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Efficacy of montelukast, in combination with loratadine, in the treatment of delayed pressure urticaria

2003; Elsevier BV; Volume: 112; Issue: 1 Linguagem: Inglês

10.1067/mai.2003.1559

1097-6825

Eustachio Nettis, A. Pannofino, E. Cavallo, A. Ferrannini, Alfredo Tursi,

Dermatology and Skin Diseases

Delayed pressure urticaria (DPU) is a type of physical urticaria characterized by the gradual onset of wheals or edema in areas where pressure has been applied to the skin. Usually, antihistamines alone are insufficient to control DPU; accordingly, corticosteroids might be beneficial to all patients with this disease, though it is associated with undesirable side effects. Montelukast is a cysteinyl leukotriene receptor (CysLT1) antagonist. Cysteinyl leukotrienes—LTC4, LTD4, and LTE4—are strong smooth muscle constrictors and contribute to the onset of inflammation by causing plasma extravasation and eosinophil recruitment.1Drazen JM Austen KF Leukotrienes and airway responses.Am Rev Resp Dis. 1987; 136: 985-998PubMed Google Scholar CysLT1 antagonists, given concomitantly with H1-receptor antagonists, have been shown to be effective in the treatment of chronic asthma and chronic urticaria.2Reiss TF Chervinsky P Dockhom RJ Shingo S Seidenberg B Edwards TB Montelukast, a once daily leukotriene receptor antagonist in the treatment of chronic asthma: a multicenter, randomized, double-blind trial.Arch Intern Med. 1998; 158: 1213-1220Crossref PubMed Scopus (498) Google Scholar, 3Nettis E Dambra P D'Oronzio L Loria MP Ferrannini A Tursi A Comparison of montelukast and fexofenadine for chronic idiopathic urticaria.Arch Dermatol. 2001; 137: 99-100PubMed Google Scholar The objective of our study was to evaluate the efficacy of the combination of montelukast and loratadine as therapeutic agents for DPU. Twenty subjects (5 male and 15 female) affected by DPU were recruited. They ranged in age from 18 to 68 years (mean age, 45.5 ± 15.17 years). One month before treatment, patients were asked to discontinue systemic corticosteroids. The study was approved by the Ethical Committee, and each subject signed an informed consent form. Exclusion criteria were as follows: inability to understand the nature and scope of the study and/or evidence of an uncooperative attitude; cardiac, renal, hepatic, or rapidly progressing fatal disease; a history of alcohol consumption or hypersensitivity to montelukast or loratadine; pregnancy; pregnancy potential; current lactation. After a careful history was taken and an accurate physical examination was performed, a challenge test was used to confirm the diagnosis of DPU. For the diagnosis of DPU, a 7-kg weight was suspended from the patient's shoulder for 15 minutes and readings of the test area were done at 0.5, 3, 6, 8, and 24 hours. Results were graded on a scale of 0 to 3, as follows: 0, severe response; 1, moderate response; 2, mild response; 3, no response.4Vena GA D'Argento V Cassano N Mastrolonardo M Sequential therapy with nimesulide and ketotifen in delayed pressure urticaria.Acta Derm Venereol. 1998; 78: 304-305Crossref PubMed Scopus (26) Google Scholar The study was conducted in a randomized, double-blind fashion; results were evaluated on an intention-to-treat basis. After diagnosis, each patient was randomly assigned to receive either loratadine 10 mg (n = 10) or loratadine 10 mg plus montelukast 10 mg (n = 10) for 15 days. At randomization, the baseline characteristics of the 2 groups were matched. Pressure-testing was repeated at baseline and after treatment and evaluations were made at each visit by the same investigator for each patient. Blood tests were performed (total blood cell count and blood chemistry [aspartate transaminase, total bilirubin, creatinine and urea]) at baseline and at the end of the study. Statistical analysis was performed with the Fisher exact test for 2 × 2 contingency tables (0-2, positive response; 3, no response). A probability of P < .05 was taken as statistically significant. All 20 patients completed the study. Twelve patients (60%) had concurrent chronic idiopathic urticaria and/or dermographism. In this study, after challenge testing had been carried out at the end of the treatment, montelukast + loratadine was significantly more effective (P < .05) than loratadine alone. In fact, rechallenge testing revealed a total suppression of response after 3 to 6 hours in 8 patients (80%) from the montelukast + loratadine group and after 6 hours in 2 patients (20%) from the loratadine group. In contrast, 1 patient in the loratadine group and 1 patient in