Assessment of the duration of action of terfenadine on histamine induced weals

In this study we aimed to quantify the reduction in area, perimeter and thickness of histamine induced weals 12, 18 and 24 h after a single oral dose of 120 mg terfenadine. Ten healthy volunteers were given 120 mg of terfenadine or placebo in a double-blind randomized two-period cross-over study. Twenty micrograms of histamine were then injected intradermally at 12, 18, and 24 h. The thickness of the resulting weal was measured by an A-scan pulsed ultrasound device. The area and perimeter of the resulting weal and flare were measured by tracing onto acetate sheets and using a digitizing tablet linked to a microcomputer. Just before each dose of histamine was injected, blood was taken to measure the level of the major metabolite of terfenadine. There was a significant difference between terfenadine 120 mg and placebo in the area and perimeter of the weal and the area and perimeter of the weal and flare at 12, 18 and 24 h, but no significant difference in weal thickness. Thus, terfenadine suppresses the wealing response caused by intradermally injected histamine over a 24 h period. It may be possible, therefore, to use a once daily dose of terfenadine.     

Quantitative time course study of the skin response to histamine and the effect of H1 blockers. A 3-week crossover double-blind comparative trial of cetirizine and terfenadine

A controlled, randomized, double-blind, crossover study was performed in 10 healthy volunteers to compare changes of cutaneous blood flow values (CBFV) determined by laser Doppler flowmetry before and after intake of a capsule containing either 10 mg cetirizine or 60 mg terfenadine. After the determination of the initial response to the anti-H1 agents, drugs were taken daily (cetirizine 10 mg, terfenadine 120 mg) over a 3-week period and the cutaneous response to histamine and saline was evaluated weekly, exactly 4 h after the last drug intake. The following significant variations were observed (analysis of variance for repeated measurements, p less than 0.05): (1) there is a decrease of histamine-induced wheal and flare under antihistamines (anti-H1), cetirizine being more potent than terfenadine; (2) CBFV, measured on the usual flare area, i.e. at 1 cm of the site of agonist injection, decreased after drug intake. There was a gradual increase of the CBFV inhibition over the 3-week follow-up, cetirizine being more effective than terfenadine, and (3) at the site of agonist injection, reduction of the edematous wheal was associated with significant increases of CBFV after drug intake. This quantitative pharmacologic in vivo assay on the agonist action indicates that at lower doses, cetirizine has a significantly higher anti-H1 activity than terfenadine and that this effect is maintained over a 3-week period. There was no tachyphylaxis.     

The effects of topical doxepin on responses to histamine, substance P and prostaglandin E2 in human skin

The tricyclic antidepressant, doxepin, is known to have H₁ and H₂ antihistaminic effects. Recently, 5% doxepin cream has been marketed in the U.S.A. for treatment of eczematous dermatoses. We investigated the effects of topical doxepin treatment on histamine-, substance P-and prostaglandin E₂-(PGE₂) induced responses in the skin of normal and atopic subjects. We compared the effects of topical doxepin with those of the oral antihistamine terfenadine. The weal volume and flare area responses to histamine were significantly reduced by treatment with topical doxepin or oral terfenadine in both normal and atopic subjects (P<0·05). The mean ±SEM percentage reduction in flare area for 10μ/site of histamine in non-atopics and atopics was 48±8% and 60±17% with terfenadine, and 54 ± 12% and 81 ± 4% with topical doxepin, respectively. The mean percentage reduction in weal volume for the same dose of histamine in non-atopics and atopics was 70 ± 9% and 63 ± 16% with terfenadine, and 96 ± 2% and 89 ± 6% with topical doxepin, respectively. The flare but not the weal response to substance P was inhibited by both treatments in all subjects (P<0·05). The mean ±SEM percentage reduction in flare area for 200 pmol/site of substance P in non-atopics and atopics was 53 ± 10% and 73 ±4% with terfenadine, and 74 ± 7% and 75 ± 4% with topical doxepin, respectively. The cutaneous responses to PGE₂ were not affected by either drug. The inhibitory effects of doxepin were as great as those of terfenadine, and doxepin had a significantly greater effect than terfenadine in inhibiting the weal response to histamine and flare response to substance P in normal volunteers (P<0·05). There was no significant difference between atopics and non-atopics in the percentage reduction of cutaneous responses by oral terfenadine or topical doxepin. Marked sedation occurred in three of the first 10 subjects treated with topical doxepin, necessitating a reduction in dosage for the remaining six subjects. In summary, topical doxepin was as effective as, and sometimes more effective than, a standard dose of oral terfenadine in the inhibition of histamine-induced and axon-reflex-mediated cutaneous responses. The marked sedative effect may limit its clinical use in some patients.     

