Safety and efficacy of terfenadine/pseudoephedrine versus clemastine/phenylpropanolamine in the treatment of seasonal allergic rhinitis.

A double-blind, randomized, placebo-controlled, parallel trial was conducted to compare the efficacy and safety of terfenadine, 60 mg (immediate-release)/pseudoephedrine hydrochloride, 120 mg (controlled-release) (T/Ps) and clemastine fumarate, 1.34 mg (immediate-release)/phenylpropanolamine, 75 mg (sustained-release) (C/Ph) in a combination tablet b.i.d. in 178 patients (12-59 years of age) with symptoms of seasonal allergic rhinitis. After seven days of treatment, the total symptom scores recorded in the diaries of 175 patients showed that both therapies had a highly significant overall treatment effect when compared with placebo (P < or = .02). The overall level of improvement, as well as improvement of individual symptoms, was similar with the two therapies. Total symptom scores assigned by physicians to 170 patients showed significant and similar levels of improvement with both therapies when compared with placebo (P < .01). The two therapies were also similar on physicians' evaluations of overall effectiveness. Both therapies relieved most histamine-mediated symptoms as well as nasal congestion, although only T/Ps showed improvement of the latter symptom in both the patients' diaries and physicians' evaluations. Among 178 patients, drowsiness and fatigue occurred more often in the C/Ph group (25% and 11.7% for the two adverse events, respectively) than in the T/Ps group (10.2% and 1.7%, respectively). The incidence of insomnia and dry mouth/nose/throat was higher with T/Ps (23.7% and 11.9%, respectively) than with C/Ph (6.7% and 3.3%, respectively). No serious or unexpected adverse events were reported. These results indicate that T/Ps and C/Ph are both superior to placebo and equally effective in the treatment of symptoms of seasonal allergic rhinitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of antibody-dependent allergic autocytotoxicity in rheumatoid arthritis by OM-89.

Rheumatoid arthritis (RA) is a disease of multiple etiologies and clinical evidence suggests that a separate variant called "allergic arthritis" induced by food antigens could exist. A missing link in the confirmation of such an observation is a relative lack of a reliable in vitro assay which can confirm the in vivo oral ingestion challenge. Therefore, white blood cells (WBC) from 33 rheumatoid arthritis patients were separated and their disintegration was measured in the presence of specific IgE RAST positive sera and gluten-gliadin antigens. This assay was called the antibody-dependent allergic autocytotoxicity (ACT) test which represents an equivalent of an oral ingestion challenge with food antigens. Control WBC expressed 10-45% disintegration as compared to 75-95% in RA. Preincubation of WBC with OM-89 (immunomodulating fractions of Escherichia coli, OM Laboratories Ltd, Geneva, Switzerland) inhibited significantly antibody-dependent ACT in a dose-related manner (P less than 0.001) in our patients.

A comparative tolerance study of terfenadine-pseudoephedrine combination tablets and pseudoephedrine tablets in patients with allergic or vasomotor rhinitis.

In this multicentre, double-blind, randomized, parallel group study, 315 patients with allergic or vasomotor rhinitis were treated on a twice daily dosing schedule with either a 60 mg terfenadine-120 mg pseudoephedrine hydrochloride combination or 120 mg pseudoephedrine hydrochloride (extended release) for 2 weeks. No clinically significant differences between the two groups were noted in body weight, temperature, respiration rate or blood pressure following the treatment period. An increase in mean heart rate of approximately 5 beats/min from entry to the final clinic visit was noted in both treatment groups. No clinically significant changes were noted in either treatment group when pre- and post-treatment electrocardiograms were compared. There were also no clinically significant alterations in laboratory values, which included serum chemistry, haematology and urinalysis, within or between either group. The adverse events profiles for both groups were similar. The most frequent adverse event was insomnia, in 40 (25.3%) patients given the terfenadine-pseudoephedrine combination and in 42 (26.8%) of those given pseudoephedrine. No unusual or unexpected adverse events were reported.

Autoreactive eosinophils associated with spontaneous autocytotoxicity in bronchial asthma.

Allergic autocytotoxicity (ACT) assay is extensively investigated as an in vitro equivalent of oral ingestion challenge with food antigens among patients with food hypersensitivity. In direct ACT, food antigenic determinants interact directly with plasma cell membranes of sensitive individuals. Antibody-dependent ACT is also known as antibody-dependent-cell-mediated-cytotoxicity (ADCC) phenomenon, when food antigens combine with specific antibody through cell membranes Fc receptors among normal and sensitive individuals. Spontaneous ACT is a separate mechanism of white blood cells disintegration which does not require in vitro priming of the cells, neither by antigen or antibody. Spontaneous ACT occurs in some individuals as "background noise" in addition to direct and antibody-dependent ACT. The exact cellular nature of ACT phenomena are unknown at the present time with the exception that the common identifying factor for each of them is the disintegration and death of human white blood cells. Electron microscopy studies among four bronchial asthma patients with spontaneous ACT demonstrated eosinophils with atypical crystalloid cores and diffuse autolytic pattern of granular membranes. These ultrastructural characteristics are associated with new functional profiles of eosinophils expressed morphologically as natural killer and/or suicidal potency. At least two subpopulations of eosinophils are mediating ACT. The first subpopulation has normal ultrastructure observed in direct ACT and the second subpopulations has altered morphology of eosinophils granules described in spontaneous ACT. The natural killer-suicidal eosinophils presented in patient with spontaneous ACT illustrate a new pathway of cytodestructive mechanism in anaphylactic injury.

