The effect of cetirizine on symptoms and wealing in dermographic urticaria

The effect of cetirizine, 10 mg at night, on dermographic urticaria, was studied in 19 patients. The study design was a randomized, double-blind, crossover comparison with placebo, each treatment being given for 7 days. Patients kept a daily diary of itch and weal severity (100-mm linear analogue scale), and recorded sleep disturbance. The dermographic weal response was measured objectively with a spring-loaded stylus, and the weal threshold calculated from the force/response curve. There was a small, insignificant subjective response to placebo, but no objective response. On cetirizine, the subjective assessment of wealing was reduced from 34.3±6.7 (mean ± SEM, 0–100 scale) to 16.8±4.1 (P= 0.02), itch was reduced from 43.2±6.6 to 19.4±4.1 (P=0.001), and nights disturbed from 46.2 to 8.8% (P=0.03). There was a shift to the right in the position of the force/response curve, and the wealing threshold increased from 24.6±3.2 to 54.7±4.4 g/mm² (P=0.00001), but there was no correlation between change in itch scores and wealing threshold. Cetirizine 10 mg daily is an effective treatment in dermographic urticaria, and its usefulness will depend on the prevalence of unwanted effects.     

Effects of H1 antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging

Histamine plays an important part in the cutaneous weal and flare response which underlies many allergic skin conditions. It has a direct effect on the local vasculature to promote vasodilatation and increase microvascular permeability and may also initiate the more widely spread neurogenic flare. Quantification of these responses and studies of the mediator mechanisms underlying them have been limited by the lack of appropriate techniques to investigate them. To address this we have used two relatively new techniques, scanning laser Doppler imaging (LDI) and dermal microdialysis to measure changes in skin blood flow and the release of histamine within the weal and flare, following intradermal injection of histamine or bradykinin. These measurements have been made both in the absence and presence of the H₁ receptor blockers cetirizine and loratadine. Scanning LDI of the inflammatory response revealed marked differences in both the development and steady state responses to the intradermal injection of histamine (1–3 μmol/L) and bradykinin (1 μmol/L). The development of the flare and the weal response to both histamine and bradykinin was significantly reduced by cetirizine but not by loratadine. The histamine-induced flare area fell by 57 ± 4% (mean ± SEM, n = 10, P < 0.001) after cetirizine and the area of the weal fell by 73 ± 11% (P < 0.009). Bradykinin-induced inflammatory responses were similarly reduced by cetirizine, the weal by 60 ± 16% (P < 0.02) and the flare by 61 ± 4% (P < 0.005). Measurement of histamine concentration in skin using microdialysis, in six subjects, confirmed that histamine levels rose in the dialysate collected from the weal to 310 ± 16 nmol/L following injection of histamine. Histamine levels also rose following bradykinin injection in some subjects (mean 147 ± 46 nmol/L, range 18–336). Little increase in histamine concentration was seen in the dialysate from the flare following injection of either histamine or bradykinin. The histamine concentration in dialysate from unprovoked skin was 4.19 ± 0.75 nmol/L. These data reveal differences in the dermal responses to different mediators when assessed using scanning LDI. They confirm that histamine is released within the weal but not the flare response to the intradermal injection of both histamine and bradykinin and that its effects on the local vasculature to cause the oedematous weal and the axon reflex-mediated flare are significantly attenuated by the H₁ antagonist cetirizine and to a lesser extent by the H₁ antagonist loratadine.     

Suppression of alcohol-induced flushing by a combination of H1 and H2 histamine antagonists

Alcohol-induced flushing of the face and neck regions is a well recognized condition, probably genetically determined and due to individual differences in alcohol metabolism. We have shown that the flushing appears only after a threshold level of blood alcohol (20–35 mg per 100 ml) is exceeded. The rate of alcohol absorption and peak blood levels were reduced by a combination of H₁ and H₂ antagonists. This reduction was accompanied by abolition of flushing in sensitive individuals.     

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.     

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 effect of H1 and H2 receptor antagonists on the dermographic response

The effect on dermographic wealing of an H1 and H2 receptor antagonist was studied separately and in combination. a double-blind protocol was used and dermographism was measured as the diameter of weal response to a measured force. Both H1 and H2 antagonists had a small but non-significant effect, but the combination of H1 plus H2 antagonist had an approximately additive effect which was significant. Although this indicates a role for H2 receptors in dermographism it does not establish the degree of involvement, nor whether H2 antagonists necessarily have any advantage over a potent H1 blocker alone in the treatment of dermographism.     

