Correlations between histamine-induced wheal,flare and itch

Correlations between the skin reactions wheal and flare and the subjectively reported degree of itch were investigated in response to 1% histamine, intradermally applied by standardized skin prick and by iontophoresis. Experiments were performed with 15 male volunteers using a threefold repeated measures design (skin prick, and iontophoresis with 0.13 mA for 10 s and with 2.0 mA for 10 s). Skin reactions (perpendicular diameters) were determined at the time of their maximum (10 min). Itch was rated on a computerized visual analogue scale which was anchored upon the individual scratch threshold. Most effective in producing itch was the skin prick which caused strong sensations markedly above the scratch threshold during the entire period of measurement (30 min), whereas iontophoresis induced only transient itch sensations. On the other hand, the largest wheals were generated by iontophoresis of both intensities (mean 10 or 14 mm vs 6 mm with skin prick). The higher current induced higher itch, wheal and flare responses, but after eliminating this effect of stimulus intensity, no correlations were found. In contrast, skin prick-induced flare reactions varied with the degree of itch above the scratch threshold ( r = 0.56; P < 0.01). Repeated measurements showed a higher stability for the itch reaction with skin prick compared with iontophoresis. It is hypothesized that in iontophoresis the brief (10-s) histamine bolus passed the most superficial pruritoceptive C fibres too quickly to induce long-lasting itch sensations, whereas the skin prick caused a deposit at the dermal-epidermal junction releasing histamine during the entire time of measurement. Consequently, both the C fibre-mediated itch and the axon reflex flare were more pronounced with the skin prick, and the wheal resulting from a permeability increase in the postcapillary venule walls was an independent phenomenon. Received: 21 June 1995     

The effects of astemizole, cetirizine and loratadine on the time course of weal and flare reactions to histamine, codeine and antigen

An open cross-over study was performed to assess the effects of astemizole, cetirizine and loratadine on weal and flare reactions to intradermal histamine, codeine and house dust mite antigen. Percentage inhibition of weal area, flare area and weal volume was greatest for cetirizine, then astemizole and smallest for loratadine. Wealing due to mast-cell degranulation with either codeine or antigen was less inhibited by all three antihistamines than that due to histamine itself. Time-course studies revealed similarities between wealing provoked by codeine and histamine but different characteristics to that induced by antigen.     

Video-optical monitoring of wheal and flare reactions

Background/aims: In order to monitor the dynamics of experimentally-induced cutaneous inflammation in humans, we developed an objective, computerized video-optical method for wheal and flare area determination.
Methods: The method was used for evaluation of PAF-acether-induced experimental inflammations on the volar aspect of the forearms of human volunteers. The study design was double-blind, randomized, placebo-controlled. Repeated measurements can be performed, e.g., with intervals of 1 min to reveal the time-course of the inflammatory reaction. In the present study, the effect of topical application of creams containing 3 different concentrations of the putative anti-inflammatory drug sodium sucrose-sulphate (SoS) on cutaneous inflammation was investigated.
Results: 30 min after intracutaneous PAF-acether injection, a statistically significantly increased (p<0.05) wheal area was found in skin sites treated by either 1%, 3% and 9% SoS cream, whereas no influence of sucrose-sulphate could be demonstrated on the flare area. The reduction of the wheal area was significantly faster in the SoS-treated areas than in the placebo (p<0.05).
Conclusions: Computerized video-optical quantification of acute skin inflammatory reactions may be a suitable experimental tool for objective dynamic monitoring of both wheal and flare reactions and hence for quantification of the effect of anti-inflammatory drugs in humans. Topical application of SoS surprisingly increased PAF-acether-induced skin oedema (wheal), significantly whereas no effect was found on the flare reaction. No concentration-related effect of SoS could be shown.     

Effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced wheal-and flare-response, sedation, and psychomotor performance

Although many antihistamines are now in clinical use, few studies directly compare their pharmacodynamic and sedative activities in humans in vivo. We designed a double-blind, placebo-controlled, crossover study to compare the inhibitory effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced flare-and-wheal response. Systemic sedative effects and impaired psychomotor activities by these drugs were also evaluated. Bepotastine (10 mg twice a day), cetirizine (10 mg once a day), fexofenadine (60 mg twice a day), and olopatadine (5 mg twice a day) or placebo was given in a double-blind manner to seven healthy volunteers before histamine challenge by iontophoresis. At 0, 1, 2, 4, 8, 12, and 24 h following the oral administration of these drugs, histamine iontophoresis-induced wheal-and-flare response was measured. Sedative effects by the drugs were also evaluated by a visual analogue scale for subjective sedation, and by word processor test for psychomotor activity. Each volunteer was tested with all of the drugs (including placebo), administered in a random order with a washout period of at least 1 week. Histamine iontophoresis induced marked wheal-and-flare response in all participants. Bepotastine, cetirizine, fexofenadine, and olopatadine yielded significant reduction of histamine-induced wheal-and-flare response compared to placebo (P < 0.01). Among the drugs, olopatadine and cetirizine suppressed most markedly and persistently histamine-induced wheal-and-flare response, while bepotastine and fexofenadine produced a significant, but less persistent suppression. Olopatadine, fexofenadine, and cetirizine showed a significant systemic sedative effect in this order with bepotastine showing the least sedative effect. Moreover, olopatadine affected psychomotor performance most markedly, which was followed by fexofenadine and cetirizine. These results indicate that bepotastine, cetirizine, fexofenadine, and olopatadine inhibit histamine-induced wheal-and-flare response of humans in vivo and induce a variable systemic sedative effect and impaired psychomotor activity. Although olopatadine and cetirizine showed the strongest and most persistent suppression of histamine-induced wheal-and-flare response, olopatadine showed a considerable sedative effect with impaired psychomotor performance.     

Effects of loratadine and cetirizine on serum levels of neuropeptides in patients with chronic urticaria

H1‐receptor inhibiting drugs, namely loratadine and cetirizine, were frequently used in treatment of chronic urticaria. Urticarial weal and flare reactions, a neurogenic reflex due to neuropeptides, were reported to be more effectively inhibited by cetirizine than loratadine. The aim of this study was to determine and compare the effects of systemic loratadine and cetirizine treatments on serum levels of selected neuropeptides in chronic urticaria. Treatment groups of either systemic loratadine or cetirizine (10 mg/d), consisting of 16 and 22 patients, respectively, were included. Serum levels of stem cell factor (SCF), neuropeptide Y (NPY), calcitonin gene‐related peptide (CGRP), nerve growth factor (NGF), vasoactive intestinal peptide (VIP), and substance P (SP) were detected before and after one week of treatment with antihistamines. Serum NPY and VIP levels were significantly decreased when compared before and after treatment with antihistamines (P < 0.001 and P < 0.01, respectively). SCF and NGF values were also decreased after antihistamine treatment (P < 0.05). Post‐treatment levels of CGRP were significantly higher compared with pretreatment values, while no significant difference was detected between pre and post treatment levels of SP. Cetirizine was significantly more effective than loratadine on lowering serum levels of SCF among the other neuropeptides. Systemic loratadine and cetirizine treatments in patients with chronic urticaria precisely caused variations in serum levels of neuropeptides. The predominant effect of cetirizine compared to loratadine on reducing serum SCF levels might be explained with anti‐inflammatory properties of cetirizine.     

A multicentric trial of loratadine and cetirizine in urticaria

Two hundred and ten patients with chronic urticaria were divided into two groups; one group was treated with Loratadine 10mg daily while the other with cetirizine 10mg daily. The total duration of treatment was four weeks. Pretreatment and post-treatment evaluations were made. It was noticed that loratadine was superior to cetirizine in terms of a rapid onset of actions, overall clinical efficacy and minimal side effects.     