The cutaneous reaction to staphylococcal protein A in normal subjects and patients with atopic dermatitis or psoriasis

Intradermal testing with the staphylococcal cell wall component, protein A, in healthy volunteers and in patients with atopic dermatitis and psoriasis produced a range of responses but in all groups there was an immediate weal and flare response. There was marked individual variation in subsequent erythema, but the patients with atopic dermatitis had less erythema at 15 min and 24 h than normal or psoriatic individuals. The greatest erythematous reaction at 48 h was seen in patients with psoriasis.     

The intradermal effects of the H3 receptor agonist R α methylhistamine in human skin

We have investigated the possible existence of the H₃ histamine receptor in human skin with the highly selective ligands R α methylhistamine (RAMHA) (H₃ agonist) and thioperamide (H₃ antagonist). We compared the intradermal effects of RAMHA with histamine, and studied their potential modulation by the H₁ antagonist terfenadine, and H₂ antagonist cimetidine. The effects of RAMHA and thioperamide on codeine phosphate-, substance P- and histamine-induced weal and flare responses were also studied. RAMHA produced dose-related weal and flare responses that were approximately 10- and fivefold less, respectively, than responses to histamine. Flare responses to RAMHA were significantly inhibited by oral terfenadine ( P  < 0.05). Weal and flare responses to histamine after oral cimetidine showed much intersubject variation, and cimetidine did not significantly alter either RAMHA- or histamine-induced weal and flare responses. Codeine phosphate-, substance P- and histamine-induced responses were not significantly affected by concurrent administration of RAMHA. Thioperamide was not found to influence codeine phosphate-, substance P-, RAMHA- or histamine-induced effects. RAMHA induces vascular (weal and flare) responses in human skin, and these responses are partially inhibited by terfenadine. There is a trend for RAMHA to have an additive effect to the weal induced by substance P and histamine, although our results largely do not reach statistical significance. Thioperamide does not affect the vascular responses to RAMHA, codeine phosphate, histamine or substance P. We cannot conclude that the effects of RAMHA are induced by H₃ receptors on cutaneous endothelial or mast cells.     

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.     

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.     

Skin reactivity to neuropeptides in atopic dermatitis

Adults with atopic dermatitis (AD), with respiratory atopy only and healthy non-atopic controls were given intradermal injections of substance P (SP), neurokinin A (NKA), neurotensin (NT), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and histamine into the normal-appearing skin on the back. The weal and flare responses were evaluated after 3, 5 and 15 min and the areas calculated using an automatic image analyser. With the three different concentrations used (1, 3 and 30 pmols) a statistically significant (P less than 0.05) reduction in both the weal and flare response to SP, NKA, NT and histamine and a reduced flare to CGRP was observed only in AD patients. Among those with AD there was no uniformity of response to the individual neuropeptide and in general the more severely affected showed a lower reactivity. Dose-response relationships were evaluated for SP and NT (10-320 pmols) in AD and healthy controls. In AD dose-response curves and time-course relationships were similar to controls, but at significantly reduced levels. The itch response to the neuropeptides and histamine was not different in atopics and controls. We suggest that this hyporesponsiveness in AD is the result of natural tachyphylaxis of the target structures (mast cells and blood vessels) and possibly due to a higher availability of neuropeptides in the skin or to a primary abnormal sensitivity of the blood vessels and mast cells to these peptides.     

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.     

Aberrant cutaneous weal and flare responses in chronic urticaria.

