Prevention of asthma by ketotifen in infants with atopic dermatitis.

To evaluate the prophylactic effect of ketotifen against the onset of asthma we selected 121 infants with atopic dermatitis, without any history suggestive of asthma (cough and/or wheezing). Sixty-one children received ketotifen twice daily. Those who weighed less than 14 kg received 0.8 mg; 14 kg or more, 1.2 mg. Sixty children, a placebo syrup indistinguishable from the active syrup. Both groups were followed for 1 year, with bimonthly evaluations. The criteria for onset of asthma were two different episodes of wheezing treated with bronchodilator drugs. Both groups were comparable regarding age, sex, weight, onset, and duration of atopic dermatitis and age at the onset of asthma. During the 1 year study, asthma was observed in eight children of the ketotifen group (13.1%) and in 25 children of the placebo group (41.6%) (P less than .001). Side effects were negligible and routine laboratory tests disclosed no significant alterations. Ketotifen is a very useful drug for prevention of asthma in children with atopic dermatitis and total IgE more than 50 IU/mL.     

A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months' treatment and 18 months' posttreatment follow-up

BACKGROUND: Because asthma is not a curable condition, the development of strategies for prevention of the disease has a high priority. Atopic dermatitis is a common precursor to the development of asthma, and 2 studies have suggested that the use of an H(1) receptor antagonist might reduce the development of asthma while the treatment is being administered, at least in subgroups with evidence of high IgE levels. However, no trial to date has conducted follow-up after the initial treatment has been stopped to establish whether the intervention has merely suppressed symptoms or truly prevented disease. OBJECTIVE: We sought to establish whether the use of cetirizine compared with placebo for 18 months in infants with atopic dermatitis suppressed or truly delayed the onset of asthma, even after cessation of therapy. METHODS: The Early Treatment of the Atopic Child study was a double-blinded, parallel-group, randomized trial of 0.25 mg/kg body weight cetirizine administered twice daily compared with placebo given to infants between 1 and 2 years of age with atopic dermatitis. After 18 months of treatment, follow-up continued for a further 18 months. This article reports the outcome over the full 3 years of follow-up and relates the outcomes to the allergic status on the basis of IgE antibody measurements at recruitment. RESULTS: Although there was no difference in cumulative prevalence of asthma between active and placebo treatment in the intention-to-treat population (P = .7), those infants with evidence of sensitivity to house dust mite, grass pollen, or both who were treated with cetirizine were significantly less likely to have asthma compared with those treated with placebo over the 18 months of treatment (P = .005 and .002, respectively), and this effect was sustained for the grass pollen-sensitized infants over the full 36 months (P = .008). In the house dust mite-sensitized group there was a gradual narrowing of the difference between active and placebo treatment in terms of cumulative prevalence of asthma at the end of 36 months but no evidence of a rebound immediately after the treatment stopped (P = .04). In the placebo population there was a significantly higher risk of development of asthma in those sensitized at baseline to egg (relative risk, 1.4 [95% CI, 1.1-1.7]), house dust mite (relative risk, 1.6 [95% CI, 1.3-1.9]), grass pollen (relative risk, 1.7 [95% CI, 1.4-2.1]), or cat (relative risk, 1.5 [95% CI, 1.2-1.9]). Early and persistent sensitization conferred a higher risk than transient or later sensitization. CONCLUSIONS: Cetirizine compared with placebo truly delays or, in some cases, prevents the development of asthma in a subgroup of infants with atopic dermatitis sensitized to grass pollen and, to a lesser extent, house dust mite. Further studies are required focusing specifically on sensitized groups to substantiate this finding. The study also highlights risk factors for asthma in infants with atopic dermatitis and indicates that early and persistent aeroallergen sensitization confers a higher risk than later development of sensitivity.     

