论 国内外常用的治疗痤疮的维A酸外用制剂是安全的.外用阿达帕林凝胶的刺激作用不但明显小于0.1%维A酸霜,也小于0.05%维A酸霜.     

Topical retinoic acid does not alter the vasoconstrictive properties of topical corticosteroids in humans

Dermo-epidermal atrophy is one of the main side effects of long-term treatment with topical corticosteroids. Retinoic acid may prevent and even reverse these effects in animals. Extension of this concept to therapy in humans implies that several studies have been performed; among others, it has to be established that treatment with topical retinoic acid does not interfere with the anti-inflammatory action of topical corticosteroids. The present study on the cutaneous vasoconstriction test comprised two different double-blind approaches: (i) vasoconstriction tests with betamethasone dipropionate (Diprolene) and clobetasone butyrate (Emovate) were carried out on skin that had previously been treated for 10 days with retinoic acid 0.01, 0.025 or 0.05% (or excipient); (ii) vasoconstriction tests with a combination of triamcinolone acetonide 0.1% and retinoic acid 0.025% were compared with triamcinolone acetonide 0.1% alone. Pretreatment for 10 days with retinoic acid did not alter the vasoconstriction induced by corticosteroids: no decrease or increase in the vasoconstriction score was observed, whether the skin had been previously treated with retinoic acid or with excipient. The vasoconstriction scores obtained with a combination of retinoic acid and triamcinolone acetonide were identical with those obtained with the steroid alone. This study indicates that retinoic acid does not inhibit the vasoconstriction induced by topical corticosteroids and suggests that the anti-inflammatory effect of the latter should be maintained in association with retinoic acid.     

Topical glucocorticosteroids modulate the expression of CRABP I and II in human skin differently

Abstract Epidermal cells express two retinotic acid-binding proteins (CRABP I and II). Because CRABP II protein is strongly induced by topical retinoic acid, the respective roles of the two proteins in the pharmacological activity and toxicity of topical retinoids deserve particular attention. Since topical steroids diminish the irritation induced by retinoic acid (RA), whereas retinoic acid may counteract the atrophogenic effects of steroids, the possible interplay of both compounds in the expression of CRABP I and II appeared worth studying. We have analyzed the effects of topical application of triamcinolone acetonide (TA) on the retinoic acid-induced altered expression of CRABP I and II in normal human skin, at the protein and mRNA levels. We found that CRABP II protein and mRNA were strongly increased upon retinoic acid application: this induction was significantly inhibited by concomitant application of triam-cinolone acetonide; a more potent steroid, dilluocortolone valerate, was also found to dimish normal endogenous expression of CRABP II. In contrast, CRABP I protein was decreased by topical retinoic acid, and the down modulating effect of retinoic acid was counteracted by triamcinolone acetonide.     

A low-salt medical water reduces irritancy of retinoic acid in facial acne

Although effective medications are available for the treatment of acne, tolerance problems may preclude adequate treatment regimens such as topical retinoic acid, and reduce patient compliance. The present study was conducted to evaluate whether a medical water (Avène) in conjunction with retinoic acid may improve local tolerance in acne. A controlled, open, randomised, multicentric study was completed after 28 days of treatment in 69 acne patients, 34 applying a retinoic acid preparation alone, and 35 applying retinoic acid in association with the water spray used ad libitum. Topical retinoic acid treatment induced prominent signs of irritation in both groups. However, a statistically significant reduction between the two treatment groups could be demonstrated on scaling at all assessment visits (p< or =0.02, Wilcoxon test). No significant water effect on erythema, burning and itching was shown during the treatment period. The overall tolerance assessed by the investigator was significantly improved with the water (p = 0.04, Wilcoxon). Taken together, water with a low mineral content appears to be a promising adjunctive treatment for improving the tolerance of topical retinoids in acne.     

