William H. Yang

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

The monosodium glutamate symptom complex: Assessment in a double-blind, placebo-controlled, randomized study

BACKGROUND Considerable debate swirls about the validity of symptoms described by many people after ingestion of monosodium glutamate (MSG), and the question has remained unresolved largely because of a paucity of well-designed challenge studies. METHODS We conducted oral challenge studies in self-identified MSG-sensitive subjects to determine whether they had a statistically significant difference in the incidence of their specific symptoms after ingestion of MSG compared with placebo. First, 5 gm MSG or placebo was administered in random sequence in a double-blind fashion. Subjects who reacted only to a single test agent then underwent rechallenge in random sequence in a double-blind fashion with placebo and 1.25, 2.5, and 5 gm MSG. A positive response to challenge was defined as the reproduction of > of 2 of the specific symptoms in a subject ascertained on prechallenge interview. RESULTS Sixty-one subjects entered the study. On initial challenge, 18 (29.5%) responded to neither MSG nor placebo, 6 (9.8%) to both, 15 (24.6%) to placebo, and 22 (36.1%) to MSG (p = 0.324). Total and average severity of symptoms after ingestion of MSG (374 and 80) were greater than respective values after placebo ingestion (232 and 56; p = 0.026 and 0.018, respectively). Rechallenge revealed an apparent threshold dose for reactivity of 2.5 gm MSG. Headache (p < 0.023), muscle tightness (p < 0.004), numbness/tingling (p < 0.007), general weakness (p < 0.040), and flushing (p < 0.016) occurred more frequently after MSG than placebo ingestion. CONCLUSIONS Oral challenge with MSG reproduced symptoms in alleged sensitive persons. The mechanism of the reaction remains unknown, but symptom characteristics do not support an IgE-mediated mechanism. According to Food and Drug Administration recommendations, the symptoms, originally called the Chinese restaurant syndrome, are better referred to as the MSG symptom complex.

C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study

To cite this article: Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, Moy JN, Offenberger J, Jacobson KW, Yang WH, Eidelman F, Janss G, Packer FR, Rojavin MA, Machnig T, Keinecke H‐O, Wasserman RL. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study. Allergy 2011; 66: 1604–1611.

Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis

BACKGROUND Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure. OBJECTIVE To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR. METHODS Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients. RESULTS Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P < .001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P < .01) and -0.15 (95% CI, -0.24 to -0.06; P < .001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment. CONCLUSION Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.

Once daily mometasone furoate aqueous nasal spray is as effective as twice daily beclomethasone dipropionate for treating perennial allergic rhinitis patients

BACKGROUND Perennial allergic rhinitis is chronic and persistent, may lead to a constellation of secondary complaints including sinusitis, mouth-breathing, and some symptoms resembling a permanent cold, and often requires constant medical intervention. Well-tolerated nasal corticosteroids, alone or in combination with antihistamines, have been found to be very effective in treating this condition. OBJECTIVE To compare the effectiveness and tolerability of mometasone furoate aqueous suspension, a new once daily nasal spray, to placebo vehicle and to beclomethasone dipropionate, administered twice daily, in patients with perennial allergic rhinitis. METHODS This was a randomized, double-blind, placebo-controlled, double-dummy, parallel group study, in 427 patients age 12 years and older at 24 centers in Canada and Europe. Patients allergic to at least one perennial allergen, confirmed by medical history, skin testing, and adequate symptomatology were eligible to receive one of the following regimens for 3 months: mometasone furoate, 200 micrograms only daily; beclomethasone dipropionate, 200 micrograms twice daily (400 micrograms total dose); or placebo vehicle control. The primary efficacy variable was the change from baseline in total AM plus PM diary nasal symptom score over the first 15 days of treatment. RESULTS Three hundred eighty-seven patients were valid for efficacy. For the primary efficacy variable, mometasone furoate was significantly (P < or = .01) more effective than placebo and was indistinguishable from beclomethasone dipropionate. Similar trends were seen among individual symptoms, physician symptom evaluations, and therapeutic response. There was no evidence of tachyphylaxis. All treatments were well tolerated. CONCLUSIONS Mometasone furoate nasal spray adequately controls symptoms of perennial allergic rhinitis, offers the advantage of once daily treatment, and is well tolerated.

Intranasal fluticasone propionate versus loratadine in the treatment of adolescent patients with seasonal allergic rhinitis

Fluticasone propionate (FP) is a topical corticosteroid with minimal systemic activity. We examined safety and compared the efficacy of FP aqueous nasal spray, 200 micrograms every day with loratadine tablets, 10 mg by mouth every day in 240 adolescents with ragweed pollen-induced seasonal allergic rhinitis for 4 weeks in a randomized, double-blind, parallel-group study. Nasal and eye symptoms were recorded daily on a 4-point (0 to 3) scale. A higher percentage of symptom-free days was observed for nasal blockage on waking during treatment with FP (p < 0.0001). Significant results were also obtained for all other nasal symptoms when analyzed for both symptom-free days and symptom scores. No differences were found for eye irritation symptoms (p = 0.14). Morning and evening nasal peak inspiratory flow (PIF) was recorded daily by 57 subjects. FP treatment was associated wit significantly higher PIF values than loratadine both morning (p = 0.0051) and evening (p = 0.0036). A greater improvement over 4 weeks was observed for PIF morning values in the FP group (p = 0.008) but not for evening values (p = 0.358). Statistically significant correlations were found for nasal blockage and PIF in the morning (r = -0.54, p = 0.0001) and in the evening (r = -0.46, p = 0.008).