This study examined cutaneous mast cell behaviour in 14 patients with chronic urticaria but no dermographism and 11 healthy controls, by measuring cutaneous weal and flare reactions evoked in response to intradermal challenge injections of 0.1 ml isotonic saline, histamine (20 micrograms), codeine phosphate (10 micrograms) and compound 48/80 (10 micrograms). Five minutes after each injection, the area of the resulting weal and flare was calculated by computer-aided planimetry. The process was repeated at 15, 30 and 45 min following the injection. In patients, saline flares were significantly larger than those of the volunteers at 15, 30 and 45 min (p < 0.05). However, histamine and codeine flare areas were significantly smaller in the patients when compared to the controls at 15, 30 and 45 min (p < 0.05). Compound 48/80 produced smaller reactions in the patients without reaching statistical significance.     

Some effects of calcitonin gene-related peptide in human skin and on histamine release

Calcitonin gene-related peptide (CGRP) produced a dose-related wheal and flare reaction in human skin at doses of 12.5 to 50 pmol. The flare response but not the wheal response to CGRP and substance P were inhibited by prior treatment of the subject with oral chlorpheniramine, 16 mg. CGRP, but not substance P, was potent in producing a delayed erythema and surrounding pallor in human skin, which peaked at 1 h and persisted for more than 3 h after injection, when wheal and flare responses had subsided. The delayed response was accompanied by infiltration of polymorphonuclear leukocytes. The delayed erythema and pallor produced in response to CGRP were not inhibited by oral chlorpheniramine, or by 4% prilocaine injected locally. CGRP released histamine from rat peritoneal mast cells over the concentration range 2.5-10 microM. CGRP was about fourfold less potent than substance P in releasing histamine. The substance P analogue, [D-Pro4, D-Trp7,9,10]SP4-11 10 microM, and benzalkonium chloride 10 microM inhibited histamine release from rat mast cells stimulated by either CGRP or substance P.     

The relationship between plasma psoralen concentration and psoralen-UVA erythema

The plasma 8-methoxypsoralen (8-MOP) concentration was measured in 60 patients commencing psoralen photochemotherapy (PUVA). At the time of blood sampling each patient was phototested using a series of 10 exposures to UVA. The resulting erythema was measured objectively 72 h after irradiation and dose-response curves for psoralen-UVA erythema were constructed. Although the dose of 8-MOP was calculated according to body weight, patients receiving 30 mg of 8-MOP had a significantly lower mean plasma concentration than those receiving higher doses. There was no significant correlation between plasma 8-MOP concentration and minimal phototoxic dose, either estimated visually or calculated from the dose-response curves. However the slope of the dose-response curve showed significant correlation with plasma 8-MOP concentration. The variation between patients in the rate of increase of the erythemal response, but not the variation in threshold sensitivity, can be explained by difference in plasma psoralen concentration.     

Laser-induced weal and flare reactions: clinical aspects and pharmacological modulation

BACKGROUND: Among the adverse effects of cutaneous laser therapy, weal and flare reactions immediately after treatment have received little attention, and the pathomechanisms are unclear. OBJECTIVES: To study clinical features and possible mechanisms of laser-induced weal and flare reactions in order to identify means of possible therapeutic intervention. METHODS: Normal skin from the inner arm of 20 volunteers was treated with an argon laser, and the size of weal and flare reactions was measured over a 60-min period. Skin biopsies were taken from four volunteers before and up to 24 h after laser treatment and examined histologically and immunohistologically. Possible underlying mechanisms were also explored using various topical or systemic pharmacological agents. RESULTS: Wealing was noted in 19 of 20, and flare reactions in all volunteers, with peak values at 15 min. Skin biopsies showed central coagulation of the tissue, cleft formation between epidermis and dermis, normal numbers of morphologically intact mast cells on toluidine blue staining close to the lesion, and only minor upregulation of endothelial and leucocyte adhesion molecules. In agreement with these findings, pretreatment with acetylsalicylic acid, the H1-blocker loratadine and triamcinolone cream was ineffective or resulted in a non-significant reduction of weal and flare reactions. In contrast, local anaesthetics as well as neuropeptide depletion of skin with capsaicin abolished the reactions almost completely. CONCLUSIONS: Transient weal and flare reactions in response to laser treatment occur in almost all persons and are based primarily on a neurogenic rather than a histamine- or mast cell-dependent mechanism.     