A short-term screening protocol, using fibrillin-1 as a reporter molecule, for photoaging repair agents

Photoaged skin is characterized by coarse and fine wrinkles. The mechanisms of wrinkle formation are undetermined, but appear to be due to changes within the matrix of the dermis and at the dermal-epidermal junction. Previous studies have identified marked reductions in procollagens I and III, collagen VII, and the fibrillin-rich microfibrillar apparatus in this area. Topically applied all-trans retinoic acid can repair photoaged dermal matrix, but this takes at least 6 mo of treatment. In this study, we have examined the abundance and distribution of fibrillin-1 prior to, and following, 192 wk of all-trans retinoic acid treatment. We have further developed a short-term protocol to determine the utility of potential repair agents, using fibrillin-1 as the marker for outcome. Individuals with clinically assessed severe photoaging were recruited to the study (n = 8). 0.025% all-trans retinoic acid, 5% sodium lauryl sulfate (irritant control), or vehicle were applied under occlusion to photoaged extensor forearm. A fourth control area was also occluded. After 96 h, punch biopsies were taken under local anesthesia and processed for either transmission electron microscopy or snap frozen. Frozen sections were prepared for immunohistochemistry and in situ hybridization immunohistochemistry. Electron microscopy revealed aberrant elastic fibers in the papillary dermis of photoaged forearm skin, with sparse microfibrillar apparatus and interstitial collagen. After application of 0.025% all-trans retinoic acid, there was increased deposition of both these dermal matrix components, with the aberrant elastic fibers no longer apparent. Significant increases (p < 0.05) were observed at the protein and mRNA levels for fibrillin-1 following all-trans retinoic acid and sodium lauryl sulfate treatments, with all-trans retinoic acid having a significantly greater effect than irritant control (p < 0.001); however, neither application had significant effect on the abundance of collagen VII or its mRNA. Investigation of collagen I synthesis revealed no difference following treatments. To ascertain the clinical relevance of using fibrillin-1 as a marker for photoaging, facial skin was biopsied at baseline and after long-term (192 wk) topical all-trans retinoic acid treatment (n = 5). Biopsies were wax-embedded and sections prepared for immunohistochemistry for fibrillin-1. Significant increases in the abundance of the microfibrillar apparatus was observed proximal to the dermal- epidermal junction (p < 0.001) following long-term all-trans retinoic acid application. This study indicates that all-trans retinoic acid can significantly affect fibrillin-1 content in photoaged skin. Furthermore, fibrillin-1 can be used as a "reporter" molecule in short-term protocols for testing the utility of topical agents in the repair of photoaged skin.     

Human in vivo pharmacology of topical retinoids

All-trans retinoic acid is used topically for treating a variety of dermatologic conditions ranging from acne to photoaged skin. Although the clinical effects of retinoic acid treatment are often considerable, relatively little is known about the basic mechanisms underlying such effects. With the development of an in vivo human assay we have investigated the pleiotypic effects of topical retinoids from the histologic to the molecular. Histologically, retinoic acid induces epidermal proliferation and differentiation coupled with dermal fibroblast production of collagen. Immunologic effects include stimulation of the antigen-presenting capacity of Langerhans cells and induction of keratinocyte ICAM-1 expression. At the biochemical level, retinoic acid regulates transglutaminase and tyrosinase activities and activates protein kinase C. Both polar metabolites and stereoisomers of all-trans retinoic acid are also biologically active. Molecular biologic techniques have revealed that elevation of mRNA for cellular retinoic acid binding protein II is a retinoid-related event and that nuclear receptors such as retinoic acid receptors and retinoid X-receptors may transduce the retinoid response.     

Periorbital allergic contact dermatitis resulting from topical retinoic acid use

Contact dermatitis to topical tretinoin or retinoic acid is rarely described. We outline the case of a 20‐year‐old woman presenting with bilateral periorbital dermatitis against the background of longstanding use of retinoic acid for the ocular complications of toxic epidermal necrolysis. Patch testing confirmed a contact allergy to retinoic acid and the symptoms of the dermatitis resolved after the cessation of retinoic acid.     

Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin.

