Cutaneous drug eruption induced by antihistamines

Topical application of antihistamines commonly leads to sensitization for patients, but systemic administration of antihistamines rarely induces allergic hypersensitivity, which is mainly linked to phenothiazine‐derived and piperazine‐derived compounds. We report a 70‐year‐old woman whose medical history included lichen planus, and who was referred by the dermatology department of our hospital for suspected allergy to corticosteroids. The reason for referral was that on the fourth day of treatment with prednisone and hydroxyzine, the patient presented a bilateral highly pruritic palmar erythema that evolved to a generalized morbilliform rash with subsequent complete desquamation. At a later time, she took cetirizine for a cold, and developed palmar erythema and desquamation. Skin tests (prick and intradermal tests) were performed with steroids, and patch tests (read after 48 and 96 h) with corticosteroids and antihistamines. Controlled oral challenge tests were performed with prednisone and with an alternative antihistamine. Skin tests were negative for all corticosteroids. Patch tests were negative for all corticosteroids, but the antihistamine test was positive for hydroxyzine. Oral challenge with prednisone and dexchlorpheniramine was negative. The patient was diagnosed with cutaneous drug eruption from hydroxyzine and cetirizine. We consider it is important to assess every patient whose skin condition worsens after treatment with antihistamines, especially hydroxyzine, because it is known that antihistamines are often not recognised as the culprit in cases of cutaneous eruption.     

Rapid effects of olopatadine hydrochloride on the histamine-induced skin responses

Olopatadine hydrochloride is one of the second-generation nonsedating antihistamines that are used for treating allergic disorders such as urticaria, rhinitis, and atopic dermatitis. We examined the inhibitory effects of this drug on the flare and wheal responses induced by histamine iontophoresis at 30, 60, and 90 min after oral administration in a double-blind, cross-over, and placebo-controlled study. Olopatadine hydrochloride significantly inhibited the histamine-induced flare and wheal responses as early as 60 min after oral administration when compared with placebo. Significant inihibitory effects of olopatadine hydrochloride on the itch responses were seen at 90 min after administration. Thus, olopatadine hydrochloride exhibited a very rapid and potent antihistamine effect on the histamine-induced skin responses.     

Effects of single therapeutic doses of promethazine, fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-responses: a randomized double-blind, placebo-controlled study in healthy volunteers

Since most first-generation antihistamines have undesirable sedative effects on the central nervous systems (CNS), newer (second-generation) antihistamines have been developed to improve patients’ quality of life. However, there are few reports that directly compare the antihistaminic efficacy and impairment of psychomotor functions. We designed a double-blind, placebo controlled, crossover study to concurrently compare the clinical effectiveness of promethazine, a first-generation antihistamine, and fexofenadine and olopatadine, second-generation antihistamines, by measuring their potency as peripheral inhibitors of histamine-induced wheal and flare. Further, we investigated their sedative effects on the CNS using a battery of psychomotor tests. When single therapeutic doses of fexofenadine (60 mg), olopatadine (5 mg) and promethazine (25 mg) were given in a double-blind manner to 24 healthy volunteers, all antihistamines produced a significant reduction in the wheal and flare responses induced by histamine. In the comparison among antihistamines, olopatadine showed a rapid inhibitory effect compared with fexofenadine and promethazine, and had a potent effect compared with promethazine. In a battery of psychomotor assessments using critical flicker fusion, choice reaction time, compensatory tracking, rapid visual information processing and a line analogue rating scale as a subjective assessment of sedation, promethazine significantly impaired psychomotor function. Fexofenadine and olopatadine had no significant effect in any of the psychomotor tests. Promethazine, fexofenadine and olopatadine did not affect behavioral activity, as measured by wrist actigraphy. These results suggest that olopatadine at a therapeutic dose has greater antihistaminergic activity than promethazine, and olopatadine and fexofenadine did not cause cognitive or psychomotor impairment.     