Ketotifen in pollen-induced asthma: a double blind placebo-controlled study

Twenty-nine children with an average age of 10.5 years were studied with respect to the protective effect of ketotifen on pollen-induced bronchial asthma. All of them were sensitive to deciduous tree pollen, the diagnosis being verified by bronchial challenge. The children were stratified in matched pairs and randomly allocated to two treatment groups, placebo or ketotifen 1 mg twice daily. The study was double-blind and was performed during the whole of the deciduous tree pollen season. Daily pollen counts were made, allergic symptoms were noted, additional medication was given and the expiratory pulmonary flow was recorded. During the birch pollen peak the ketotifen group showed significantly fewer, and less severe asthma and rhinoconjunctivitis than the placebo group. The anti-asthmatic medication was also used significantly less than in the placebo group. Ketotifen appeared to have good protective properties in the treatment of pollen-induced asthma and rhinoconjunctivitis.     

Effects of ketotifen on symptoms and on bronchial mucosa in patients with atopic asthma

Ketotifen is marketed throughout the world as an antiallergy drug, but whether it affects infiltration of inflammatory cells into airway mucosa is not known. We studied the effects of ketotifen on symptoms, pulmonary function, and airway inflammation in 25 patients with atopic asthma. Patients took ketotifen (1 mg twice daily) or a matching placebo for 8 weeks in a double-blind, parallel-group study. Data recorded on diary cards were used for 2 weeks before treatment began, and they were used for the last 2 weeks of treatment to study asthma symptoms, use of β2–agonists, and peak expiratory flow (PEF). Pulmonary function tests, bronchial responsiveness to methacholine, and fiberoptic bronchoscopy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. Specimens were stained immunohistochemically with monoclonal antibodies against stored eosinophil cationic protein (EG1), the secreted form of eosinophil cationic protein (EG2), mast-cell tryptase (AA1), neutrophil elastase (NP57), CD3, CD4, CD8, and CD25. The numbers of positively stained cells in the lamina propria were counted. Compared with the placebo, the ketotifen-treated group exhibited significant improvement of asthma symptoms ( P <0.05) and bronchial responsiveness (P<0.05). This was accompanied by a reduction of EG2+ eosinophils ( P <0.05), CD3+ T cells ( P <0.001), CD4+ T cells (P<0.01), and CD25+ activated T cells ( P <0.01) in the bronchial mucosa. These results suggested that the beneficial effects of ketotifen in bronchial asthma may result from consequent inhibition of activated eosinophils and T-cell recruitment into the airway. Moreover, ketotifen may relieve allergic inflammation in bronchial asthma.     

A Canadian multicenter study with Zaditen (ketotifen) in the treatment of bronchial asthma in children aged 5 to 17 years

One hundred thirty-eight children with chronic asthma, requiring daily treatment with bronchodilators, took part in a 7-month, double-blind, multicenter clinical study. Patients were randomized into two groups, and after a 1-month baseline, were administered Zaditen (ketotifen), 1.0 mg twice daily, or an identical placebo for a period of 6 months. After 10 weeks of receiving the study medication, bronchodilator use was reduced or stopped. In the Zaditen-treated group, 60% of the children taking theophylline were able to stop its use completely, compared to 34% of the patients taking placebo (p less than 0.05). Of the patients who were unable to stop taking theophylline, the Zaditen-and placebo-treated groups recorded average dosage reductions of 62% and 26%, respectively. These differences were statistically significant (p less than 0.05). Thus, a high percentage of patients in the placebo-treated group maintained asthma symptom control with theophylline, whereas most of the Zaditen-treated patients could stop using this medication. Although pulmonary function readings improved in both groups, those patients taking Zaditen demonstrated earlier improvement and greater changes from baseline. Significant differences (p less than 0.05) in favor of Zaditen were found for reduction of concomitant medications, patient's global evaluation, physician's clinical evaluations, incidence of emergency room visits for asthma, and upper respiratory tract infections. No unexpected side effects were observed. It is concluded that Zaditen is an effective medication for long-term control of asthma in children.     