Histologic and clinical improvement of sun-exposed skin following topical treatment with retinoic acid has been reported. Daily application of retinoic acid typically results within 2-5 d in an erythematous scaling reaction, which lessens with continued usage. The cellular, immunologic, and biochemical basis of this retinoid reaction and its role in the repair of photodamaged skin are not known. To investigate the retinoid reaction in man, we have treated non-sun-exposed skin with 0.1% retinoic acid cream (Retin-A, Ortho Pharmaceutical Corporation, Raritan, NJ) under occlusion for 4 d to induce erythema and then examined changes in 1) histology, 2) expression of cell-surface molecules, 3) the enzymes and second messengers of the phospholipase C/protein kinase C signal-transduction system, 4) levels of eicosanoids, and 5) levels of interleukin-1 protein and mRNA. These parameters were chosen for measurement both because they are indicators of epidermal function and previous studies suggest they may be responsive to retinoic acid treatment. Epidermal cell growth as judged by increased epidermal thickness and mitotic figures was significantly increased in retinoic acid-treated skin compared to vehicle-treated controls. Increased numbers of CD4+ T cells accompanied by prominence of dermal dendrocytes in the papillary dermis and focal keratinocyte expression of intercellular adhesion molecule-1 were observed in retinoic acid-treated biopsies. Phosphoinositide-specific phospholipase C activity and 1,2-diacylglycerol content were also elevated in retinoic acid-treated epidermis. Protein kinase C activity was reduced by one third in both the soluble and membrane fraction, suggesting down-regulation. Surprisingly, in view of the inflammatory nature of the retinoid reaction, no increases were observed in arachidonic acid, its metabolites, interleukin-1 alpha, or interleukin-1 beta. To examine the specificity of the retinoid reaction, subjects were treated with the irritant sodium lauryl sulfate, under conditions that resulted in a reaction clinically similar to that observed with retinoic acid. The histologic alterations induced by sodium lauryl sulfate were found to be indistinguishable from those induced by retinoic acid. These data indicate that, although a wide range of cellular and molecular alterations occur in retinoic acid-treated skin, these changes may not be necessarily specific or unique for retinoic acid.     

The retinoic acid derivative Ro 11-1430 (Tasmaderm) in patients with acne vulgaris not tolerating retinoic acid. A controlled multicenter trial against placebo.

In a double-blind randomized comparative multicenter trial, consisting of 29 patients with acne vulgaris who were unable to tolerate daily applications of retinoic acid, the retinoic acid derivative Ro 11--1430 (0.1% vanishing cream) was compared in a 6--8 weeks topical treatment with vanishing cream alone (placebo). Regarding efficacy, for most criteria measured the response was always better with Ro 11--1430 than with placebo, although the differences were not always statistically significant for several reasons, one probably being the small number of patients in the trial. Regarding tolerance, both treatments were satisfactory. Ro 11---1430 and placebo did not differ significantly regarding frequency and severity of erythema, desquamation and burning. These results suggest that treatment with Ro 11--1430 should be considered in acne patients who are unable to use retinoic acid due to severe local reactions.     

Clinical effect of tocoretinate on lichen and macular amyloidosis

Lichen amyloidosis and macular amyloidosis are commonly therapy-resistant. Tocoretinate is a hybrid compound of retinoic acid and tocopherol that is commonly used for the treatment of skin ulcers. Although beneficial effect of oral retinoic acid on lichen amyloidosis is reported, tocoretinate has not been reported to be useful for the treatment of lichen amyloidosis or macular amyloidosis. We evaluated the effects of topical tocoretinate on lichen amyloidosis and macular amyloidosis lesions. Tocoretinate was topically applied daily to the lesions and clinical improvement and histological changes were evaluated. The outcome was very good for four, good for two, moderate for two and poor for two of 10 treated patients. Epidermal hypertrophy was reduced and expression of involucrin, keratin 1 and keratin 10 was decreased by tocoretinate treatment, suggesting the normalization of epidermal differentiation. Amyloid deposits remained histologically detectable, even in clinically responsive patients. Together, topical application of tocoretinate reduced the clinical symptoms of lichen amyloidosis and macular amyloidosis, and normalized disturbed epidermal differentiation.     

局限性硬皮病的研究新进展

对近期局限性硬皮病研究的新进展作一综述,包括临床表现和分型,发病机制(感染、创伤、药物和遗传等相关的病例),多种评价病情的方法及治疗手段(光疗,维A酸联合PUVA,MTX,外用他克莫司、咪喹莫特)。     

Topical tretinoin or adapalene in acne vulgaris: an overview

Retinoids target several pathoetiologic events of acne vulgaris. The undisputed efficacy of tretinoin, and yet its underutilization, due to apprehension of retinoid dermatitis, triggered a search for newer, well-tolerated retinoids. The discovery of nuclear retinoic acid receptors has provided clues to a rational design of synthetic, receptor-selective retinoic acid agonists. Adapalene is an addition to the arsenal of topical retinoids. It possesses the biological properties of tretinoin, but has a distinct physiochemical profile, including high lipophilicity and increased chemical and photostability. It exhibits selective affinity for nuclear retinoic acid receptors and does not bind to cytosolic retinoic acid binding proteins. It exemplifies the formulation of a novel retinoid with specific pharmacologic profile and clinical objectives. Accordingly, numerous clinical trials have compared adapalene and tretinoin in the management of acne vulgaris and concluded that tretinoin 0.05% gel exhibits a greater anti-acne efficacy than adapalene 0.1% gel, but has higher skin irritation potential. This article reviews the pharmacology of adapalene, including its retinoid receptor binding profile, antiproliferative effects, cell differentiation modulation, comedolytic and anti-inflammatory activity, and specifically focuses on the comparison of the efficacy and irritation profile of adapalene and tretinoin.     