Selective inhibition of antibody-dependent allergic autocytotoxicity by OM-89, in patients with bronchial asthma and urticaria having food allergy toward wheat.

Twenty-five patients with bronchial asthma and urticaria expressing hypersensitivity to ingested wheat were examined and compared with fourteen controls using the allergic autocytotoxicity assay (ACT). To establish a possible interaction between wheat antigen and antibody with OM-89 (immunostimulating fraction extracted from E. coli), peripheral WBC of the above individuals were tested in vitro. Preincubation with OM-89 and subsequent exposure toward wheat antigen in the direct ACT assay and antibody-dependent ACT assay using specific wheat antibody were performed. A separate study of spontaneous ACT was conducted in which unprimed white blood cells were pre-incubated with OM-89 alone. Our results show that OM-89 exerted its most potent inhibitory activity in the antibody-dependent ACT assay when the wheat antigen-antibody test system was used. Only borderline inhibition of the direct ACT response was observed, while OM-89 did not exert any effect on spontaneous ACT. This observation may be of importance in future clinical trials since patients sensitive to wheat with high antibody levels toward this common ingestant antigen may benefit from oral therapy with OM-89.

Spontaneous allergic autocytotoxicity in bronchial asthma associated with food allergy.

Spontaneous allergic autocytotoxicity of white blood cells was assessed in six patients with bronchial asthma and 18 normal control volunteers. The observed alterations in non-primed white blood cell membrane were revealed as an increased uptake of trypan blue exclusion dye, an indicator of cell death. The phenomenon of spontaneous allergic autocytotoxicity might be associated with increased permeability of the white blood cell membrane leading to enhanced releasability of chemical mediators of anaphylaxis, which probably bypasses immunoglobulin E mechanisms and T suppressor cell intervention. Of six patients with bronchial asthma, three were sensitive to wheat, two had cows milk sensitivity, and one had corn sensitivity. When white blood cells of these patients were studied in the direct allergic autocytotoxicity assay, augmentation of spontaneous allergic autocytotoxicity by specific food antigens was observed. Two of the patients were professional sports coaches. It is plausible to suggest that increased membrane permeability, presumably indicating increased releasability (i.e., for histamine), may be associated with a low membrane threshold for physical trauma expressed in exercise-induced anaphylaxis syndromes.

Broncho-Vaxom and spontaneous allergic autocytotoxicity (spACT) in bronchial asthma associated with food hypersensitivity.

Spontaneous allergic autocytotoxicity (spACT) of white blood cells (WBC) was assessed in six bronchial asthma patients and eighteen normal control individuals. The observed alterations of non-primed WBC membrane were revealed as an increased uptake of trypan blue exclusion dye, an indicator of death cells. The phenomenon of spACT might be associated with a lack of T suppressor cell intervention, increased refractoriness of WBC membrane leading to its increased permeability and enhanced releasability of chemical mediators of anaphylaxis, which probably bypasses IgE events. In six bronchial asthma patients, three were sensitive toward wheat, two had cow milk sensitivity, and one had corn sensitivity. When WBC of these patients were studied in the direct ACT assay, an additional augmentation of spACT effect by specific food antigens was observed. Surprisingly, Broncho-Vaxom (BX) did not inhibit or enhance spACT. However, BX has antagonistic activity toward direct ACT response in the dose-dependent concentration as previously reported. Our preliminary clinical experience leads us to believe that the spACT assay can serve as a useful clinical discriminator of potential responders versus non-responders to therapy with new agents, when WBC disintegration by autoinduction is involved.

A model test system for food allergy ingestion challenge study.

The aim of this paper is to propose a standardized mathematical model to be used as a reference for future studies. The mathematical model is presented for oral food ingestion challenge single-blind study, controlled with placebo. This model will meet the increasing demand for an easily used, valid and reproducible clinical rating scale that is sufficiently sensitive and discriminatory to accurately assess the effects of various treatment regimens on the food-allergic patient. The model assumes that at least a fraction of ingested food antigen circulates in the patient's blood stream, the resultant antigenemia thereby provides a stimulus-response signal in the susceptible host. The testing regimen will include subjective symptoms measurements and objective, diagnostic measurements. Accumulated data will be transformed to a unified factorial rating score system which will allow examination of relevant profiles and correlations within the subject and the patient groups. Care has been taken to keep the mathematics to a minimum to assure that any properly motivated investigator with cooperative patients can implement the model, with the aid of a hand calculator.