Thymopentin therapy reduces the clinical severity of atopic dermatitis

One hundred patients with moderate to severe atopic dermatitis were entered into a two-center, double-blind trial. Patients were randomized to receive either thymopentin (Timunox, n = 48) or placebo (n = 52), administered as daily subcutaneous injections for 6 weeks. Clinical extent of disease and severity parameters were measured at baseline and at regular time intervals during the study. Both the placebo- and thymopentin-treated groups demonstrated a progressive and statistically significant (p less than 0.001) decline in the overall severity of their disease, but reduction in the clinical severity score was higher in the thymopentin-treated group and statistically significant (p = 0.04) in comparison with the placebo-treated group after 6 weeks of treatment. Of the individual symptoms comprising the total severity score, pruritis (p = 0.02) and erythema (p = 0.04) were reduced significantly when thymopentin therapy was compared to placebo therapy. In addition, both the extent of body involvement and severity index (a combined severity/extent index) were significantly reduced after 6 weeks in the thymopentin-treated group in comparison to the placebo-treated group (p = 0.04). There were no serious adverse experiences in either treatment group. We conclude that treatment with thymopentin is safe and offers significant therapeutic promise for atopic dermatitis.     

Fc receptors for human, rabbit and pig antibodies on human eosinophils from normal persons and patients with atopic dermatitis

The presence of Fc receptors on eosinophils from normal persons and atopic patients was investigated using a rosetting technique. Normal eosinophils were found to react with pig antibody (32.5% rosettes), rabbit antibody (46,6% rosettes) and human antibody (29.3% rosettes). Eosinophils from atopic dermatitis patients also formed rosettes with these antibodies, but the percentage of rosettes with pig antibody was significantly higher (63,5%; p less than 0.001) than that given by normal eosinophils. A similar result was found with eosinophils from patients with other atopic diseases (asthma and hay fever) suggesting a similar pattern of eosinophil alteration in all atopic patients. On the other hand, eosinophils from patients with non-atopic eczemas did not differ from those of normals.     

The effect of repirinast on airway responsiveness to methacholine and allergen.

Repirinast, a novel ingested antiallergic asthma medication from Japan, was compared versus placebo on airway responsiveness to methacholine and was compared versus placebo and cromolyn on airway responses to allergen. In 14 patients with mild, stable, atopic asthma, we performed a double-blind, double-dummy, random-order trial with ingested repirinast 300 mg twice daily for 7 days, inhaled cromolyn 40 mg spincaps single dose, and double placebo on allergen-induced early (EAR) and late (LAR) asthmatic responses and increased airway responsiveness. In the 14 subjects, no difference occurred in methacholine PC20 after 6 days of repirinast or 6 days of placebo. In the 13 subjects who completed the allergen study, single-dose cromolyn significantly reduced the EAR by 63% and the LAR by 65% versus placebo (p < 0.02); repirinast was not significantly different from placebo, both the EAR and LAR being reduced by less than 10%. Allergen-induced increase in methacholine responsiveness was borderline (p = 0.052), and no significant drug effects occurred. In these models, a 1-week treatment period with repirinast, like other oral antiallergic asthma medications (e.g., ketotifen, fumarate), provides no protection against airway responses to methacholine or allergen.     

Sublingual immunotherapy in mite-sensitized children with atopic dermatitis: a randomized, double-blind, placebo-controlled study

BACKGROUND: Atopic dermatitis often has an allergic component, and immunotherapy may therefore prove beneficial. OBJECTIVE: To assess the effect of sublingual immunotherapy (SLIT) in children with atopic dermatitis. METHODS: Children age 5 to 16 years with atopic dermatitis (Scoring Atopic Dermatitis [SCORAD] > 7) and sensitization to dust mites alone, without food allergy or chronic asthma, were enrolled in a randomized, double-blind, placebo-controlled study and stratified according to disease severity. SLIT or placebo was given for 18 months in addition to standard therapy. SCORAD, visual analog scale, and rescue medication consumption were recorded at 3-month intervals. RESULTS: Fifty-six children were enrolled, and 28 were allocated to SLIT. Forty-eight completed the study, with 2 dropouts in the active and 6 in the placebo group. The difference from baseline in the SCORAD was significant (P = .025) between the 2 groups starting from month 9. Similarly, there was a significant reduction in the use of medications only in the active group. A trend toward significance was seen for the visual analog score only in the active group versus baseline (P = .07). A significant difference in the considered parameters was found only in patients with a mild-moderate disease, whereas severe patients had only a marginal benefit. SLIT had to be discontinued in 2 patients because of exacerbation of dermatitis. CONCLUSION: Sublingual immunotherapy to dust mite improves mild-moderate atopic dermatitis. CLINICAL IMPLICATIONS: Sublingual immunotherapy may represent an additional therapeutic tool for the treatment of extrinsic atopic dermatitis in properly selected children.     