Effects of H1- and H2-antihistamines on platelet-activating factor and bradykinin-induced inflammatory responses in human skin

Previous studies show that oral antihistamines affect the Weal and flare response to intradermal injections of the inflammatory mediators platelet-activating factor (PAF) and bradykinin (BK). The aim of this study was to compare the effects of terfenadine (an H₂-antagonist) and cimetidine (an H₂-antagonist) on weal and Hare responses to PAF and BK in healthy non-atopic human volunteers. The effects of doxepin on PAF responses were investigated, as there is evidence that doxepin may have direct anti-PAF ejects in addition to its known antihisiaminic actions.     

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.     

Histamine H2-receptor antagonists inhibit enzymic histamine degradation in human skin

The histamine H₂-receptor antagonists burimamide and cimetidine cause inhibition of human skin histamine-N-methyl transferase (HMT) in the dose range 10^-3–10^-4 M. Amodiaquin, a recognized inhibitor of animal HMT, also produced dose-related inhibition of human HMT. These findings may explain the observation that H₂-receptor antagonists enhance certain types of inflammatory response in skin.     

The effectiveness of montelukast for the treatment of anti-histamine-resistant chronic urticaria

Many patients with chronic idiopathic urticaria are not sufficiently controlled with histamine H₁-receptor antagonists. Leukotriene receptor antagonists have been reported to be effective for certain cases of urticaria, although their proper application remains to be established. To study the effectiveness of montelukast, a leukotriene receptor antagonist, for the treatment of chronic urticaria that was not controlled by histamine H₁-receptor antagonists. Twenty-five patients with chronic idiopathic urticaria were treated with 10 mg of montelukast for one week or more, without changing any precedent treatment that they were using before the study including histamine H₁-receptor antagonists. The effectiveness of montelukast for each patient was evaluated and compared with clinical features and/or backgrounds of the patients. Twelve patients, including six who had been treated with corticosteroids, were evaluated as “markedly improved” or “improved” following treatment with montelukast. There was no statistically significant relation of the effectiveness to the complications with non-steroidal anti-inflammatory drugs (NSAIDs) intolerance, mechanical urticaria, or reactions to autologous serum skin test. However, the patients for whom montelukast was effective were younger (33.2±16.3 years, mean ± SD)(P<0.05, Mann-Whitney test) and their duration of illness shorter (15.9±18.3 months) (P<0.005, Mann-Whitney test) than those of patients for whom montelukast was ineffective (45.9±15.0 years, 89.6±71.7 months). Montelukast may be worth trying for patients with chronic idiopathic urticaria, when the condition is not sufficiently controlled with histamine H₁-receptor antagonists.     

Novel insights into the molecular mechanism of the cardiac actions of histamine H1 receptor antagonists

ABSTRACT: When compared to older first‐generation antihistamines, second‐generation antihistamines are characterized by improved selectivity for histamine receptors, absence of sedation, and, possibly, antiallergic properties distinct from their antihistaminic activity. Such a pharmacologic profile, arising from specific pharmacodynamic and pharmacokinetic properties, bears an obvious clinical advantage for the therapy of allergic diseases; thus second‐generation antihistamines have become the treatment of choice for chronic urticaria and allergic rhinitis. Despite such a therapeutic advantage, adverse cardiovascular effects associated with the use of some congeners belonging to the class of second‐generation antihistamines (particularly terfenadine and astemizole) have been reported, and a major concern about the therapeutic selection of antihistamines now is represented by their potentially severe arrhythmogenic properties. This article reviews the recent advances in the understanding of the pathogenesis and etiology of the cardiotoxic actions of some second‐generation antihistamines, underlining their molecular actions at the level of K⁺ channels controlling the cardiac action potential. In particular, emphasis is given to the interaction of second‐generation antihistamines with the K⁺ channels encoded by the human ether‐a‐gogo‐related gene (HERG), which is crucially involved in the repolarization process of the cardiac action potential. This review will also focus on the recent concerns over the potential cardiac adverse effects of first‐generation H₁ receptor blockers. The present exploration of the molecular basis of the adverse cardiac effects of antihistamines shows how important contributions in deciphering such complex phenomenon have emerged from disciplines and techniques not traditionally related to immunology, such as molecular genetics and cellular electrophysiology; it seems possible to anticipate that the exchange of results from such different disciplines in the future will provide patients and physicians with medications with improved therapeutic efficacy and safety for the clinical management of allergic diseases.     

