prostaglandin-d2 and Urticaria

Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need.. To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H1-antihistamines.. We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D2 (PGD2)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content.. Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD2-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed.. This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD2-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD2/CRTh2 pathway will be an -effective treatment for CSU.

Topics: Acetates; Administration, Oral; Adult; Aged; Chronic Disease; Eosinophils; Female; Humans; Indoles; Male; Middle Aged; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Urticaria

Topics: Abdominal Pain; Adult; Anaphylaxis; Angioedema; Anti-Asthmatic Agents; Biomarkers; Cromolyn Sodium; Diarrhea; Dinoprost; Female; Histamine Antagonists; Humans; Leukotriene E4; Male; Mast Cells; Mastocytosis; Middle Aged; Omalizumab; Prostaglandin D2; Treatment Outcome; Tryptases; Urticaria

Heat contact urticaria is very rare and it is characterized by the development of wheal limited to the areas of heat contact. We report a case of heat contact urticaria in a 65-year-old women. The wheal was induced by hot bathing, washing in hot water or leaning on hot radiators. Symptoms started within 5 minutes of exposure and lasted 30 to 60 minutes. She had no systemic symptoms. The clinical diagnosis of localized heat urticaria was confirmed by experimental induction of localized wheals. Our investigation showed that the threshold temperature needed for induction of the heat urticaria was 39 degrees C. We tried to investigate the plasma levels of prostaglandin D2 and blood histamine before and after heat challenge. The patient showed marked improvement after a combination treatment of desensitizing by repeated exposure to heat and indomethacine.

Topics: Aged; Female; Hot Temperature; Humans; Prostaglandin D2; Urticaria

A 5-year-old white boy had a history of generalized urticaria on total body exposure to a cold environment. Standard ice cube testing was negative. Plasma analysis revealed the presence of cryofibrinogen. Systemic cold challenge with serial plasma assays for complement, histamine, and prostaglandin D2 disclosed an elevation and peak of plasma histamine and prostaglandin D2 levels after the onset of generalized urticaria with no change in serum complement levels.

Topics: Child; Cold Temperature; Complement System Proteins; Histamine; Humans; Male; Prostaglandin D2; Urticaria

Six patients with acquired primary cold urticaria and six normal control subjects were challenged with a 5-minute immersion of an arm in cold water, at 10 degrees C, to induce cold urticaria. Venous blood draining the arm was sampled before and at 5 and 20 minutes after challenge. Prostaglandin D2 levels in the serum increased significantly after cold challenge but did not correlate with the severity of the urticaria. Significant elevations in histamine after cold challenge tended to be higher in the patients with a low threshold to cold reaction. Two markers of platelet activation, platelet factor 4 and beta-thromboglobulin, remained at basal levels 5 minutes and 20 minutes after challenge.

Topics: Adult; beta-Thromboglobulin; Blood Platelets; Cold Temperature; Histamine Release; Humans; Middle Aged; Platelet Factor 4; Prostaglandin D2; Urticaria

Recent evidence suggests that mast cell derived mediators other than histamine are likely to be involved in the pathogenesis of physical urticarias. Much of the work has been performed in idiopathic cold contact urticaria where the presence of neutrophil and eosinophil chemotactic factors, and platelet activating factor-like lipid substances have been previously demonstrated. Now, an increase in prostaglandin D2 measured by GC-MS has been demonstrated in venous blood draining the cold challenged area. This appeared a few minutes later than histamine, but then both substances paralleled the onset, development and subsidence of the urticarial reaction. There appeared to be no quantitative relationship between histamine and PGD2 release. A similar rise in histamine and PGD2 occurred on heat challenge of a subject with the rare localized form of heat urticaria. This rise of both substances was considerably reduced after combined treatment with induction of tolerance and oral indomethacin. The concentrations of PGD2 measured suggested that it plays an indirect role.

Topics: Cold Temperature; Histamine; Humans; Indomethacin; Physical Stimulation; Prostaglandin D2; Prostaglandins D; Urticaria

The interaction of prostaglandin D2 (PGD2) and histamine in human skin was studied by intradermal injection of the compounds alone or in combination in healthy volunteers. Responses were recorded by measurement of areas of wheal and erythema, and changes in cutaneous blood flow quantified using a laser Doppler flow meter. The effect of a near-threshold dose of PGD2 on histamine dose-response relationships and on the response to a single low dose of histamine were examined. Histamine caused dose-related increases in blood flow and in areas of wheal and erythema in human skin. Prostaglandin D2 caused dose-related increases in blood flow and erythema area, but not wheal area, in the dose range used. When the compounds were injected together, PGD2 did not potentiate the increase in blood flow and areas of wheal and erythema due to histamine. The modest augmentation of histamine response in the presence of PGD2 could be attributed to summation alone. The role of PGD2 in cutaneous disorders such as the physical urticarias, in which its release has been demonstrated, is therefore uncertain. In the amounts measured in the urticarias, it is unlikely alone to cause a significant cutaneous response; nor does it appear to act by potentiation of the response to histamine.

Topics: Adult; Aged; Differential Threshold; Dose-Response Relationship, Drug; Drug Interactions; Erythema; Female; Histamine; Humans; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Regional Blood Flow; Skin; Urticaria

Prostaglandin (PG) D2 and histamine concentrations have been measured in blood draining cold-challenged forearm skin in patients with cold urticaria. Local venous concentrations of both histamine and PGD2 rose in four patients who developed a whealing response. Plasma histamine concentration increased from a mean resting value of 0.24 +/- 0.09 (SD) ng/ml to peak values of 16.9 to 96.6 ng/ml. Resting concentrations of PGD2 were below the limit of detection (5 pg/ml) in three patients and 62 and 27 pg/ml in the fourth. Peak plasma PGD2 concentration after challenge ranged from 166 to 279 pg/ml. Time course of histamine and PGD2 release was similar with peak concentrations at 6 and 10 minutes, respectively. The maximum clinical response occurred between 10 and 20 minutes after challenge. Our findings demonstrate that PGD2 is produced in association with mast cell degranulation in man, but the amount, relative to histamine, is low. Despite its high potency in production of inflammatory effects, PGD2 probably has only minor direct effects in cold urticaria, although it may act to potentiate other mediators.

Topics: Adolescent; Adult; Cold Temperature; Female; Histamine; Histamine Release; Humans; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Urticaria

A case of localized heat urticaria in a 70-year-old woman is reported. Increased plasma levels of prostaglandin D2 and blood histamine after heat challenge indicate a role for mast cell degranulation in the pathophysiology of the syndrome. Treatment with astemizole increased the temperature threshold to wealing, but not to itch or erythema. The patient was partially desensitized by repeated exposure to heat and this was further improved by indomethacin. After treatment there was no increase in plasma prostaglandin D2 on challenge. No evidence was found for the activation of the alternative complement pathway.

Topics: Aged; Female; Histamine; Histamine Release; Hot Temperature; Humans; Prostaglandin D2; Prostaglandins D; Urticaria

Topics: Basophils; Cell Separation; Cold Temperature; Histamine Release; Humans; Mast Cells; Models, Biological; Physical Exertion; Platelet Activating Factor; Prostaglandin D2; Prostaglandins D; Urticaria