Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0152030 (skin irritation)
 2,146 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preclinical studies pertaining to the pharmacology and toxicology of BMY 30123 (4-acetamidophenyl retinoate) are reported. BMY 30123 is a novel compound which has topical retinoid activity. This compound exhibits lower toxicity, both local and systemic, than other clinically used topical retinoids such as tretinoin (all-trans retinoic acid) in animal models. BMY 30123 is effective in a number of retinoid sensitive skin models including the rhino mouse utriculi reduction assay, the mouse epidermal hyperplasia model and in the suppression of DNA synthesis in mouse skin stimulated with phorbol ester. BMY 30123 was equipotent with tretinoin in these topical models. In the rhino mouse model the ED30 values for BMY 30123 and tretinoin were 0.037 and 0.015 mM, respectively. In addition, BMY 30123 was active in the UVB-induced photodamaged mouse model, another retinoid sensitive model. One of the problems associated with topically applied tretinoin is local irritation. Therefore, for topical therapy to be optimal, it is important to reduce or minimize local irritation. Repeated applications of BMY 30123 to rabbit skin resulted in low skin irritation. The first perceptible signs of skin irritation produced by BMY 30123 occurred at a dose 10 times higher than that observed for tretinoin. BMY 30123 also exhibits low retinoid activity after oral or i.p. administration in mice and produced no signs of hypervitaminosis A-related toxicity at twenty times the no effect dose of tretinoin. Because retinoids are effective modulators of epidermal growth and differentiation, this compound should be useful for the treatment of cutaneous disorders that exhibit altered epidermal differentiation such as acne, psoriasis, ichthyosis and epithelial tumours.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pharmacology of a novel topical retinoid, BMY 30123: comparison with tretinoin. 135 51

In the treatment of various dermatological disorders, topically applied retinoids have potential therapeutic use with the advantage of improved localized activity and lower toxicity over systemically administered retinoids. However, most retinoids cause a significant degree of local irritation. In the present study, the ability to produce local activity with low local irritation potential was evaluated with a novel retinoic acid derivative. BMY 30047 (11-cis, 13-cis-12-hydroxymethylretinoic acid delta-lactone) is one of a series of retinoic acid derivatives in which the carboxyl function of the polar end was modified with the aim of achieving reduced local irritation and systemic toxicity while retaining the local therapeutic effect. BMY 30047 was evaluated and compared with all-trans retinoic acid for topical retinoid activity in several preclinical assay systems, including the utricle reduction assay in rhino mice, 12-o-tetradecanoylphorbol 13-acetate ester-stimulated ornithine decarboxylase induction in hairless mice and the UV light-induced photodamaged skin model in hairless mice. BMY 30047 was assessed for retinoid-type side effects by evaluating the skin irritation potential in rabbits after repeated topical application, and hypervitaminosis A-inducing potential in mice after i.p. injection. BMY 30047 demonstrated significant topical retinoid activity in several in vivo models with less skin irritation potential relative to the most used clinical concentrations of all-trans retinoic acid. BMY 30047 also showed very little systemic activity and did not produce any evidence of hypervitaminosis A syndrome at systemic doses 20 times greater than the no-effect dose of all-trans retinoic acid.
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PMID:BMY 30047: a novel topically active retinoid with low local and systemic toxicity. 198 66

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.
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PMID:UVB-induced pigmentation in hairless mice as an in vivo assay for topical skin-depigmenting activity. 263 67