Effects of cetirizine and epinastine on the skin response to histamine iontophoresis

Epinastine and cetirizine are second-generation, nonsedating and long-lasting antihistamines that are now frequently used for the allergic disorders. We have examined the inhibitory effects of these two drugs on the histamine-induced flare and wheal responses using iontophoresis at 1, 2, 4, 8 and 24 h after the oral administration by a double-blind, cross-over and placebo-controlled study. Both cetirizine and epinastine significantly inhibited the histamine-induced flare and wheal responses at 2 h after the oral administration when compared with placebo. The inhibitory effects of cetirizine and epinastine on the flare response lasted long until at 24 h, however, epinastine was less potent than cetirizine. The inhibitory effects on the wheal response was also clearly and significantly evident at 2-8 h by cetirizine and epinastine. At 24 h cetirizine only showed the significant inhibition on the histamine-induced wheal response. In contrast, epinastine seemed to exhibit the inhibitory capacity earlier than did cetirizine. The inhibitory action of the drugs on the histamine-induced wheal response peaked at 4 h after the oral administration. The histamine-induced itch sensation was also markedly or completely suppressed at 2-8 h by the drugs. Thus, both drugs exhibited the potent and long-lasting antihistamine activity on the skin responses induced by histamine iontophoresis.     

Effects of acrivastine, loratadine and cetirizine on histamine-induced wheal and flare responses

It is accepted that studies evaluating histamine-induced wheal and flare reactions in the skin represent a simple and reliable method for demonstrating pharmacodynamic activity and pharmacokinetics of the H1-receptor antagonists. In this study, the effects of single oral doses of acrivastine (8 mg), loratadine (10 mg) and cetirizine (10 mg) on the histamine-induced wheal and flare reactions were compared in 60 healthy volunteers. The wheal and flare responses were produced by prick test using 1% histamine solution. Measurements were performed before the ingestion of antihistamines (baseline values) and afterwards at 15, 30, 90, 240, 360 min and 24 h. The values obtained for each antihistamine were compared with each other and with baseline values. Cetirizine was found to be superior to acrivastine and loratadine for the suppression of wheal and flare responses at 240, 360 min and 24 h (P < 0.05) and acrivastine was superior to the other two antihistamines for the suppression of flare response at 30 min (P < 0.05). Our results indicate that a single dose of cetirizine provides a more effective and long acting suppression on wheal and flare reactions in urticaria when compared to acrivastine and loratadine.     

花生四烯酸人体皮肤炎症模型

目的　建立花生四烯酸 (arachidonicacid ,AA)人体皮肤炎症模型。方法　在健康志愿者前臂屈侧做0 .0 3 %AA、0 .16%AA、0 .8%AA、4%AA、2 0 %AA、40 %AA浓度的点刺试验 ,分别记录其 3 0min红斑面积、风团面积。结果　点刺AA后 5min左右即可产生红斑、风团 ,大约 3 0min产生最大红斑与风团 (个别在 3 0～ 60min达最高峰 ) ,2～ 4h后消退(个别在 6h后消退 )。炎症模型中以 2 0 %AA产生的红斑、风团表现较为稳定。结论　通过点刺试验可建立稳定的AA人体皮肤炎症模型。     

Suppression of immediate-type hypersensitivity elicitation in the skin prick test by ultraviolet B irradiation

Reproducibility of skin prick testing (SPT) and its modulation by ultraviolet B (UVB) radiation is of clinical interest. Sensitized atopic volunteers (groups A and B, n=21) were prick tested with common commercial allergen solutions (undiluted, diluted 1:10 and diluted 1:100) before, 24 h after one and 24 h after three suberythematous UVB irradiations. Volunteers in group A (n=8) received local UVB irradiation of prick test areas, whereas volunteers in group B (n=13) received whole body UVB irradiation, with prick test areas covered. In group A, the wheal intensities, expressed as the ratio allergen wheal size to histamine wheal size, were decreased by 28% (1:10 dilution) (P=0.01) and 45% (1:100 dilution) (P=0.02) after one UVB irradiation. Flare intensities were decreased by 48% (1:10 dilution) (P=0.03) after three UVB irradiations. In group B, the wheal and flare responses tended to decrease. Possible mechanisms of this short-term suppressive effect of UVB irradiation on SPT reactions include a direct effect on mast cells. It is concluded that UV irradiation, even a single exposure, prior to skin testing may compromise the validity of SPT testing.     

Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil

Background:Several dermatoses are mediated by histamine, such as urticaria, angioedema, and papular urticaria. There are no Brazilian studies comparing the potency of antihistamines.Objectives:To evaluate the tolerability and efficacy of the main commercial brand and generic H1 antihistamines, regarding the suppression of the wheal and flare to the histamine test.Methods:A quasi-experimental, open study with 10 healthy adults submitted to the histamine test on the ventral aspect of the forearms. After 20 minutes, wheal and flares were measured. The tests were performed after two hours of intake of dexchlorpheniramine, hydroxyzine, levocetirizine, fexofenadine, cetirizine, loratadine, ebastine, desloratadine, epinastine and rupatadine, as well as generics of loratadine, cetirizine and fexofenadine.Results:All antihistamines presented a reduction in the wheal compared to the control (p <0.02), as well as in the flare, except for rupatadine (p = 0.70). In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1). As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1). The most common adverse effect was drowsiness, which was more prevalent among first-generation drugs (p < 0.01). Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p >0.03)..Study limitations:A single-center study evaluating only aspects related to histamine.Conclusions:Brazilian commercial antihistamines presented different profiles of inhibition of wheal and flares in the histamine test, as well as adverse effects. Generic loratadine, fexofenadine and cetirizine presented larger flares than brand drugs.     

Antipruritische Wirksamkeit einer hoch dosierten Antihistaminikatherapie

Background and objectives

The causal treatment of chronic pruritus is not always possible or effective necessitating symptomatic antipruritic therapy. Antihistamines are the only drugs approved for the treatment of chronic pruritus, but they are rarely effective at standard doses. The aim of this investigation was to describe the efficacy and safety of high-dosage antihistamine treatment in patients with chronic pruritus of different origin.

Patients

A total of 67 patients with chronic pruritus caused by different skin diseases or chronic pruritus of unknown origin were treated with levocetirizine 10 mg/fexofenadine 360 mg or levocetirizine 10 mg/fexofenadine 360 mg/azelastine 4 mg or desloratadine 20 mg per day.

Results

A therapeutic response was achieved in 43.8% of patients with a combination of two antihistamines, 68.4% of patients with three antihistamines and 76.9% of patients with high dosage desloratadine. The average reduction in pruritus was 57.5% (two antihistamines), 67.4% (three antihistamines) and 89% (desloratadine). Adverse drug effects were observed rarely.

Conclusions

The results of this case series suggest a high antipruritic effect in chronic pruritus by administration of high-dosage, non-sedating antihistamines. These results have to be confirmed in controlled trials. The combination was not more effective than the high dosage monotherapy. The latter one might be preferable due to unknown interactions and addition of side-effects in the combination therapy.     

Start and end of the effects of terfenadine and astemizole on histamine-induced wheals in human skin

A study was made of effects of two antihistamines, terfenadine (60 mg twice daily) and astemizole (10 mg once daily) on wheals induced by histamine dihydrochloride (10 mg/ml) in the prick test on the upper back of 15 healthy students. The suppressive effects of terfenadine on the histamine wheal appeared earlier (2 h), and disappeared earlier (within 1 day) than those of astemizole (3 days and 28 days, respectively). No difference between the maximal effects of the two drugs was seen.     

Suction blister formation in skin after acute and repeated mast cell degranulation.

Mast cells and their proteases are thought to participate in the development of skin blisters in various pathological conditions. In this study, suction blistering was used as an experimental model to evaluate the significance of mast cells in blister formation after pre-treatment of normal skin with intradermal injections of 100 microg/ml compound 48/80 (a mast cell degranulator) or with 0.1% capsaicin cream. Tryptic and chymotryptic enzyme activities in blister fluids were measured with sensitive p-nitroanilide substrates. Repeated injections of compound 48/80 once a day on 3 or 5 consecutive days or capsaicin applications 3 times a day for 7 or 10 days were used to induce mast cell degranulation and inflammation in normal skin. Both treatments ultimately led to decreased wheal and erythema reactions before suction blistering, but neither treatment affected the size or formation rate of suction blisters. No suction blister fluids had detectable levels of chymotryptic activity, but blister fluids from bullous pemphigoid, herpes zoster and insect bullous eruption, used as the control, revealed clear chymotryptic activity. In addition, tryptic activity in suction blister fluids was not significantly altered after compound 48/80 and capsaicin pre-treatments. However, if the wheal reaction was induced immediately before suction blistering, a significantly increased rate in blister formation together with increased tryptic activity was found, but, unexpectedly, no chymotryptic activity could be detected in blister fluids. The results show that repeated mast cell degranulation in normal skin has no effect on the formation rate of suction blisters, which developed more rapidly on acutely whealing skin. This is probably due to skin oedema rather than mast cell proteases, since no chymotryptic activity was detected in suction blisters where tryptic activity exhibited high individual variation.     