Cytodestructive mechanisms provoked by food antigens. I. Direct, allergic autocytotoxicity.

In vitro challenge of peripheral white blood cells (WBC) from 62 food sensitive patients and 22 asymptomatic control individuals was performed using standardized extract of cow milk, corn and wheat. 81% of the patients reacted at least toward one food antigen, showing disintegration of WBC, as measured by trypan blue exclusion technique. The presented experimental condition of the direct binding between food antigen and cell wall membrane suggests that this phenomenon is multicellular in its origin. The interpretation of these studies is of distinct value in directing human food hypersensitivity research in the future.

Cytodestructive mechanisms provoked by food antigens. II. Antibody-dependent, allergic autocytotoxicity.

Antibody-dependent, allergic autocytotoxicity (ACT) is an in vitro process through which WBC from patients and/or controls, passively sensitized with RAST positive serum, are damaged in the presence of corresponding food antigens. Studies among 13 patients, sensitive to cow milk, corn and wheat, and 13 asymptomatic controls revealed that antibody-dependent ACT is mediated by thermolabile cytotoxic factor, presumably IgE antibody. The resultant cellular interactions might contribute to the induction of the autoimmune response.

Immunomodulation of allergic autocytotoxicity in bronchial asthma by a bacterial lysate--Broncho-Vaxom.

The direct and antibody-dependent allergic autocytotoxicity (ACT) response, mediated by food antigens and its immunoregulation with bacterial lysate of the eight most common pathogens of the upper respiratory tract--Broncho-Vaxom (BX), was investigated in fifteen bronchial asthma patients and eight normal control individuals. Under the described experimental conditions, the BX inhibits ACT response in vitro. In analyzing the mechanism of this effect, the enhancement of T suppressor cells by BX was under consideration.

Cytodestructive mechanisms provoked by food antigens: III. Inhibition of direct and antibody-dependent allergic autocytotoxicity (ACT) by ketotifen.

In vitro challenge of peripheral white blood cells (WBC) from 15 food sensitive individuals and 16 asymptomatic controls was studied in allergic autocytotoxicity (ACT) assay using extracts of cow's milk, corn, and wheat. The observed disintegration of the WBC in the direct and antibody-dependent ACT was inhibited by ketotifen in a linear, dose-dependent manner. Therefore, our data demonstrate that the ACT response is associated with anaphylactic injury which is prevented by pretreatment with ketotifen, in vitro.

Inhibition of eosinophils degranulation by Ketotifen in a patient with milk allergy, manifested as bronchial asthma--an electron microscopic study.

Electron microscopic studies provided evidence that a patient with cow's milk allergy, manifested as bronchial asthma, has prominent eosinophil granule discharge, attributable to the release of cytotoxic major basic protein (MBP). This finding illustrates a critical role of eosinophil MBP in anaphylactic injury induced by food allergen. Patient white blood cells pretreated with Ketotifen revealed intact ultrastructure of eosinophils granules and cytoplasm. Inhibition of eosinophils degranulation by Ketotifen demonstrates a new pharmacologic mode of action of this anti-allergic, anti-anaphylactic agent.

Long term trial of ketotifen in bronchial asthma.

Ketotifen in a dose of 1 mg p.o. q 12 h was compared with placebo in a double-blind, twelve month parallel group trial in 17 randomly selected patients with bronchial asthma. Among 13 patients treated with ketotifen, nine have been classified as responders and four as non-responders. Responders were young and teenaged individuals, athletically oriented, with moderate asthma. It is our impression that ketotifen offers a new therapeutic dimension in the prophylaxis of bronchial asthma.

Factorial rating system for comparative efficacy of antiasthmatic medication: a multicentric study report.

Faced with 1-year daily medication diaries from over 300 patients, each documenting the use of from one to five medications a day, we found it was necessary to devise a system which would reduce this data into a form which would allow a meaningful interpretation of changes of medications in a single patient or group of patients. Since the medications were principally steroids, beta agonists, or xanthines, representative agents were chosen as the standard for each class and the other medications were rated against them. A conversion factor was then determined to allow comparison between classes. Each medication taken by a patient could now be expressed as a single number and the sum of all the medications would be the individual's Asthma Medication Index. The AMI allowed (i) evaluation of a single patient over time, (ii) comparison of different patients at any single point or over a period of time, and (iii) evaluation of entire groups of patients over time as was the case in our evaluation of Zaditen. Application of the system allowed the differentiation of two therapeutic agents versus placebo during a 1-year study, revealing excellent correlation with the physician's global assessment of the patient's improvement. With proper modification of the basic drug groups and intergroup factor relationship, the Index can be adapted to any disease state where a change in concomitant medication is an indicator of therapeutic effect.