Effect of neonatal sepsis on the development of allergies and asthma in later childhood

BACKGROUND: Exposure to large amounts of endotoxins and other bacterial products in early childhood may protect against the development of allergic diseases later in childhood. The aim of this study was to investigate the effects of neonatal sepsis on subsequent development of asthma, allergic rhinitis, and atopic dermatitis in children. METHODS: We recruited 85 children (mean age 48.67 +/- 12.88 months) who had been hospitalized for sepsis in their neonatal period and their siblings (n = 85) as controls (mean age 61.81 +/- 21.34 months) to investigate the prevalences of asthma, atopic dermatitis and allergic rhinitis. After asking the questions in the International Study of Asthma and Allergies in Children (ISAAC) questionnaires to the parents, total IgE levels in sera were measured and skin prick tests were performed. RESULTS: Children with neonatal sepsis had lower total IgE levels and less sensitivity to Dermatophagoides pteronyssinus than controls (25.9 vs. 9.4%, p = 0.003). In addition, wheeze ever, wheeze in the last 12 months, physician-diagnosed asthma, and use of asthma drugs were less common in these subjects. Prevalences of allergic rhinitis and atopic dermatitis were equal in both groups. CONCLUSION: Exposure to severe infections such as sepsis in the neonatal period may decrease sensitization to environmental allergens and prevalence of asthma in later childhood.     

A double-blind comparison of ketotifen and disodium cromoglycate in atopic adult asthmatics

The therapeutic effects of inhaled disodium cromoglycate (DSCG) and orally administered ketotifen were compared in thirty atopic asthmatics aged 15-34 years during a 22-week double-blind parallel group study. Ketotifen is a cycloheptathio-phene with experimental antihistaminic, anti-allergic and anti-anaphylactic effects equal or superior to those of DSCG. During the first 6 weeks of treatment, mean airflow meter readings increased and bronchodilator use diminished in those receiving DSCG, but no improvement was seen in those given ketotifen. In the next 10 weeks. concomitant therapy was reduced in both groups, but this reduction was greater in the group receiving DSCG. No serious adverse effects occurred. Asthma worsened after abrupt discontinuation of DSCG but not ketotifen. Although a small number of patients may have benefited from ketotifen. its effect on asthma was not comparable with that of inhaled disodium cromoglycate.     

Short-term effect of partially hydrolyzed formula on the prevention of development of atopic dermatitis in infants at high risk

This short-term, prospective study was aimed to assess the effects of partially hydrolyzed formula (PHF) on the prevention of the development of atopic dermatitis in infants at high risk. The infants of parents with allergy symptoms and serum total IgE over 200 kU/L were divided into 3 groups by their feeding patterns: PHF group (n=15), standard formula (SF) group (n=32), and breast milk (BM) group (n=22). No allergenic food was given during the study period of 6 months, and breastfeeding mothers avoided egg ingestion. Their atopic symptoms were monitored every 2 months. The cumulative incidence and prevalence of atopic dermatitis at the age of 6 months were significantly less in the PHF group than in the SF group (47% vs. 78%, p<0.05; 20% vs. 59%, p<0.05). Those rates of the PHF group were also less than those of the BM group, but they were not statistically significant. There was no difference in the onset age and disease severity. These results suggest that early feeding of PHF to infants at high risk has a short-term preventive effect on the development of atopic dermatitis during the first 6 months of life. Long-term preventive effects should be evaluated.     

