息斯敏和息斯敏联合雷尼替丁对组胺诱导人皮肤反应强度的比较

目的探讨组胺Ｈ１和Ｈ２受体拮抗剂联合使用治疗Ⅰ型过敏性疾病的可行性。方法对三组志愿者（每组１２人）分别服用息斯敏１０ｍｇ,１次／ｄ;息斯敏１０ｍｇ和雷尼替丁３００ｍｇ,各１次／ｄ,息斯敏１０ｍｇ,１次／ｄ和雷尼替丁３００ｍｇ,每１２ｈ１次。５天后停雷尼替丁,继续服用息斯敏２天。第１～５天,每日比较服药前和服药后第３ｈ、第６ｈ组胺（１００μｇ）诱导即刻型皮肤（风团和红晕）的反应强度（％）。第８天组胺皮试重复１次。结果息斯敏１０ｍｇ,１次／ｄ和雷尼替丁３００ｍｇ,每１２ｈ１次组对组胺诱导皮肤风团和红晕的反应强度在各个时间点均明显低于息斯敏１０ｍｇ,１次／ｄ组,统计学处理除第２次服药前风团强度无显著性差异外（Ｐ＞０．０５）,其它各时间点均有显著性差异（Ｐ＜０．０１或＜０．０５）。结论息斯敏联合雷尼替丁与息斯敏单独使用相比,明显加快和加强组胺诱导皮肤反应抑制作用,该方案为临床治疗Ⅰ型过敏反应性疾病提供了可行性依据。     

Efficacy and safety of antihistamines in allergic skin disorders

Background For patients with urticaria, H₁-antihistamines remain the gold standard medical treatment of choice. They act by blocking H₁ receptors on the vascular endothelial cell surface. Newer, non-sedating antihistamines such as loratadine also act to some extent by blocking the release of histamine from mast cells, basophils and human skin tissue. Efficacy All of the newer antihistamines (loratadine, terfenadine, astemizole and cetirizine) have been shown to have comparable efficacy to the classic sedating antihistamines and to be significantly superior to placebo in terms of symptom improvement. Loratadine has been shown to be at least as effective as the other non-sedating agents and cetirizine. Antihistamines also have a potential benefit in the management of patients with atopic dermatitis. In two studies, loratadine was found to be significantly superior to placebo in the reduction of pruritus. Safety In terms of safety, the newer antihistamines have important differences. Cetirizine, for example, causes dose-related sedation and functional impairment compared to placebo. In contrast, loratadine has no such sedative effects. Terfenadine and astemizole have also been shown to be free of sedative effects, but exceeding the recommended dose of either may increase the risk of a serious cardiac arrhythmia, torsades de pointes. Plasma levels of both terfenadine and astemizole may also be increased as a result of interaction with various drugs. In contrast, loratadine has not been shown to induce ECG changes, even at doses of 40 mg o.d. for 90 days.     

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.     

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.     

The skin as a target organ for the investigation of antiallergic drugs: comparison between cetirizine and terfenadine.

Two double-blind clinical pharmacology studies were performed in atopics in order to compare the inhibitory effects of cetirizine (CTZ) 2 HCl and terfenadine (TER) on histamine and antigen-induced skin reactions. In the first study, the subjects took single intakes of CTZ 10 mg and TER 60 mg. In the second study, they took CTZ 10 mg once a day and TER 60 mg b.i.d. for 3 weeks. CTZ was more effective than TER in inhibiting histamine skin reactivity. CTZ and TER were equally effective in inhibiting antigen-induced reactions. There was no tachyphylaxis, either for CTZ or for TER.     

Clinical and immunohistological characterization of cutaneous lesions in chronic lymphocytic leukaemia

The effects of the H I receptor antagonists astemizole and chlorpheniramine on dermographism were compared in a double-blind study in sixteen patients. Both drugs resulted in a parallel and significant depression of the dermographic force-response curve and an elevation of the weal-force threshold, but the changes were greater in the patients receiving astemizole (a maximal potency shift of 74% for astemizole and 37% for chlorpheniramine). Subjective itch (10 cm line) and frequency of dermographic episodes were also reduced more by astemizole than by chlorpheniramine. The effect of astemizole was greater at 4 weeks than at 2 weeks, whereas the effect of chlorpheniramine had decreased at 4 weeks. The effect of astemizole but not chlorpheniramine was still apparent 4 weeks after treatment had been stopped. Since the degree of residual dermographism was comparable despite great differences in histamine weal inhibition a vasoactive mechanism in addition to that mediated by histamine must be involved in dermographic urticaria.     