A comparison of cetirizine and terfenadine in the management of solar urticaria.

Many solar urticaria patients may benefit from the use of antihistamines. Historically, the value of such therapy was limited by sedation. Newer agents such as terfenadine and cetirizine that are relatively non-sedating appear to be better tolerated by patients. The latter drug, in addition to its antihistamine effect, also appears to inhibit eosinophil migration, which terfenadine and other potent H1 antagonists do not significantly affect. Eosinophils have been reported as early migrating cells in induced solar urticaria, raising the possibility that the dual action of cetirizine may provide a greater potential benefit in the management of solar urticaria. Six patients with idiopathic solar urticaria were entered into a double-blind, phototest study to compare cetirizine and terfenadine. Using the minimal urticarial dose as a phototest end-point, both drugs were equally effective in raising the threshold of sensitivity in 4 patients. Two patients failed to respond to either therapy, which is in keeping with the known variable response to histamine blockade in solar urticaria. At the dosage used, cetirizine therapy appears to be no more effective than terfenadine.     

Acquired cold urticaria: H1 and H2 antagonists versus cold induced histamine release

Three patients with idiopathic cold urticaria were treated with either or both cyproheptadine (Histamine H₁ receptor antagonist) and cimetidine (Histamine H₂ receptor antagonist). Cold induced histamine release (CIHR) was significantly higher in the patients (71.0 ± 23.8 pm/ml) than in normal volunteers (4.5 ± 1.0 pm/ml). Improvement of clinical manifestations with reduced CIHR was obtained by combination therapy using cyproheptadine and cimetidine but no favorable response was noted with either drug alone. The combined therapy with both drugs completely suppressed pruritis and edema but failed to suppress the erythematous reaction. Single cyproheptadine therapy was rather favored by the patients despite positive CIHR with the therapy. Histamine release from patients' leukocytes under three different conditions (37°C, 4°C→37°C, 4°C) was not significantly different.     

The effect of H1 and H2 histamine antagonists on symptomatic dermographism

In ten patients suffering from symptomatic dermographism the combined administration of chlorpheniramine + cimetidine produced a greater reduction in the weal and flare response provoked by a standardized scratch than the administration of chlorpheniramine alone. There was a statistically significant improvement in the overall assessment of the patient's skin condition with the combined administration of chlorpheniramine + cimetidine. Chlorpheniramine given alone produced no significant benefit whilst cimetidine alone produced a marked exacerbation in itching in nearly half the patients who initially entered the study and was sufficient to require withdrawal.     

H2 Blockers in Chronic Urticaria

Two hundred unselected patients with chronic idiopathic urticaria were treated with adequate doses of conventional antihistamines given at frequent intervals; 98.5% were completely freed of disease while on therapy. In three cases, the lesions subsided but did not clear completely. The addition of 800 mg of cimetidine in divided doses cleared the lesions in two cases, and in the third case the dose of H1 blocker was increased, which resulted in complete clearance of wheals and symptoms. Addition of H2 blockers play a role, but only in a very small percentage of patients with chronic idiopathic urticaria who do not completely respond to adequate doses of H1 blockers.     

The apparent volumes of distribution of H1 receptor antagonists

ABSTRACT: The apparent volume of distribution (V_D) of a drug estimates its distribution into the body. Referring to the volume of exchangeable water (0.6 L/kg body weight), it indicates if tissue distribution is extensive when V_D is greater than 0.6 L/kg or poor if V_D is less than 0.6 L/kg. Its interest in the selection of an appropriate drug is found after comparing the map of selected targets (mainly receptors) to be reached by the drug, the accessibility of these targets by the drug, and the V_D necessary and sufficient to reach them. This analysis is here applied to H₁ receptor antagonists, a pharmacologic class, where target cells, endothelial cells such as eosinophils, mastocytes, basophils, and smooth fibers have receptors on the external side of cell membranes and thus are more readily accessible from blood than toxic sites located inside cells (heart, brain, liver). Of the H₁ receptor antagonists marketed today, cetirizine has the lowest V_D, 0.4 L/kg, enough to reach selected targets without extensive distribution in organs where it would be useless. These characteristics are related to its chemical amphoteric structure.     