Comparison of weal and flare responses to platelet activating factor (PAF) and histamine, and the ultrastructural effects of PAF in the skin of atopic and normal subjects

Weal volume and flare area responses to intradermal platelet activating factor (PAF) and histamine, both in the presence and absence of the protein carrier, human serum albumin (HSA), were measured in the skin of normal subjects, atopics without dermatitis, and in the normal-appearing skin of patients with atopic dermatitis. The ultrastructural effects of intradermal PAF were also studied in the same groups of subjects. Weal and flare dose-responses to PAF were enhanced by the presence of human serum albumin, HSA itself producing a significantly greater mean weal response in each group than lyso-PAF (P < 0.01). However, comparison of normal subjects, atopics without dermatitis and patients with atopic dermatitis, showed the differences in dose-response effects of PAF and histamine on weal volume and flare area to be nonsignificant. The cellular response to PAF in normal subjects and atopics consisted predominantly of neutrophil extravasation; eosinophils were noted in the normal-appearing skin of atopics and patients with atopic dermatitis 30 min and 4 h after injection. At an ultrastructural level PAF induced opening of endothelial gaps and extravasation of neutrophils in each group.     

Comparison of the new antihistamine acrivastine (BW 825C) versus cyproheptadine in the treatment of idiopathic cold urticaria

A double-blind, crossover trial with a new triprolidine derivative, acrivastine (BW 825C; 8 mg 3 times daily), cyproheptadine (4 mg 3 times daily) and placebo was carried out in 18 patients suffering from idiopathic cold urticaria. Acrivastine and cyproheptadine significantly (p less than 0.01) reduced weal areas following ice cube challenge when compared to placebo. Acrivastine was found to be significantly more effective (p less than 0.01) than cyproheptadine in reducing weal areas. Furthermore, cyproheptadine caused significantly more drowsiness than acrivastine (p = 0.021) or placebo (p = 0.013), which did not differ from each other. This study shows that acrivastine is an effective agent in the treatment of cold urticaria and suggests that acrivastine in the dose used lacks adverse effects, such as drowsiness, traditionally associated with antihistamine therapy.     

The effect of methoxsalen dose on ultraviolet-A-induced erythema

There is considerable interindividual variation in bioavailability of Methoxsalen (8-methoxypsoralen) after ingestion of the standard dose used in photochemotherapy (psoralen plus ultraviolet A). A dose change may be used to alter the degree of photosensitivity, although there is limited information on the effect of 8-methoxypsoralen dose alterations on phototoxicity within individuals. We studied the effect of changes of 8-methoxypsoralen dose over a narrow range in 15 subjects with psoriasis. Two hours after ingestion, serum 8-methoxypsoralen concentration was determined and phototesting was performed at 350 +/- 30 nm (0.45-14 J per cm2). The minimal phototoxic dose at 72 h was recorded, erythema was measured using a reflectance instrument, and dose-response curves were constructed. Each subject was tested on three occasions using doses of 25 mg per m2 (conventional dose) or conventional dose +/- 10 mg. Median serum 8-methoxypsoralen concentration increased from 96 to 143 to 229 ng per ml with dose increases from conventional dose - 10 mg to conventional dose and conventional dose + 10 mg, respectively (p < 0.001). The median minimal phototoxic dose and D0.025 (the objective equivalent of the minimal phototoxic dose derived from the dose-response curve) were significantly reduced with increasing 8-methoxypsoralen dose from conventional dose minus 10 mg (minimal phototoxic dose 1.7 J per cm2; D(0.025) 2.8 J per cm2) to conventional dose (1.2; 1.4 J per cm2) and conventional dose plus 10 mg (0.9; 1.0 J per cm2) (p < 0.001). Change in 8-methoxypsoralen dose had no detectable effect on the maximum slope of the psoralen plus ultraviolet A erythema dose-response curve. Thus, 8-methoxypsoralen dose changes within individuals, over a narrow but clinically relevant range, significantly altered the threshold response to psoralen plus ultraviolet A erythema but not the rate of increase in erythema with increasing ultraviolet A dose.     