All-trans-retinoic acid is a potent developmental toxicant in all species examined. The teratogenic risk of topical all-trans-retinoic acid is reviewed. Experimental studies are limited because of the high maternal toxicity, including skin irritation, with doses below those resulting in significant teratogenic response with other application routes, such as oral application. The maximal systemic availability reported for transdermal exposure of all-trans-retinoic acid was 5-6% in the rat, 9.6% in the monkey (48% with dermatitic skin) and 5-7% in the human. Oral administration of threshold teratogenic doses of all-trans-retinoic acid (6 mg/kg/day) to Wistar rats and Swiss hare rabbits resulted in embryonic area under the concentration time curve levels (approximately 1,000 ng.h/g) which were 2- to 4-fold higher than the endogenous all-trans-retinoic acid levels; corresponding maternal plasma area under the concentration time curve values were 98 and 321 ng.h/ml in rat and rabbit, respectively. The 4-oxo-metabolite was also found in maternal plasma and embryo. Large, controlled studies on the possible developmental toxicity of topical all-trans-retinoic acid in the human are not available. Isolated case reports appeared in the literature claiming teratogenic outcome resembling effects after oral isotretinoin use or those observed in experimental studies with oral or parenteral all-trans-retinoic acid administration. The dose absorbed from daily cosmetic or therapeutic application of all-trans-retinoic acid is expected to be below 0.015 mg/kg, which is at least 30-fold lower than the lowest teratogenic dose of isotretinoin in the human. Topical all-trans-retinoic acid application did not appreciably alter endogenous plasma retinoid levels. The influence of nutrition, diurnal variation and in particular oral vitamin A supplements are more important determinants of plasma retinoic acid compounds than topical all-trans-retinoic acid. These results imply a low risk of therapeutic or cosmetic application of topical all-trans-retinoic acid. However, the highly specific spatial and temporal distribution of binding proteins and nuclear receptors in the embryo suggests that even small alterations in endogenous levels of all-trans-retinoic acid in the embryo may alter crucial developmental processes such as morphogenes; this aspect should be further investigated.
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PMID:Embryotoxicity and teratogenicity of topical retinoic acid. 814 10

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.
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PMID:Combination of 4-hydroxyanisole and all-trans retinoic acid produces synergistic skin depigmentation in swine. 834 15

Topically applied all-trans retinoic acid (RA) is often associated with skin irritation. A detailed quantification of RA-induced functional changes in stratum corneum is, however, still limited. Using non-invasive bioengineering techniques of measurements of transepidermal water loss (TEWL), stratum corneum hydration and cutaneous blood flow (CBF), we quantified the irritant effects of 0.05% and 0.1% RA in ethanol on normal skin compared with 1% sodium lauryl sulphate (SLS) in water as a model irritant in a 24-h occlusive patch-test assay. Additionally, in order to document data possibly related to the mechanism of action, skin responses to both compounds applied in tandem was also investigated over 18 days. The extent of the irritant response to 0.05 and 0.1% RA, respectively, were similar, implying analogous irritation potency. While RA caused more intense scaling than SLS, other skin responses to RA were significantly weaker than those due to SLS. An increase in TEWL, on day 7, in RA-exposed sites indicates a secondary delayed impairment of the stratum corneum (SC) barrier. In a tandem-design assay, pretreatment with RA appeared to reduce the irritant effects of SLS on SC hydration and CBF. In contrast, pre-exposure to SLS showed a synergestic response in erythema, scaling and TEWL. Our results demonstrate that RA, like SLS, is capable of impairing SC water barrier function, which may be responsible, in part, for the irritation associated with its topical use. However, the distinctive biological responses to these compounds suggest a different mode of action of RA and SLS. In addition, the precise reason for the unique results observed in the tandem-design assays is not clear.
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PMID:Differential irritant skin responses to topical retinoic acid and sodium lauryl sulphate: alone and in crossover design. 873 64

In clinical practice, the cutaneous exposure to chemical irritants such as surfactants and topical drugs is frequent. Topical all-trans retinoic acid (RA) is often associated with irritation and induces epidermal changes similar to those produced by sodium lauryl sulphate (SLS). Using bioengineering techniques, e.g. assessing transepidermal water loss (TEWL), capacitance and chromametry, we investigated the variations of the skin response to SLS and RA and to both chemicals applied sequentially, allowing different time periods (from 1 h to 2 weeks) between applications of SLS and RA. Both chemicals caused irritation as assessed by visual scoring, but the values from the objective variables differed at different time periods. TEWL increased dramatically shortly after applying SLS but the increase was delayed after RA. After applying SLS, the capacitance generally decreased then returned to basal values; treatment with RA produced an overall increase. Only the results from chromametry were similar. After tandem application, the drugs were synergistic for all variables except capacitance, showing an antagonistic interaction for skin hydration. These results suggest that non-specific skin irritation profoundly reflects different mechanisms of action at tissue level. With sequential application, SLS injury modified the response to RA for at least 1 week after applying SLS. These late effects of detergents should be considered when studying irritant chemical interactions and in developing strategies for the management of occupational and other irritant dermatitis.
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PMID:Differential irritant skin responses to tandem application of topical retinoic acid and sodium lauryl sulphate: II. Effect of time between first and second exposure. 964 Apr