the montelukast + loratadine group had a moderate response, whereas 7 patients in the loratadine group and 1 patient in the montelukast + loratadine group had a mild response or no response. Blood chemistry tests conducted at the end of treatment revealed no changes in any of the studied patients, and no serious adverse effects were observed by the investigator or reported by the patient, confirming the tolerability of montelukast and loratadine. Somnolence was reported only in 2 patients receiving montelukast + loratadine. The pathogenesis of DPU remains unclear. Characterized by a late-phase–type reaction occurring several hours after the application of weight, DPU is a disorder in which lymphocytes, eosinophils, mast cells, and mediators play an important role. Other authors have hypothesized that leukotrienes (particularly LTB4) might play a role in such reactions.5Czarnetzki BM Meentken J Rosenbach T Pokropp A Clinical, pharmacological and immunological aspects of delayed pressure urticaria.Br J Dermatol. 1984; 111: 315-323Crossref PubMed Scopus (40) Google Scholar Increased levels of LTE4 were observed in patients with cold urticaria and atopic dermatitis,6Maltby NH Ind PW Causon RC Fuller RW Taylor GW Leukotriene E4 release in cold urticaria.Clin Exp Allergy. 1989; 19: 33-36Crossref PubMed Scopus (27) Google Scholar, 7Sansom JE Taylor GW Dollery CT Archer CB Urinary leukotriene E4 levels in patients with atopic dermatitis.Br J Dermatol. 1997; 136: 790-791Crossref PubMed Scopus (27) Google Scholar and injection of the CysLTs into human skin produced a wheal and flare reaction.8Maxwell DL Atkinson BA Spur BW Lessof MH Lee TH Skin response to intradermal histamine and leukotrienes C4, D4 and E4 in patients with chronic idiopathic urticaria and in normal subjects.J Allergy Clin Immunol. 1990; 86: 759-765Abstract Full Text PDF PubMed Scopus (55) Google Scholar The anti-inflammatory potential of anti-leukotrienes in asthma has been confirmed in a number of studies.2Reiss TF Chervinsky P Dockhom RJ Shingo S Seidenberg B Edwards TB Montelukast, a once daily leukotriene receptor antagonist in the treatment of chronic asthma: a multicenter, randomized, double-blind trial.Arch Intern Med. 1998; 158: 1213-1220Crossref PubMed Scopus (498) Google Scholar, 9Pizzichini E Leff JA Reiss TF Hendeles L Boulet LP Wei LX et al.Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial.Eur Respir J. 1999; 14: 12-18Crossref PubMed Scopus (326) Google Scholar In vitro, it has been demonstrated that loratadine induces a reduction in LTB4 levels10Amsellem C Czarlewsky W Lagarde M Pacheco Y Inhibitory effect of loratadine on leukotriene B4 production by neutrophils either alone or during interaction with human airway epithelial cells.Pulm Pharmacol Ther. 1998; 11: 245-252Crossref PubMed Scopus (17) Google Scholar; in vivo, loratadine has been shown to inhibit histamine release and to decrease eosinophils counts in blood and sputum.11Chyrek-Borowska S Siergiejko Z Michalskz I The effects of a new generation of H1 antihistamines (cetirizine and loratadine) on histamine release and the bronchial response to histamine in atopic patients.J Invest Allergol Clin Immunol. 1995; 5: 103-107PubMed Google Scholar CysLT1 antagonists, such as montelukast 10 mg, have been shown to be effective with or without antihistamines in patients with chronic urticaria.3Nettis E Dambra P D'Oronzio L Loria MP Ferrannini A Tursi A Comparison of montelukast and fexofenadine for chronic idiopathic urticaria.Arch Dermatol. 2001; 137: 99-100PubMed Google Scholar, 12Friedman PS Persanowska M McGuire C Nayak N Clough GF Sampson AP New therapeutic indication for Cys-LT1 antagonists: atopic dermatitis and urticaria.Clin Exp Allergy. 2001; 31: 1607-1614Crossref PubMed Scopus (167) Google Scholar The effect of leukotriene antagonists in the control of chronic urticaria has not been extensively studied. This is the first study to demonstrate the therapeutic benefit of montelukast given concomitantly with loratadine in patients affected by DPU. Indeed, the favorable response to montelukast + loratadine might reflect the involvement of leukotrienes in the pathogenesis of DPU. It could also suggest that leukotriene antagonists might have a potential role in the treatment of inflammatory skin diseases. Despite the limitations of this preliminary report (eg, there was no placebo control difference in DPU with or without chronic urticaria), our results are encouraging. Therefore, we believe that more studies are needed to evaluate the efficacy of the concomitant administration of montelukast and loratadine in the treatment of DPU.