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.     

Participation of mast cells and complement in the immediate phase of hematoporphyrin-induced phototoxicity

We have investigated the roles of mast cells and the complement system in the immediate phase of hematoporphyrin-induced phototoxicity in guinea pigs. Clinically, i.v. injection of hematoporphyrin, followed by irradiation with a light source containing 400-405 nm wavelength, resulted in the immediate onset of erythema and edema, which subsided partially in 30-60 min. This was followed by the appearance of delayed erythema and edema, which peaked at 6-12 h after irradiation. Histologic examination of the response of the immediate phase, using a 1 micron-thick section, revealed eosinophil infiltration and mast cell degranulation. The immediate phase of the clinical response was further quantitated by the extravasation of intravenously injected [125I]bovine serum albumin. Pretreatment of the guinea pig skin with the intradermal injection of compound 48/80 significantly suppressed the increase in vascular permeability induced by hematoporphyrin and irradiation (p less than 0.05). This hematoporphyrin-induced alteration in vascular permeability was also significantly inhibited by antihistamines, either H1 receptor antagonist alone (p less than 0.05) or a combination of H1 and H2 receptor antagonists (p less than 0.05). Guinea pigs depleted of complement also showed significantly less vascular permeability changes (p less than 0.05). These results indicate that functionally intact mast cells, and the complement system, are required for the full development of the immediate phase of phototoxicity induced by hematoporphyrin.     

Histamine is released following aminolevulinic acid-photodynamic therapy of human skin and mediates an aminolevulinic acid dose-related immediate inflammatory response

Acute skin inflammation occurs following topical aminolevulinic acid-photodynamic therapy (ALA-PDT), but its nature and mediation are ill defined. As we observed an urticarial response, a potential role for histamine was explored. In 13 healthy volunteers, we assessed the time course and dose-response of the acute cutaneous response(s) to ALA-PDT, the impact of H(1) antihistamine blockade, and measured dermal histamine release. An ALA dose series was iontophoresed into ventral forearm skin and exposed to red light. All participants exhibited an immediate urticarial response, both wheal and flare correlating with log ALA dose. Subsequently, a dose-related erythema developed at treatment sites by 3 hours and persisted at 24 hours. H(1) blockade with oral cetirizine doubled the median minimal urticating dose of ALA and reduced the slope of dose-response for wheal and flare, whereas at the highest ALA dose, mean wheal and flare areas reduced by 68 and 60%, respectively. In contrast, cetirizine did not influence the 24 hour minimal phototoxic dose or erythema dose-response. Histamine release after ALA-PDT mirrored the urticarial response, levels peaking within 30 minutes and returning to baseline by 24 hours. Thus, two discrete acute inflammatory responses to topical ALA-PDT occur in human skin; histamine mediates the immediate response, but does not appear involved in the delayed phototoxicity.     

Similar dose-response and persistence of erythema with broad-band and narrow-band ultraviolet B lamps.

Psoriasis may be treated with ultraviolet B from lamps that have a broad emission spectrum or, more effectively, with lamps that have a narrow emission spectrum at 311 +/- 2 nm. There are conflicting reports of either greater or lesser burning episodes with narrow-band compared to broad-band ultraviolet B, even when treatments are based on predetermined minimal erythema dose measurements. This suggests that either the characteristics of the dose-response curve for erythema or the time course for erythema may be different for the two lamps. We examined the erythemal response to narrow-band and broad-band ultraviolet B in 12 patients with psoriasis. A geometric series of 10 doses from each lamp type were used on nonlesional skin on the back. Dose-response curves were constructed from reflectance measurements of erythema at 24 h and 72 h after irradiation. No significant difference was found in steepness of the erythema dose-response curve for the two lamps at 24 or 72 h. Persistence of erythema was assessed as the percentage of erythema remaining at 72 h. The mean persistence was 63% for narrow-band and 64% for broad-band lamps (p = 0.94). Therefore, in terms of erythemal response, no evidence has been found for a difference in burning potential for the two lamps.