The effect of terfenadine on dermographic wealing

A double-blind comparison of terfenadine with placebo showed a reduction in potency of measured dermographic force-response of 67%, which is similar to that for inhibition of histamine weals by terfenadine. This and the parallel displacement of the force-response curves indicates that histamine is the main cause of dermographic wealing. Dermographic threshold and itch change together and appear to be the main determinant of the patients' subjective response. Dermographism relapsed towards its pre-treatment state during the 3 days after treatment was stopped. There was a small decrease in effect after administration of 60 mg b.d. for 47-84 days and a further small increase in response when the dose was increased to 120 mg t.d.s., but neither change was significant. None of the patients had a sedative response to the drug and terfenadine should prove useful in the treatment of wealing disorders.     

Terfenadine and brompheniramine maleate in urticaria and dermographism

The effects of brompheniramine maleate (12 mg twice daily in sustained release form) and terfenadine (60 mg twice daily) on the symptoms and well-being of 16 adults with urticaria with or without dermographism were assessed by symptom questionnaire. Following an initial 2-week period without therapy, each drug was taken for 2 weeks in a randomised double-blind cross-over study. Both drugs produced significant relief of itch and rash but only brompheniramine produced significant drowsiness. Brompheniramine maleate was more effective than terfenadine in the patients with dermographism.     

Failure of terfenadine in relieving the pruritus of atopic dermatitis

We report the results of a double-blind, placebo-controlled, cross-over study of terfenadine 120 mg twice daily for pruritus in atopic dermatitis. Twenty-eight subjects with chronic atopic dermatitis received both terfenadine 120 mg b.d. and placebo each for a period of 1 week. Response was recorded by the subjects using visual analogue scales for severity of pruritus twice daily for the last 4 days of each treatment phase. There was no benefit from terfenadine.     

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 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.     

Minimal effect of complete H1 receptor blockade on urticaria pigmentosa

The effect of complete H1 receptor blockade on urticaria pigmentosa was studied in 6 patients. Astemizole 10 mg tds was given for 6 weeks to achieve complete H1 receptor blockade and the response measured by change in force-weal response measurements using two different forces on a dermographic stylus and measuring response as weal diameter. Weal and flare reactions to 8 micrograms histamine were completely abolished by the astemizole but dermographic weal-force responses were reduced only by 12-15% indicating that histamine acting at the H1 receptor plays only a small part in the wealing of urticaria pigmentosa.     

The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis

A double-blind, randomized, cross-over study was carried out on the effect of a sedative and a non-sedative antihistamine on 25 adults with atopic dermatitis. Intensity of itch was recorded using a computerized method for self-assessment (Pain-Track) and using conventional visual analogue scales. The antipruritic effect of 3 days of treatment with the non-sedative H1 antagonist terfenadine (60 mg b.i.d.) and with the sedative antihistamine, clemastine (2 mg b.i.d.) did not differ from that found with the placebo. Our findings support the view that histamine is not of importance in the pathogenesis of itch in atopic dermatitis.     

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.     

Astemizole in urticaria--a multicenter study by 412 established dermatologists

In the course of a multicenter study on 2122 patients treated by 412 dermatologists in general practice, we investigated the effect of astemizole (Hismanal) on urticaria. During 2 weeks of treatment with astemizole 10 mg daily, the percentage of the patients with severe or moderate affection dropped from 82.4% to 9.1%, while the figure of the patients with severe or moderate pruritus decreased from 83.9% to 7.8%. In 74% of the patients, the onset of action occurred during the first 24 hours. The peak of effect was reached within the first day in 36.6% of the patients, and within 2 days in 57.5% of the patients. The physicians observed an excellent outcome in 44.4% and good results in 31.9% of the patients. The therapeutic success was considered moderate in 12.0% and unsatisfactory in 9.6% of the cases. The incidence of side effects was very low, i.e., 5.4%. Slight sedation was observed in 1.9% of the cases.     