The reaction of the normal and pathologically changed skin to tangential vibration effect of drugs on this reaction

Summary A tangential vibration at a frequency of 50 Hz and 630 m W/s results depending on vibration time in a shearing action in the epidermal layers, and produces an erythema, a weal and intra-epidermal vesicles. Electromicroscopically an expansion of the intra-epidermal interstices, a vacuolisation in the cytoplasma but an intact basal membrane can occur. Dermatoses with increased permeability of the microvessels have been examined. In urticarial factitia the vibration does not show a decrease threshold to to vibration. In cholinergic urticaria the marked erythema with intensive itching seems to be characteristic. In urticaria pigmentosa the quick and marked weal eruption is evident. In drug reactions the development of oedema and satellites beside the weal is remarkable. In erythropoetic porphyria a decreased threshold of weal eruption after the vibration of the unchanged skin occurs. Application of the vibration head in pemphigoid, does not result in blistering, and there is no increase in the ingress of fluid into existing blisters. In peripheral paralyses the early stages of hemiplegia show an increased tendency to erythema and to wealing. On the other hand, in spastic paralysis, lon established, there was a delay in the formation of erythema and wealing in the unparalysed side. Topical application of drugs as benzyl nicotinate in normal probands resulted in an extended oedema, rather than a weal, in the vibrated area.Cortico-steroids given topically, produced no detectable inhibition of wealing. Antihistamines topically applied certainly reduced the urticarial reaction. Cortico-steroids given intravenously resulted in appreciable reduction in weal-like eruption. Aprotinine at a dose of 300 000 IU and higher, produced distinct inhibition of wealing within 10 min of i.v. infusion. Oral administration of anti-inflammatories as butazolidine, acetyl salicylate was not followed by any change in tendency to wealing on vibration. One effect of these anti-inflammatories was demonstrable, however, in vibration of benzyl nicotinate areas. Instead of oedema which occurred after vibration of benzyl nicotinate areas, these effect of vibration was abolished by anti-inflammatories and normal weal in the benzyl nicotinate area occurs. General anaesthesia was found to produce considerable reduction in the formation of weals and erythema.Hospital das Clinicas, Department of Tropical Medicine and Dermatology, P.O. Box 8091, São Paulo (Brazil)     

Therapy of acute and chronic urticaria

Background The drug management of chronic urticaria can be divided into three approaches: (i) blockade of released histamine at the receptor sites; (ii) blockade of histamine release from mast cells; and (iii) blockade of other mediators and possible inflammatory and cellular components. The first approach is the most successful and widely used. It primarily involves the use of H₁-antihistamines, although tricyclic antidepressants and H₂-antihistamines also have a place. Treatments The usefulness of classic H₁-antihistamines, such as hydroxyzine, may be limited by side-effects (most notably, sedation). The four most widely used of the newer antihistamines are loratadine, terfenadine, astemizole and cetirizine. These antihistamines are significantly superior to placebo and have similar efficacies comparable with hydroxyzine. Novel agents and methods, including nifedipine, sulphasalazine and plasmapheresis have been tried with some success in refractory patients. Guidelines If acute cases are inadequately controlled, short-term oral corticosteroids may be added. Systemic corticosteroids are occasionally indicated for the management of severe acute urticaria, severe serum sickness, pressure urticaria or urticarial vasculitis, or to break the cycle of a resistant case, but have no place in regular therapy for chronic urticaria. For those with severe acute urticaria with signs of respiratory distress, possible treatments include subcutaneous epinephrine, systemic corticosteroids and intramuscular H₁-antihistamines. Patients with chronic urticaria inadequately controlled on H₁-antihistamines alone may benefit from the addition of a classic antihistamine, a tricyclic antidepressant or an H₂-antihistamine. A short course of systemic corticosteroids may help those with severe chronic refractory disease.     

Treatment of chronic urticaria with cetirizine dihydrochloride a non-sedating antihistamine

The efficacy of cetirizine dihydrochloride, a new H₁-antagonist with minimal sedative or anticholinergic side effects was evaluated in 30 patients with chronic idiopathic urticaria. In the first part of the study, cetirizine 10 mg and placebo were compared in a double-blind cross-over trial. In the second part, patients who did not respond adequately in the first part were randomized, still double-blind, to receive 10 mg cetirizine either once daily or twice daily. In the first part, treatment was discontinued by 17 patients on placebo and two patients on cetirizine because of lack of efficacy. Cetirizine dihydrochloride was found significantly to reduce occurrence of weals, erythema and pruritus compared with placebo (P <0.001). Twenty-six of the patients improved on cetirizine and two on placebo. Mild sedation was noted by two patients on cetirizine and by one on placebo.     

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.