血清IL-33、IFN-γ与IgE在支气管哮喘患者中的表达及临床意义

目的观察血清白细胞介素-33(IL-33)、干扰素-γ(IFN-γ)及IgE在支气管哮喘患者中的表达及意义。方法选取94例急性发作期支气管哮喘患者,同时选取同期60例健康体检的人群为对照组,采用酶联免疫法测定血清中IgE、IL-33及IFN-γ水平。比较两组IgE、IL-33和IFN-γ的水平。分析IL-33、IFN-γ和IgE的相关性。结果支气管哮喘患者外周血中IFN-γ水平低于正常人群(t=4.533,P<0.001);IL-33、IgE水平高于正常人群(t=5.831、66.129,P<0.001,<0.001),差异有统计学意义。IgE水平与IL-33水平呈正相关(r=0.667,P=0.032),IFN-γ与IgE、IL-33呈负相关(r=-0.714,P=0.024;r=-0.623,P=0.038)。结论血IgE、IL-33和IFN-γ水平的变化在支气管哮喘患者发病过程中起到一定的作用。     

Blood eosinophils,eosinophil-derived proteins,and leukotriene C4 generation in relation to bronchial hyperreactivity in children with atopic dermatitis

To assess the relation among eosinophil-related variables in the peripheral blood, bronchial hyperreactivity, and the presence of atopic dermatitis in children aged 5–14 years, we studied 11 patients with atopic dermatitis alone, six with asthma and atopic dermatitis, 12 with asthma alone, and 12 healthy controls. Eosinophil counts, levels of eosinophil cationic protein, and the capacity of eosinophils to generate leukotriene (LT) C₄, as well as bronchial hyperreactivity and a severity score for atopic dermatitis, were determined. Eosinophil variables were significantly higher in both patient groups with atopic dermatitis than in normal controls. In particular, ionophore A 23187 LTC₄ generation was higher in patients with atopic dermatitis alone (median 82, range 25–273 ng/10⁶ cells) and patients with combined asthma and atopic dermatitis (median 68, range 32–583 ng/10⁶ cells) than in normal controls (median 9, range 1–67 ng/10⁶ cells). However, there was no difference between the group of atopic dermatitis patients with asthma and without asthma. We conclude that eosinophil variables in the peripheral blood are mainly influenced by the presence of atopic dermatitis, and not the presence and the severity of asthma in patients with both asthma and atopic dermatitis.     

The efficacy of ketotifen in a controlled double-blind food challenge study in patients with food allergy

The effectiveness of oral ketotifen was compared with that of placebo in 26 patients with food allergy in a randomized, double-blind parallel study. Patients were selected on the basis of food allergy as established by history, clinical improvement after an exclusion diet, and reappearance of the symptoms after a challenge with the food. Thirteen patients were given ketotifen and 13, placebo. Ketotifen or placebo were administered twice daily for 1 month after the first oral provocation test and the last dose was given 12 hours before the second oral provocation test. Ketotifen protected patients (7/13) significantly more than placebo (2/13; P less than .05). The results of this study suggest that ketotifen may be useful for some patients with food allergy.     

"Food allergy in children: an attempt to improve the effects of the elimination diet with an immunomodulating agent (thymomodulin). A double-blind clinical trial"

During 90 days of elimination diet nineteen children with food allergy manifesting atopic dermatitis were treated with either 120 mg/day of thymomodulin (10 subjects) or placebo (9 subjects) in a double blind design. After this period an improvement in skin lesions was observed in both groups. Subsequently a food challenge was performed for two weeks: in the group treated with thymomodulin skin lesions did not modify while they worsened in the placebo group and the comparison was statistically significant (p less than 0.01). Before the beginning of the trial laboratory assessments evidenced an increase in total and specific IgE serum levels, which decreased by the end of the study only in the group receiving the thymic derivative (p less than 0.05).     

A multicenter trial of the prophylactic effect of ketotifen, theophylline, and placebo in atopic asthma

Three hundred seventy-four patients with asthma were entered into a year-long, double-blind, double-placebo controlled study comparing the prophylactic effect of ketotifen (229 patients), theophylline (73 patients), and placebo (72 patients). The ketotifen group was larger to allow the accumulation of additional long-term safety data. The primary measure of therapeutic effect was a decrease in concomitant medication without a significant increase in symptomatology or a decrement in pulmonary functions. A patient daily diary was used to document symptoms (cough, shortness of breath, and wheeze) and concomitant medications taken during the 2-week baseline and the subsequent 12 monthly periods. After 2 months of study-drug therapy, the ketotifen patients had a greater decrease in both concomitant medication and symptomatology than either of the other groups. This delay in the onset of therapeutic activity has been observed in other studies and is characteristic of this compound. The principal side effect observed with ketotifen is initial sedation, which was found to be self-limiting and of little concern to the patient after the first month.     