Fexofenadine, an H1-receptor antagonist, partially but rapidly inhibits the itch of contact dermatitis induced by diphenylcyclopropenone in patients with alopecia areata

Antihistamines have been used for the treatment of not only allergic diseases such as allergic urticaria and rhinitis, but also of eczematous skin diseases because of their anti-pruritic effects. Moreover, the pruritus associated with eczematous diseases is considered to be induced, in part, by histamine. However, it is unclear whether antihistamines inhibit the itch of eczematous diseases in the absence of topical corticosteroids. In this study, we investigated the anti-pruritic effect of the antihistamine, fexofenadine, on the itch of contact dermatitis that was induced by topical application of diphenylcyclopropenone for the treatment for alopecia areata. Thirteen patients with alopecia areata, who had been treated weekly with topical immunotherapy with diphenylcyclopropenone for 3 months to 2 years, recorded the severity of their itching on a visual analog scale before and 3, 6, 12, 24, 48 and 72 h after application of diphenylcyclopropenone for 4 consecutive weeks. Seven patients took fexofenadine during the first and third weeks, and six patients took fexofenadine during the second and fourth weeks. The severity of itching reached a maximum 6-12 h after the induction of the contact dermatitis in most of the patients. However, fexofenadine partially but rapidly reduced the severity of itching for 72 h during the entire period of treatment in the absence of topical corticosteroids. Our results suggest that fexofenadine can be beneficial in the daily management of patients with itching due to eczematous disease.     

Multiple H1-antihistamine-induced urticaria

H₁‐antihistamines are widely used in the treatment of various allergic diseases. Particularly, a cornerstone of the management of chronic idiopathic urticaria is treatment with H₁‐antihistamines. However, a few cases of H₁‐antihistamine‐induced urticaria have been reported. A 34‐year‐old woman presented with a 4‐month history of recurrent urticaria, which was prominently exacerbated by the administration of H₁‐antihistamines. The patient consented to a provocation test of fexofenadine among drugs including cetirizine and hydroxyzine, which were suspected of inducing severe symptoms in episodes. One hour after challenge with 12 mg fexofenadine (one‐fifth of the therapeutic dose), a urticarial reaction rapidly developed on nearly the entire body with remarkably increased levels of plasma histamine (190 nmol/L) and plasma leukotriene B4 (150 pg/mL). In challenge tests with other antihistamines, generalized urticaria occurred 5 and 1 h after intake of 10 mg loratadine and 10 mg bepotastine, respectively, whereas challenges with chlorpheniramine, mequitazine and azelastine were all negative. Skin prick tests with H₁‐antihistamines used in the challenges were all negative, indicating that the urticarial reactions after challenges with the causative drugs might not be immunoglobulin E‐mediated. Among the causative drugs in our case, cetirizine and hydroxyzine are the piperazine derivatives, whereas fexofenadine, bepotastine, ebastine and loratadine are the piperidine derivatives. The chemical structures of both derivatives are very similar. Therefore, in this case, H₁‐antihistamine‐induced urticaria may have been due to cross‐reactivity between metabolites of these drugs, but not to drugs before metabolization. Hypersensitivity to H₁‐antihistamines should be considered when urticarial lesions worsen after H₁‐antihistamine treatment.     

Comparison of the potency of antihistamines

ABSTRACT: First- and second-generation antihistamines have proven effective in the management of patients with urticaria and allergic rhinitis; however, the efficacy of first-generation antihistamines has been compromised by undesirable side effects such as sedation, dry mouth, and blurred vision. Second-generation antihistamines, on the other hand, are less sedating and have fewer side effects than first-generation agents. Recently second-generation agents have been compared for their pharmacologic activities using an epicutaneous histamine-induced wheal and flare model in normal volunteers. Cetirizine was found to be superior to epinastine, ebastine, fexofenadine, terfenadine, loratadine, and placebo in inhibiting the wheal and flare response. Epinastine had the fastest onset of action at 30 minutes and terfenadine proved to be superior to its metabolite fexofenadine.     