The ability of the synthetic retinoid MDI-301, in which the carboxylic acid of 9- cis-retinoic acid (9-cis-RA) is replaced with an ester linkage, to induce epidermal and dermal thickening and skin irritation (erythema and flaking) in hairless (rhino) mice following its topical application was investigated in comparison with that of 14-all- trans-retinoic acid (14-all-trans-RA) and 9-cis-RA. MDI-301 induced epidermal proliferation leading to a thickened epidermis. Treated animals also demonstrated a prominent band of organized connective tissue immediately below the epidermis. In its ability to induce epidermal thickening, MDI-301 was quantitatively similar to 14-all-trans-RA and 9-cis-RA. However, unlike 14-all-trans-RA and 9-cis-RA, which produced skin irritation associated with a perivascular influx of mononuclear leukocytes into the dermis, there was no evidence of irritation with MDI-301 and little leukocyte infiltration. Intraperitoneal injection of either 14-all-trans-RA or MDI-301 also resulted in epidermal and dermal thickening. Irritation of skin was not observed in these animals but splenomegaly was prominent in animals treated with either agent.
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PMID:Separation of retinoid-induced epidermal and dermal thickening from skin irritation. 1456 58

Retinoic acid derivatives have been used successfully for the treatment of various dermatoses, such as psoriasis; however, topical application of these compounds often elicits skin irritation. We hypothesized that this irritation was as a result of the local production of interleukin-8 (IL-8). To test this hypothesis, we investigated whether all-trans-retinoic acid (ATRA) induced IL-8 production in normal human keratinocytes. Stimulation with 10(-7) M ATRA enhanced IL-8 mRNA expression and induced IL-8 production. We also studied the intracellular signaling mechanisms of ATRA-induced IL-8 production in keratinocytes. ATRA increased the expression of RelA (p65), RelB, nuclear factor (NF)-kappaB2 (p52), and NF-kappaB1 (p50), and elevated the DNA-binding activity of p65 and phosphorylation of inhibitor kappaB (IkappaB) alpha. Introduction of a dominant-negative mutant of IkappaBalpha completely abolished ATRA-induced IL-8 production, which indicates that this process is NF-kappaB-dependent. We also studied the role of the p38 mitogen-activated protein kinase (MAPK) pathway in this phenomenon. ATRA phosphorylated the p38 MAPK, and SB202180 inhibited ATRA-induced IL-8 production, which indicates that the p38 MAPK is also involved in ATRA-induced IL-8 production. In summary, ATRA induces IL-8 production in both NF-kappaB- and p38 MAPK-dependent manners in normal human keratinocytes.
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PMID:All-trans-retinoic acid induces interleukin-8 via the nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways in normal human keratinocytes. 1561 May 18

Mice on a calorie-restricted (CR) diet (total calories restricted to 70% of ad libitum; AL) for periods of time ranging from 3 to 18 months were examined for response to topical treatment with all-trans retinoic acid (RA). Daily application of a 0.1% solution of RA to the shaved skin of UM-HET3 mice on an AL diet produced a severe irritation that was evident by day 4, maximal at day 7-8 and still detectable at day 14. Skin irritation was characterized by redness, dryness, flaking and failure of the hair to grow at the treated site. In CR mice, the same treatment produced little detectable irritation. Animals were sacrificed at the end of the retinoid-treatment period (day 7 or day 14) and skin from these animals was examined histologically. In both AL and CR mice, a similar degree of epidermal hyperplasia was observed. Numerous inflammatory cells (mononuclear cells and granulocytes) were present in the skin of both groups. Occasional S100-positive cells (presumably Langerhans cells) were also observed in the epidermis of skin from both groups. S100-positive cells were also observed in the dermis. When skin from CR and AL mice was incubated in organ culture for 3 days (on day 7 after initiation of RA treatment), similar levels of four different pro-inflammatory cytokines were found in the conditioned medium. Soluble type I collagen levels were also similar. In contrast, the level of matrix metalloproteinase-9 was lower in the conditioned medium of skin from CR mice than in conditioned medium from skin cultures of AL mice. Taken together, these studies suggest that CR may provide a way to mitigate the irritation that normally accompanies RA treatment without compromising the beneficial effects of retinoid use. CR appears to exert a protective effect at the target tissue level rather than by a reduction in pro-inflammatory events, per se.
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PMID:Inhibition of retinoic acid-induced skin irritation in calorie-restricted mice. 1796 74


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