酮替酚对鸡蛋过敏特应性皮炎患儿淋巴细胞增殖反应的抑制作用

作者探讨了鸡蛋过敏特应性皮炎(AD)患儿外周血单个核细胞(PBMCs)对卵白蛋白(OA)刺激的增殖反应并观察了酮替酚(KF)对此反应的影响.结果提示AD患儿的PBMCs增殖反应显著高于健康儿童;KF可剂量依赖性地抑制鸡蛋过敏AD患儿PBMCs对OA刺激的增殖反应,且这一效应可通过KF抑制T细胞的作用而得以实现.KF对植物血凝素(PHA)和破伤风类毒素(TT)诱导的PBMCs增殖反应无抑制作用.这说明KF只抑制食物过敏AD患者PBMCs对食物抗原的特异性增殖反应.     

Ketotifen inhibits the cutaneous but not the airway responses to platelet-activating factor in man

We studied the effect of ketotifen, an oral antiallergic and antihistaminic drug, on the airway and cutaneous responses to platelet-activating factor (PAF) in a double-blind, randomized, and crossover study in six normal subjects. Ketotifen (three doses of 2 mg taken during a 14-hour period before PAF) did not alter PAF-induced bronchoconstriction and did not prevent the accompanying flushing and coughing. The transient neutropenia (74.5 +/- 4.8% fall; p less than 0.001) and rebound neutrophilia (104 +/- 55% rise) induced by PAF were not affected by ketotifen. On the day placebo was received, airway responsiveness to methacholine increased after PAF exposure with the concentration needed to cause a 40% fall in baseline partial expiratory flow rate (PC40), decreasing from 69.2 mg/ml (geometric standard error of the mean, 2.69) to 23.3 mg/ml (2.34) on day 3 (p less than 0.001). Ketotifen had no effect, because on the day ketotifen was administered, mean PC40 also decreased from 52.7 mg/ml (2.5) to 21.5 mg/ml (2.14) (p less than 0.01). In the skin, ketotifen reduced the flare area (from 8.05 +/- 3.60 to 1.14 +/- 0.29 cm2; p less than 0.05) and the wheal volume (from 0.068 +/- 0.010 to 0.045 +/- 0.008 cc; p = 0.02) induced by intradermal PAF (200 ng). Cutaneous responses to histamine (1 microgram) were significantly inhibited. Thus, the bronchoconstriction and bronchial hyperresponsiveness induced by PAF are not inhibited by ketotifen. Ketotifen inhibits PAF-induced wheal and flare in the skin, which is probably histamine dependent. The airway effects of PAF are unlikely to be mediated by histamine release.     

Allergy in asthma. I. The dose relationship of allergy to severity of childhood asthma

The relationship between allergy and childhood asthma was investigated. We hypothesized that if allergy were a factor in aggravating asthma, we should find that allergy (defined by symptoms and numbers of positive prick skin tests) increased with increasing severity of asthma. One hundred forty-two children with asthma, referred to a pulmonologist and an allergist, 123 of whom were skin tested, were graded according to clinical severity and compared to a group of 29 normal individuals, 48 patients with allergic rhinitis, and 52 patients with cystic fibrosis. The 29 symptom-free individuals had only one positive skin test among them, whereas 65% of the clinic patients with asthma had three or more positive skin tests (p less than 0.001). This compared with 35.4% of the patients with rhinitis (p less than 0.001) and 14% of the patients with cystic fibrosis (p less than 0.001). There was an increase in the number and size of positive skin tests with increasing severity of asthma. Similarly, there was increased reporting of allergic symptoms, such as sensitivity to animals with increasing severity of asthma. These data indicate that atopy is associated with asthma in a crude dose-response fashion, and children with chronic, steroid-dependent asthma are often highly atopic, easily sensitized, and form IgE antibodies to a broad range of allergens.