Topically applied aspirin decreases histamine-induced wheal and flare reactions in normal and SLS-inflamed skin,but does not decrease itch. A randomized,double-blind and placebo-controlled human study

Topically applied aspirin has recently been reported to decrease histamine-induced itch in human volunteers. Our aim is to confirm this and to study the antipruritic ability of topical aspirin in inflamed skin. In 24 non-atopic volunteers, an inflammatory skin reaction was induced in forearm skin at 5 different sites by sodium lauryl sulphate contained in Finn Chambers. Aspirin 10%, aspirin 1%, mepyramine 5% and vehicle were applied to the inflamed and corresponding non-inflamed areas 20 min before itch induction with intradermal histamine injection. Itch and pain were scored on a visual analogue scale at regular intervals. Wheal and flare areas were measured. No difference in itch intensities was found after application of aspirin, mepyramine and vehicle, but more itch was induced in aspirin and mepyramine pretreated sites in inflamed skin compared to normal skin (p<0.05). In normal skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.05) and mepyramine (p<0.001), as were wheal areas after mepyramine (p<0.01), compared to vehicle pretreatments. In inflamed skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.01) and mepyramine (p<0.001), as were wheal areas after aspirin 10% (p<0.01), aspirin 1% (p<0.05) and mepyramine (p<0.001). We conclude that despite a significant skin penetration as measured by the influence on wheal and flare reactions, topically applied aspirin did not decrease histamine-induced itch in the model used.     

咪唑斯汀、氯雷他定及西替利嗪对小鼠变应性接触性皮炎作用的比较研究

目的:比较咪唑斯汀、氯雷他定及西替利嗪对小鼠变应性接触性皮炎(ACD)的抑制作用。方法:建立小鼠ACD模型,采用致敏前及诱发后两种给药方法,口服不同剂量咪唑斯汀、氯雷他定及西替利嗪,观察抑制作用。结果:致敏前开始给药,3种药物均能明显抑制ACD小鼠耳肿胀(P<0.05),但咪唑斯汀的抑制作用强于氯雷他定及西替利嗪(P<0.05);诱发后开始给药,咪唑斯汀组小鼠耳肿胀消退快于氯雷他定及西替利嗪(P<0.05)。结论:咪唑斯汀对小鼠ACD抑制作用强于氯雷他定和西替利嗪。     

Effects of histamine receptor antagonists on histamine-induced responses in human skin.

The effects of intradermally administered histamine H1- and H2-receptor antagonists on the cutaneous responses--redness, weal, flare and itch--induced by intradermal injection of histamine were studied in man. Weal and redness were studied after blockade of the axon reflex by local infiltration with lidocaine. All responses were significantly inhibited by the H1-receptor antagonist mepyramine. The H2-antagonists cimetidine and metiamide reduced flare and itch significantly but not to the same extenet as mepyramine and not in a clearly dose-related manner. The size of weal and redness was not significantly reduced by cimetidine. No further reduction of flare, itch or weal was obtained by adding metiamide or cimetidine to mepyramine. After blockade of the axon reflex with lidocaine the histamine-induced weals turned white at the centre. This blanching was more prominent when histamine was injected in combination with cimetidine. Substituting mepyramine for cimetidine resulted in small weals with an intense red colour. It is concluded that, apart from being engaged in the direct vasodilatory response to histamine, H2-receptors do not seem to be involved in the other cutaneous responses to histamine studied.     

新一代抗组胺药对变应性接触性皮炎小鼠3种细胞因子影响的比较研究

目的:研究咪唑斯汀、氯雷他定及西替利嗪对变应性接触性皮炎(allergiccontactdermatitis,ACD)小鼠产生干扰素(IFN)、肿瘤坏死因子(TNF)及白介素(IL)-4的影响,探讨抗组胺药治疗ACD的作用机制。方法:建立小鼠ACD模型,采用ELISA法检测ACD小鼠产生IFN-γ、TNF-α和IL-4的水平及3种药物分别对它们的作用。结果:ACD小鼠血清及脾淋巴细胞IFN-γ水平均明显升高(P<0.01);血清TNF-α水平明显升高(P<0.01),腹腔巨噬细胞产生TNF-α水平无明显变化(P>0.05);血清及脾淋巴细胞产生IL-4水平无明显变化(P>0.05)。咪唑斯汀对血清及细胞培养液中3种细胞因子的水平均有显著或不同程度的抑制作用,而氯雷他定、西替利嗪仅对部分细胞因子产生一定的抑制作用。结论:咪唑斯汀对ACD小鼠产生的3种细胞因子的抑制作用强于氯雷他定和西替利嗪。它们对ACD小鼠3种细胞因子的抑制作用与临床疗效的关系有待进一步研究。     