Attenuation of axon reflexes to compound 48/80 after repeated iontophoresis of compound 48/80 in skin of the human forearm

The aim of this study was to determine whether the iontophoretic administration of the mast cell degranulator compound 48/80 influences axon reflex vasodilatation in the skin of the human forearm. In stage 1, compound 48/80 was administered by iontophoresis to a circular site in the forearm of 9 healthy men and 8 healthy women on four occasions spread over 24 h. Two control sites were also prepared by passing the iontophoretic current through 0.9% saline. Large wheals initially developed at the compound 48/80 site in 8 of the males and in 2 of the females, but wheals were minimal in all subjects by the fourth administration. In stage 2, compound 48/80 iontophoresis provoked substantial flaring at the first control site, whereas saline iontophoresis induced only minor flaring at the second control site, indicating that compound 48/80 induced axon reflex vasodilatation. However, prior treatment with compound 48/80 inhibited flaring to compound 48/80 in subjects who initially developed wheals, consistent with mast cell degranulation. In stage 3, flaring after iontophoresis of histamine was investigated at the site of compound 48/80 pretreatment and at the second control site in 12 subjects. Flaring was impaired only slightly in 6 subjects who initially developed wheals to compound 48/80. The persistence of flaring indicates that repeated administrations of compound 48/80 did not abolish neurogenic inflammation. Transcutaneous iontophoresis of compound 48/80 may be an attractive alternative to intradermal injection in studies that aim at clarifying the function of mast cells in healthy and diseased skin.     

Onset and duration of action of topical antihistamine: a study of histamine skin test response

Background   Most patients who require skin prick testing cannot deal with their pruritus without taking antihistamines (AH). Orally administered AH has a quick onset of action, but it will suppress skin test responses (STR) from several days to weeks. In this study, we aimed to determine the onset and duration of action of single topical AH application by observing histamine-STR suppression over time.
Methods   A two-step, randomized, intraindividual parallel-comparative, double-blind, placebo-controlled trial was conducted on the volar side of the forearm. Step 1 was aimed to determine the onset, while step 2 determined the duration of action. The topical AH tested was a single application of 5% doxepin hydrochloride cream, while 10 mg/ml histamine dihydrochloride was used to test the skin responses.
Results   Our 10 subjects' mean age was 35.8 ± 3.179 years. Histamine wheal response was suppressed starting on minute 90 and the wheal width were back to ≥ 7 mm² on minute 270. Significant histamine reactivity difference between genders ( P  = 0.201) and atopic status ( P  = 1.000), which could be a source of bias in histamine STR, was not found among our subjects.
Conclusion   Single application of topical AH has an onset of action in 90 min and duration of action < 180 min. Because of its short duration of action, topical AH can be used in a patient who needs AH but is scheduled to undergo skin prick testing after a few hours, without influencing the patient's STR.     

Thermographic analysis of skin test reaction using AGA thermovision

The course of infrared thermography including isothermograms on the skin surface was investigated considering blood flow, redness of the skin and permeability of blood vessel, in the following skin reactions: 1. Intracutaneous injection of histamine and histamine liberator compound 48/80 increased the heat radiation. Local application of antihistamine externa which decreased the development of the urticarial histamine reaction, increased the infrared radiation of the skin surface. Combined injection of histamine or histamine liberators with antihistamines in a sufficient dosis (1:1 respectively 4:1) diminished also the heat radiation in addition to the urticarial reaction. 2. The Pyrexal reaction of the skin with early erythema and later papule development shows an equivalent picture in the AGA Thermovision. The pretreatment shows an equivalent picture in the AGA Thermovision. The pretreatment of the skin with corticosteroid ointments shows a corresponding lowering of the erythema, of papule development as well as of heat radiation. The blanching of corticosteroids after occlusive dressing is difficult to recognize by the isotherms of AGA Thermovision. 3. Allergic reactions of the immediate type show, corresponding to the wheal eruption, a marked increased of heat radiation combined with a projection of the enlarged veins on the skin surface. 4. Allergic reactions of the delayed type are combined with a definite elevation of heat radiation of the skin. The area of a positive skin test with allergic eczematous reaction shows a distinct elevation of ann infrared radiation. Although the allergic skin area which was substantiated by a positive skin test was no longer visible, a distinct infrared radiation could be detected. Preventive treatment of the test area of skin patch-testing with corticosteroids inhibits the heat radiation even if the allergic eczematous reaction occurs faintly. The thermographic analysis of the different skin test reactions complied with the morphological aspects of the reaction.     