Lack of enhancement of experimental photocarcinogenesis by topical retinoic acid

Summary A controversy exists regarding the ability of retinoic acid to enhance photocarcinogenesis. Divergent results have been obtained with albino hairless mice. We examined this issue with the lightly pigmented variety. We followed two designs: 1. ultraviolet light and topical retinoic acid were given concomitantly while the retinoic acid was continued for many weeks after stopping irradiation; 2. tumors were first induced by ultraviolet light and then treated topically with retinoic acid. In both studies, retinoic acid did not enhance photocarcinogenesis with regard to latent period, tumor yield or tumor progression. It appears that different treatment schedules and different varieties of mice can produce widely disparate results.     

TOPICAL TREATMENT OF MELASMA

Melasma is a common hypermelanotic disorder affecting the face that is associated with considerable psychological impacts. The management of melasma is challenging and requires a long-term treatment plan. In addition to avoidance of aggravating factors like oral pills and ultraviolet exposure, topical therapy has remained the mainstay of treatment. Multiple options for topical treatment are available, of which hydroquinone (HQ) is the most commonly prescribed agent. Besides HQ, other topical agents for which varying degrees of evidence for clinical efficacy exist include azelaic acid, kojic acid, retinoids, topical steroids, glycolic acid, mequinol, and arbutin. Topical medications modify various stages of melanogenesis, the most common mode of action being inhibition of the enzyme, tyrosinase. Combination therapy is the preferred mode of treatment for the synergism and reduction of untoward effects. The most popular combination consists of HQ, a topical steroid, and retinoic acid. Prolonged HQ usage may lead to untoward effects like depigmentation and exogenous ochronosis. The search for safer alternatives has given rise to the development of many newer agents, several of them from natural sources. Well-designed controlled clinical trials are needed to clarify their role in the routine management of melasma.     

Short-term retinoic acid treatment increases in vivo, but decreases in vitro, epidermal transglutaminase-K enzyme activity and immunoreactivity.

Epidermal transglutaminase-K is believed to catalyze the covalent linking of loricrin and involucrin to form cross-linked (CE) envelopes. In normal skin, transglutaminase-K is expressed as a band immediately below the stratum corneum, whereas in psoriasis and healing skin its expression is considerably expanded throughout the suprabasal layers. We have investigated whether the hyperproliferative state induced by short-term application of topical retinoic acid is similarly characterized by an increase in transglutaminase-K enzyme activity and immunoreactivity. Retinoic acid (0.1% cream) or vehicle were applied to human skin and occluded for 4 d. Skin biopsies were obtained for measurement of transglutaminase-K and transglutaminase-C activity and immunoreactivity. For comparison, cultured normal human keratinocytes were incubated for 4 d in the presence of 1 microM retinoic acid and the subsequent transglutaminase-K activity and immunoreactivity measured. Transglutaminase-K activity was increased 2.8 times in retinoic acid compared to vehicle-treated skin (p less than 0.005, n = 12) whereas there was no significant difference in transglutaminase-C activity. However, transglutaminase-K mRNA levels were not significantly different between retinoic acid- and vehicle-treated skin. In vehicle-treated skin, transglutaminase-K immunoreactivity was limited to a narrow, substratum corneal band, but was considerably expanded in a diffuse suprabasal pattern in retinoic acid-treated epidermis. In contrast, transglutaminase-K immunostaining was decreased and its enzymatic activity reduced sixfold in retinoic acid-treated keratinocytes (p less than 0.01, n = 4). These results demonstrate that retinoic acid treatment in vivo, in contrast to in vitro, leads to not only increased transglutaminase-K protein expression but also increased enzymatic activity in the absence of detectable increases in mRNA levels. These data, taken with the previously reported lack of in vivo modulation of the differentiation markers keratins 1 and 10 by retinoic acid, indicate that certain aspects of keratinocyte terminal differentiation that are altered in vitro by retinoic acid do not occur in vivo in human skin.