Dose-response relationship between objective measures of histamine-induced weals and dose of terfenadine.

Terfenadine is a safe non-sedative H1-receptor antagonist. This study aimed to quantify the relative reduction in weal and flare area, thickness and erythema at 4, 8, 12 and 24 h following a single but variable oral dose of terfenadine compared with pre-treatment measurements, in order to compare the dose-effect relationship and time course of the different dosages. In a double-blind randomized cross-over study, 12 healthy volunteers were given 60, 120 or 240 mg of terfenadine or placebo. Twenty micrograms of histamine acid phosphate was then injected intradermally at 4, 8, 12 and 24 h. The weal and flare areas were measured by planimetry, the thickness of the weal by an A-scan pulsed ultrasound device and the redness of both the weal and flare by an erythema-meter. A definite dose-response relationship was demonstrated between the weal and flare areas and the three active treatments. For the weal area, there was a significant difference between 60 mg and 240 mg of terfenadine at 4 h (p less than 0.01), at 8 and 12 h (p less than 0.05). For the flare area there was a similar significant difference at 4 h (p less than 0.01) and at 8 h (p less than 0.05). A dose-response relationship was demonstrated between weal erythema and 120 mg or 240 mg and 60 mg of terfenadine (p less than 0.05). There was a correlation between the plasma levels of the major metabolite and the initial dose of terfenadine, demonstrating their expected proportionality. This metabolite was also demonstrated in tissue fluid.     

The effect of histamine receptor antagonists on immunosuppression induced by the cis-isomer of urocanic acid

Urocanic acid (UCA) is found in the stratum corneum predominantly as the trans-isomer; on ultraviolet B (UVB) irradiation, isomerization to the cis-isomer occurs. Cis-UCA has been shown to mimic the consequences of UVB irradiation in generating transient suppression of contact and delayed hypersensitivity (DH) responses. In an attempt to elucidate the mechanisms of action of UCA, the effects of 2 histamine receptor antagonists, cimetidine and terfenadine, were examined. One day after skin painting murine ears with cis-UCA, the number of ATPase- cells was reduced from 1068 to 408 mm-2. However, if cimetidine or terfenadine was applied at the same time as cis-UCA, the number of ATPase- cells was reduced only slightly from the control value, to 1028 and 892 respectively. Cis-UCA given subcutaneously or epidermally 5 h before infection of mice with herpes simplex virus suppressed the DH response on subsequent challenge with the virus. If cimetidine or terfenadine was added at the same time as cis-UCA, little suppression of the DH response to the virus occurred. Thus 2 effects of cis-UCA, on the number of ATPase+ epidermal cells and on DH response, were reduced or abrogated by histamine receptor antagonists, which may indicate that cis-UCA acts through histamine-like receptors in the skin.     

Localized periorbital edema induced by Ibuprofen

We documented localized periorbital edema in one patient with ibuprofen sensitivity without underlying chronic urticaria. The reaction developed one hour after ingestion of 200 mg of ibuprofen. No systemic symptoms were observed. No other NSAIDs did not induce symptoms. This patient was able to tolerate doses of ibuprofen after pretreatment with terfenadine. These observations suggest that histamine played a central role in this ibuprofen-induced skin reaction. Treatment with terfenadine enabled the patient to tolerate ibuprofen without experiencing any side effects. To the best of our knowledge, this is the first reported case of periorbital edema induced by ibuprofen.     

Terfenadine does not inhibit non-immunologic contact urticaria

To investigate the mechanisms of non-immunologic contact urticaria (NICU), the effect of 120 mg of terfenadine (H1-antagonist) on contact reactions to methyl nicotinate, diethyl fumarate, benzoic acid, cinnamic acid, cinnamic aldehyde and dimethyl sulfoxide was studied in 20 subjects. Erythema and edema were observed visually, and the changes in the skin blood flow were monitored with laser-Doppler flowmetry. Terfenadine did not have any significant inhibitory effect on erythema or edema from 6 contact urticariants tested, but it inhibited erythema and edema of prick test reactions to histamine. Non-specific histamine release from mast cells does not seem to be the mechanism of NICU from these substances.