Skin response to histamine dry skin prick test: influence of duration of the skin prick on clinical parameters and on skin blood flow monitoring

This comparative trial (histamine dry skin prick test versus control prick test) evaluates with subjective and objective clinical methods (i.e. itch scores, wheal area, and wheal and flare area) and with laser Doppler flowmetry (multiple sites measured between 5 and 15 min after prick test) the effect of increasing the duration of the skin prick (1, 3 and 10 s). As compared with control prick tests, all objective clinical parameters after histamine prick test were significantly different from the control prick tests. There was no interaction between agonist-duration of prick test and clinical parameters. When present, itch was reported only after histamine prick test. Skin blood perfusion values were evaluated with Laser Doppler flowmetry at prick test sites and at 1 cm distance from the prick test site. At control and histamine prick test sites, increased blood flow values were observed and a moderate interaction between agonist-duration of prick test and repeated measurement was noted (one tail P less than 0.05); there were indeed lower values 9 min after histamine prick tests whatever the duration of the prick test. At 1 cm distance from histamine prick test sites, all skin perfusion measurements (either 5-8 or 11-14 min) showed increased values over data recorded after control prick test (P less than 0.0001). On pooled data recorded at distance from histamine or control prick tests, there was a significant interaction between agonist-duration of prick test and laser Doppler flowmetry (P less than 0.0004).(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral tacrolimus treatment for refractory eosinophilic cellulitis

A 72‐year‐old man presented with a 1‐month history of a rash. The eruption had previously been successfully treated with oral corticosteroids (prednisolone 30 mg/day) and antihistamines on two previous occasions, but recurred several days after stopping treatment. On examination, multiple, indurated, round to annular erythematous plaques were found on the trunk and limbs. Histological examination revealed interstitial oedema, a dense infiltrate of eosinophils in the dermis, and flame figure formation. These results led us to the diagnosis of eosinophilic cellulitis. Treatment with oral corticosteroids (prednisolone 15 mg/day) was unsuccessful. Four weeks after the start of oral tacrolimus 1 mg/day, the eruption completely resolved.     

Study of reservoir effect of clobetasol propionate cream in an experimental animal model using histamine-induced wheal suppression test

Background:

Topical corticosteroids used in various dermatological diseases several times a day led to an increase risk of side effects. By demonstrating a significant reservoir of corticosteroids in the stratum corneum, one can maximize their efficacy and safety as therapeutic agents.

Aim:

The study was designed to demonstrate a reservoir of topically applied corticosteroid clobetasol propionate cream experimentally in rabbits using histamine-induced wheal suppression test.

Materials and Methods:

The work was carried out on albino rabbits, as rabbit skin is akin to human skin, using a topical steroid. The topical steroid clobetasol propionate 0.05% cream was applied on the back of rabbit, and after 1-h occlusion histamine-induced wheal suppression test was performed and wheal area measured at 10 min till day 7. Statistical analysis was done by ANOVA followed by “Post Hoc” test.

Results:

Maximum wheal suppression was seen on day 1 (P < 0.001). Interday comparison of mean wheal size showed no significant difference (P > 0.05) on day 2, 3, and 4 as compared to day 1. Day 5-7 show highly significant difference (P < 0.001) as compared to day 1, thereby suggesting that the reservoir effect of topical clobetasol propionate 0.05% cream persisted till day 4.

Conclusions:

This work demonstrated that histamine-induced wheal by the topical steroid clobetasol propionate 0.05% cream was suppressed till day 4, indicating that the reservoir of topical corticosteroid persisted till day 4.