C1-Esterase Inhibitor Transfusions in Patients with Hereditary Angioedema

BACKGROUND Hereditary angioedema results from the deficiency of C1-esterase inhibitor (C1-INH), and C1-INH replacement would represent definitive treatment for angioedema attacks. In Canada, C1-INH is available only on a compassionate basis at select medical facilities. Our objective is to assess the efficacy of C1-INH transfusions during angioedema attacks at a single Canadian institution. METHODS A retrospective chart review of transfusion data between January 1, 1995 and June 30, 1996 was performed. Phone interviews with patients elicited their opinions of the treatment. Data collected included the number and duration of angioedema attacks, dose of transfused C1-INH, and side effects of treatment. RESULTS Of a cohort of 13 patients with hereditary angioedema, seven received transfusions with C1-INH. Attacks totaled 87, and more than 100,000 units of the product were transfused. The mean time for abatement of an attack after initiation of transfusion was 50 +/- 8 minutes (1 SD). There were no reports of adverse effects. Although patients were satisfied with the treatment, they raised concerns regarding long-term safety and availability. CONCLUSIONS C1-INH transfusion is a satisfactory means of treating angioedema attacks.

Positive skin tests and Prausnitz-Küstner reactions in metabisulfite-sensitive subjects

Sulfiting agents have been reported to cause anaphylaxis, asthma, urticaria/angioedema, seizure, nausea, abdominal pain and diarrhea, and death. There is no consensus regarding the pathogenesis of these reactions. The possible role of IgE-mediated mechanism has been debated. To clarify the pathogenesis of these reactions, we studied 53 patients with a variety of symptoms related to either restaurant meals or alcoholic beverages. Food allergy was excluded as a cause of their symptoms by means of skin testing and elimination diet. Symptoms included urticaria/angioedema (32), asthma (nine), headache (eight), rhinoconjunctivitis (two), and abdominal pain (one), and one patient with anaphylaxis. Twenty normal control subjects were studied as well. Prick and intradermal skin testing with potassium metabisulfite (K2S2O5, 1 mg/ml) were carried out on all subjects. Single-blind oral provocative challenge tests were conducted with placebo (lactose) and with 1, 5, 10, 25, and 50 mg of K2S2O5 in all nine subjects with asthma, nine patients with urticaria/angioedema (excluding one subject with severe coronary insufficiency and positive skin testing to 1 mg of K2S2O5), four subjects with headache, one subject with rhinoconjunctivitis, and one patient with anaphylaxis. Pulmonary function tests (FEV1 and FVC) were measured in all subjects with asthma. Five patients had positive skin tests. One subject with asthma had a positive prick test. Four positive intradermal tests occurred (two subjects with asthma, one subject with urticaria/angioedema, and one subject with anaphylaxis). Single-blind oral provocative challenge testing was positive in the subject with anaphylaxis, as was intradermal skin testing, and also in three subjects with asthma, two of whom had positive skin testing.(ABSTRACT TRUNCATED AT 250 WORDS)

An anaphylactic reaction to intra-articular triamcinolone: a case report and review of the literature

OBJECTIVE The primary objective was to report a case of triamcinolone-induced anaphylaxis and review the proposed mechanisms of corticosteroid-associated hypersensitivity reactions. DATA SOURCES Articles in French and English were identified from references in relevant articles and from articles retrieved from the PubMed web site. Indexing terms consisted of corticosteroids in conjunction with the terms anaphylaxis, hypersensitivity reactions, asthma, urticaria, and angioedema. STUDY SELECTION We reviewed all articles that described a case or cases of allergic-type reaction in association with corticosteroid use and for which we could obtain the full text of the article (>95%). RESULTS We report an anaphylactic reaction occurring after an intraarticular injection of triamcinolone in a 75-year-old man who had positive prick skin tests to triamcinolone and negative tests to lidocaine, methylprednisolone, and hydrocortisone. CONCLUSIONS To date, there have been approximately 100 published reports of immediate hypersensitivity reactions occurring after oral and parenteral administration of corticosteroids. Both immunologic and nonimmunologic mechanisms are proposed, but there is no definitive evidence in favor of either hypothesis. Our patient demonstrated positive prick skin tests to triamcinolone in a dose-response manner, suggesting the likelihood that an immunoglobulin E-mediated hypersensitivity mechanism may play a role.

Aspartame is no more likely than placebo to cause urticaria/angioedema: Results of a multicenter, randomized, double-blind, placebo-controlled, crossover study

BACKGROUND Anecdotes and single case reports have suggested that the high-intensity sweetener, aspartame, may be associated with allergic/hypersensitivity-type reactions. METHODS We conducted a multicenter, placebo-controlled clinical study to evaluate individuals who had experienced urticaria and/or angioedema allegedly associated with ingestion of an aspartame-containing product. Despite extensive recruiting efforts over 4 years, only 21 subjects could be enrolled. After admission to clinical research units, subjects were given aspartame and placebo in a randomized, double-blind, crossover fashion. Subjects received, on different days, increasing doses (50, 300, 600 mg) of aspartame and placebo at 8:00 AM, 10:00 AM, and noon. Subjects who weighed less than 40 kg received one half of these doses. Conversion products of aspartame, aspartyl-phenylalanine diketopiperazine and beta-aspartame, were also included in the aspartame arm of the study. Positive reactions were defined as urticaria (hives with wheals 4 mm or more in diameter with a collective diameter of at least 15 mm or one or more hives with a wheal of 4 mm or greater with a flare of 8 mm or greater) or as angioedema. RESULTS According to these criteria, four reactions were observed; two followed aspartame ingestion and two followed placebo ingestion (p = 1.00). The incidence of other adverse experiences was no different after aspartame versus placebo ingestion (p = 0.289). CONCLUSION These results indicate that aspartame and its conversion products are no more likely than placebo to cause urticaria and/or angioedema reactions in subjects with a history consistent with hypersensitivity to aspartame.