Regulation of wheal and flare by tea tree oil: complementary human and rodent studies

When applied 20 min after injection of histamine into human forearm skin, tea tree oil (TTO) reduces the developing cutaneous vascular response. In this study, the effect of TTO on inflammatory microvascular changes was dissected at the base of an experimental blister on rat skin. 1,8-Cineole, representing 2% of TTO, reduced vascular changes induced by sensory neuropeptides released when the distal portion of a cut sciatic nerve was electrically stimulated. The pre-terminal modulatory effect of 1,8-Cineole was confirmed in tests in sensory-denervated rats. Terpinen-4-ol (approximately 40% TTO) reduced substance P-induced microvascular changes and protein extravasation by a direct nitric oxide-mediated effect on the microvasculature, without sensory nerve involvement. alpha-Terpineol (3% of TTO) regulated both pre- and post-sensory nerve terminals. In human skin, terpinen-4-ol applied 10 min after histamine injection, but not alpha-terpineol or 1,8-cineole, regulated the developing wheal and flare suggesting that the histamine-induced responses in humans (at the dose used in this study, 50 microL of 330 microM histamine) are in large part determined by histamine directly affecting the vasculature via post-terminal-mediated events. The underlying strength of these studies is the use of a well-established rat physiologic model to differentiate the mechanism of regulation of microvascular changes by modulatory agents.     

Agonist-antagonist interactions in the skin: comparison of effects of loratadine and cetirizine on skin vascular responses to prick tests with histamine and substance P.

The skin vascular responses (weal, flare, blood flow measurements) elicited by intradermal administration by pricking of histamine (HS) and substance P (SP) were evaluated 6 h after a single intake of anti-H1 agents displaying different activity profile on skin tests at currently recommended dosages (loratadine 10 mg, cetirizine 10 mg) as compared to placebo (P). The weal and flare response and the increases of blood flow occurring in the usual flare area after HS and SP were almost completely abolished by cetirizine. Inhibition of HS- and SP-induced weal and flare reactions was less marked after loratadine and blood flow in the expanding flare after HS and SP showed significant fluctuations over time. In view of the present results and of data obtained in previous experiments with intradermal injection of agonists, we hypothesize that mode of administration of agonists significantly influences the size of the residual weal after anti-H1 agents. We demonstrate that SP weals induced by pricking are largely inhibited by a potent H1 blockade which supports the view that this phenomenon, as well as the SP-flare, is due to SP-induced histamine liberation. We also, for the first time, report on fluctuations recorded at the edge of the developing flare with laser Doppler flowmetry early after prick testing with a weak H1 blockade. This opens up new avenues in dynamically testing H1-receptor occupancy in vivo and in situ in human skin.     

A quantitative comparison of the effect of local analgesics on argon laser induced cutaneous pain and on histamine induced wheal, flare and itch

A quantitative comparison was made of the effect of infiltration of local analgesics and topical analgesic cream (EMLA) on laser-induced pain and histamine-induced wheal, flare and itch. Wheal and flare were quantified by planimetry and analgesia was quantified by the pricking pain threshold to argon laser stimulation. The intensity of histamine-induced itch was scored on a 4-point scale. Local analgesics had no effect on the wheal area. The flare reaction was abolished by infiltrating lignocaine, and gradually inhibited by increased application times of EMLA. Itch was abolished after local lignocaine infiltration, but not significantly reduced after EMLA cream applied for less than 120 min, although the skin was anaesthetized to laser-induced pain. The reduction of flare area correlated to the level of analgesia, which may therefore reflect the cutaneous responsiveness to neurogenic inflammation. It is suggested that itch and pricking pain are mediated by different populations of nerve fibres, as itch can be evoked even when the sensation of pricking pain is abolished. Surgery, skin prick tests and other traumatic procedures should therefore be performed under local anaesthesia to reduce neurogenic inflammation.     

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.     

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.     

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.